Resveratrol mitigates NSAIDs-induced intestinal injury in rats exposed to high altitude hypoxia by reducing the expression levels of Ang- II

Resveratrol mitigates NSAIDs-induced intestinal injury in rats exposed to high altitude hypoxia by reducing the expression levels of Ang- II | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Resveratrol mitigates NSAIDs-induced intestinal injury in rats exposed to high altitude hypoxia by reducing the expression levels of Ang- II Paziliya Abulaiti, hui Shi Wen, Huan Liu, Ailifeire Tuerxuntayi, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4607078/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective The study aimed to investigate the protective effects of resveratrol against NSAIDs drug-related intestinal injury in rats by regulating the expression of Ang II, as well as mitigating oxidative stress and inflammatory reactions in the intestinal mucosa. Method 60 male Sprague-Dawley rats were randomly assigned to five groups. The control group received a daily gavage of saline (1 ml/100 g/d) in a standard plain-air environment. The rest were housed in a hypoxic chamber, and gavage aspirin at a dosage of 200 mg/kg daily was used to induce NSAID-related intestinal injury in rats. The resveratrol intervention group received resveratrol at varying doses (25, 50, and 100 mg/kg) 2 hours post-aspirin gavage for 3 weeks. Behaving activities, macroscopic appearance, and histological injury of the small intestinal mucosa were assessed and scored in each group. Oxidative stress indicators MPO and SOD, along with inflammatory factors IL-1β, IL-10, and TNF-α, were quantified using ELISA. Immunohistochemistry was employed to detect the expressions of Ang II and ICAM-1 in small intestinal tissues, and their correlation with the degree of intestinal pathology was analysed. Result The small intestine mucosa of rats in the PC group did not show significant macroscopic or pathological injury, whereas other groups exhibited varying degrees of damage. The overall morphology and pathological damage scores were significantly higher than those in the PC group rats ( P < 0.05). In comparison with the HN group, intervention with resveratrol led to a reduction in the overall morphology and histopathological injury score of rats ( P < 0.05). (1)ELISA test results indicated that, in contrast to the PC group, levels of MPO, SOD, IL-1β, and TNF-α were increased in the HC group rats, while IL-10 levels were notably reduced (P < 0.01). Similarly, compared to the HC group, levels of IL-1β and TNF-α in the HN group rats were elevated, with decreased IL-10 levels ( P < 0.05). The resveratrol intervention group rats exhibited significantly lower levels of IL-1 β and TNF-α than the HN group rats (P < 0.01), alongside higher levels of IL-10 ( P < 0.05). Notably, the most difference was observed in the medium-dose resveratrol group. (2)Immunohistochemical results revealed a significant increase in Ang II levels in both the HC group and HN group rats ( P < 0.05), with ICAM-1 levels significantly elevated in the HN group rats ( P < 0.05). (3)The expression of Ang II and ICAM-1 correlates positively with the histological injury to the small intestine mucosa. Following intervention with resveratrol, the expression of Ang II and ICAM-1 was notably lower than that in the HN group rats ( P < 0.05). Conclusion Resveratrol can effectively mitigate intestinal injury induced by NSAIDs in a high-altitude environment. The mechanism may involve downregulating the expression of Ang Ⅱ and ICAM-1, alleviating oxidative stress and the inflammatory response of the intestinal mucosa, and preserving intestinal barrier function. Biological sciences/Drug discovery Health sciences/Gastroenterology NSAIDs High altitude hypoxic environment Resveratrol Angiotensin II Intercellular adhesion molecule-1 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 STRENGTHS AND LIMITATIONS OF THIS STUDY The characterization of the modified intestinal injury resulting from the extended oral intake of non-steroidal anti-inflammatory drugs in highland environments has not yet been definitively documented. Resveratrolshows promise as a natural remedy for preventing NSAIDs drug-related intestinal injury. This study is that it only relies on animal models and lacks the validation of in vitro cellular experiments. Our study only relies on animal models and lacks the validation of in vitro cellular experiments. Therefore, the results of animal experiments may not be directly applicable to humans, and the feasibility of clinical application has not been verified. This experiment was conducted in a controlled, special laboratory environment. However, people living at high altitudes are affected by many factors in their living environment, which may lead to a deviation of the experimental results from the actual situation. Therefore, the results may need to be further verified by long-term, repeated experiments. Introduction The main characteristics of the high-altitude environmentt include low air pressure, hypoxia, low temperature, strong ultraviolet rays, and climatic variability, which exert different degrees of adverse effects on the human body [1, 2] . As the altitude increases, the partial pressure of arterial blood oxygen decreases, leading to progressive hypoxia in human tissues. Inflammatory factors and oxygen-free radicals are produced when the oxygen supply to human tissues and cells becomes insufficient, and these factors can induce damage to cells and lead to dysfunction or apoptosis [2, 3] . Due to these special conditions at high altitude, individuals entering high-altitude areas are prone to plateau adverse reactions, with gastrointestinal reactions being more significant, including nausea, vomiting, diarrhea, peptic ulcers, gastrointestinal hemorrhage, and even perforation and other injuries [4] . Wu et al. demonstrated that the incidence of gastrointestinal hemorrhage in workers who had operated for an extended period at high altitude was 0.49%, and that incidence increased with altitude [5] . It has been demonstrated that the hypoxic environment at high altitudes activates the inflammatory pathway and the oxidative stress process in the human body and promotes the production of inflammatory factors, thereby triggering a cascade of inflammatory responses leading to intestinal damage [6, 7] . These oxidative stress products increase intestinal permeability, allowing harmful microorganisms and antigens from the luminal environment to enter the circulation and increasing the risk of systemic reaction syndrome [8] . Nonsteroidal anti-inflammatory drugs (NSAIDs) cause gastroduodenal adverse effects [9] . Recently, attention has been drawn to NSAID-induced small bowel injuries. Current evidence suggests that NSAIDs increase the risk of bleeding and perforation in the lower gastrointestinal (GI) tract to a comparable degree as in the upper GI tract [10] . Aspirin is a non-steroidal anti-inflammatory drug with favorable anti-inflammatory, antipyretic, and analgesic effects and is widely used in clinical practice [11] . Studies have shown that the incidence of small intestinal mucosal erosions, ulcers, and mucosal bleeding can be as high as 70% in patients undergoing video capsule endoscopy following long-term oral administration of nonsteroidal anti-inflammatory drugs, such as aspirin [12, 13] . However, the characteristics of altered intestinal damage caused by prolonged oral administration of nonsteroidal anti-inflammatory drugs in high-altitude environments are rarely reported. In this study, we simulated and observed NSAID-induced intestinal injury in a high-altitude environment by administering aspirin through gavage to rats in a specialized hypoxic chamber. Our objective was to investigate the potential exacerbating impact of the high-altitude hypoxic environment on NSAID-related intestinal injury. Angiotensin II, a peptide hormone, is produced by the kidney. Numerous studies have demonstrated its crucial role in regulating blood pressure, hydrosalinity balance, and kidney function [14] . It participates in the regulation of gastrointestinal physiological functions through various means and significantly affects gastrointestinal blood flow, motility, secretion, and other aspects [15] . Recent research has shown that angiotensin II may also contribute to the inflammatory response, particularly in intestinal inflammation [16–18] . It can modulate the process of apoptosis in intestinal epithelial cells [19] . Research has indicated that the angiotensin 2 receptor (AT2 receptor) is widely distributed in the intestine, and its activity may correlate with the onset and progression of intestinal inflammation [20] . It has been observed that the renin-angiotensin system (RAS) is activated in the body during hypoxia, leading to the increase of circulating renin activity, Ang II, and ACE activity, resulting in hypoxic diseases in local tissues and organs [21] .However, further research is necessary to verify the precise relationship between hypoxia, angiotensin II expression levels, and intestinal inflammation. Our study focuses on the alteration of Ang II expression levels in intestinal tissues in high-altitude hypoxic environments and NSAID drugs through animal models to further clarify the mechanism of intestinal injury generation induced by plateau badlands and NSAID drugs.Our study focuses on the alteration of Ang II expression levels in intestinal tissues in high-altitude hypoxic environments and NSAID drugs, using animal models to elucidate the mechanism of intestinal injury caused by high altitudes and NSAIDs. Resveratrol, a plant polyphenol isolated from grape seeds and peel [22] , possesses antioxidant, anti-inflammatory, anti-apoptotic, and other pharmacological effects [23] . It shows promise as a natural drug for preventing and treating intestinal diseases. Studies have demonstrated that resveratrol can protect against intestinal injury by reducing oxidative stress, inhibiting the inflammatory response, and regulating apoptosis, among other pathways [24, 25] . This study administered resveratrol at various doses to assess its protective effect on intestinal injury and to investigate whether resveratrol can mitigate non-steroidal anti-inflammatory drug-induced intestinal injury in rats by regulating the expression level of Ang Ⅱ in a high-altitude hypoxic environment. This research aims to provide insights into the prevention and treatment of intestinal injury in patients on long-term oral NSAIDs in clinical high-altitude environments Methods and Materials 1.1Chemicals and reagents The aspirin was acquired from Shanghai Yuanye Biotechnology Co. The resveratrol standard, sourced from Sigma Aldrich (Shanghai) Trading Co. Ltd., was prepared as a suspension using distilled water for the experiments. The pentobarbital sodium was procured from Shanghai Sinopharm Chemical Reagent Co. The Ang-II polyclonal antibody and monoclonal antibody targeting intercellular adhesion molecule-1 (ICAM-1) were obtained from Shanghai Snowdance Biotechnology Co. Ltd. The measurement kits for myeloperoxidase (MPO) and superoxide dismutase (SOD), interleukin (IL)-10, interleukin (IL)-1β, and tumor necrosis factor-α (TNF-α) were procured from Shanghai Wei Ao Biotechnology Co. 1.2 Animal grouping and drug administration All experiments were approved by the Institutional Animal Protection and Use Committee of Xinjiang medical University (ethics no. KY20230209135), and the methods were conducted in accordance with the guidelines for the Animal Experiments of Xinjiang medical University and ARRIVE guidelines.Sixty male SD rats, aged 6 weeks, weighing 250 ± 50 g, were obtained from the Animal Experiment Centre of Xinjiang Medical University. Rats for this experimental modeling and drug intervention will be accommodated in a specialized hypoxia chamber in the northwest region (SPF-grade clean laboratory) of Urumqi General Hospital of Lanzhou Military Region.With the parameters adjusted to an altitude of 5500 m, the atmospheric pressure to 93.2 KPa (699.1 mmHg), and the partial pressure of oxygen to 19.54 KPa (146.6 mmHg). Every 5 rats were housed in standard rat experimental cages (485*350*200mm),and provided with standard mouse feed ad libitum throughout the experiment, maintained at a controlled temperature of 22 ± 2°C, with a relative humidity of 40–60%, and subjected to an alternating daily and diurnal cycle of 12 hours. All the rat were subjected to acclimation for 1 week and assigned randomly to six groups with different treatments: plain blank control group (PC group, n = 10), high-altitude blank group (HC group), high-altitude NSAIDs injury group (HN group), resveratrol intervention low dose (RES-L group), medium dose (RES-M group), and high dose (RES-H group), with 10 rats in each group. The daily oral dose of each drug was converted from the human oral dose by reference. The plain blank control group was exposed to the conventional atmospheric environment, while the other groups were placed in the hypoxia chamber in a special environment. The control group received daily gavage with saline (1 ml/100 g), while the remaining rats were administered aspirin at a dosage of 200 mg/kg daily. The resveratrol intervention group received resveratrol at doses of 25 mg/kg, 50 mg/kg, and 100 mg/kg in the low, medium, and high dose groups, respectively, for 2 hours following the 200 mg/kg aspirin administration,continuously for 3 weeks. All drugs were ground into powder and dissolved in a 5% carboxymethyl Na solution at a ratio of 1:1 to prepare a suspension, The liquid volume for each gavage was given at 10 ml/kg。In order to minimize potential confounders, treatments, measurements, and animal/cage locations were randomized. During the experiment, all experimenters excepting the designer were blinded to group assignment. 1.3 Physical Evaluation of rats Record and observe specific general symptoms of rats in each group, including their mental state, eating habits, activity levels, defecation patterns, and other relevant indicators. 1.4Tissue sample collection Following the last administration, the rats underwent a 24-hour fasting period and were anesthetized with a 3% sodium pentobarbital solution at a dosage of 40 mg/kg via intraperitoneal injection. With adherence to strict aseptic procedures, the abdominal cavity was promptly opened to observe its contents. Subsequently, the intestinal segments were carefully dissected to assess damage, with the most severely affected 3cm segment of the small intestine excised and placed in a 10% formaldehyde solution for 24 hours for fixation. Following fixation, the tissue slices were embedded in paraffin wax for subsequent microscopic scoring and immunohistochemical staining. Additionally, intestinal tissue located 5 cm from the proximal jejunum was isolated, and the homogenization medium from the test box was added and ground on ice to produce a 5% tissue homogenate.The activities of TNF-α, IL-1β, IL-10, MPO, and SOD in rat jejunal tissues were detected by the Enzyme-Linked Immunosorbent Assay (ELISA) method, following the instructions provided by the kit in strict accordance with the prescribed steps. 1.5 Histological Analysis The severity of intestinal mucosal tissue damage was observed, and the degree of intestinal injury was macroscopically scored according to the Reuten score [26] . The cut intestinal tissue was fixed in a 10% formaldehyde solution and then embedded in paraffin for routine sectioning. Three pathologists observed the histopathological changes of the small intestine under a light microscope using a blind method and then scored the intestinal injury histology according to Chiu's scoring method [27] . 1.6 Immunohistochemical Analysis small intestinal tissues were fixed in 10% formalin buffer, embedded in paraffin, and cut into 4 µm-thick sections. They were then deparaffinized in xylene and rehydrated with gradient ethanol. Thermal antigen repair was performed twice in high fire using EDTA antigen repair solution (50X). Sections were incubated in 5% BSA for 35 minutes and washed well in PBS. Then, the sections were incubated with angiotensinogen antibody (1:200 dilution) and Icam-1 antibody overnight at 4°C, followed by incubation with goat anti-rabbit secondary antibody HRP Polymer Quanto at 37°C for 35 min. They were then visualized by DAB horseradish peroxidase color solution (brownish-yellow staining), and the nuclei of the cells were restained with hematoxylin. Finally, the sections were dehydrated, sealed, scanned with a digital scanner, and analyzed with Visiopharm AI pathology analysis software. 2.Statistical Analysis Statistical analysis was performed using the GraphPad Prism 9 software (GraphPad, San Diego, CA, USA). The results were presented as the mean ± standard deviation (SD). One-way ANOVA and the least significant difference (LSD-t) method were used to assess statistical significance between multiple groups. Pearson correlation analysis was employed to determine the correlation between Ang-II and ICAM-1 and the degree of pathological damage to the intestinal mucosa of rats, respectively. p < 0.05 was considered statistically significant (two-tailed). Result 3.1Physical stiuation of Rats During the experimental period, no rats died. The rats in the PC group demonstrated a sensitive response, had shiny fur, displayed a healthy appetite, passed well-formed stools. The rats in the HC group showed a slightly reduced response, a minor decrease in appetite, well-formed stools. The rats in the HN group demonstrated decreased appetite, loss of hair luster, delayed response, dull quietness, irregular stools, and reduced urine volume. The rats in the resveratrol intervention groups displayed average reactions, exercise, and appetite, with no significant abnormalities observed in their bowel movements. 3.2 macroscopic appearance No macroscopic damage, adhesion, or ulcers were observed in the rats in the PC group. Mild adhesion and edema of the intestinal mucosa were observed in the rats in the HC group without any ulcers or bleeding points; the tissue injury score was 1.15 ± 0.34 points. The HN group of rats showed severe intestinal mucosal adhesion with varying degrees of congestion and edema, and some exhibited necrosis of the intestinal wall, which appeared purple-black in color. No intestinal perforation or ulcer was observed, and the tissue injury score was 2.00 ± 0.62 points, significantly higher than that of the HC group rats( P < 0.001). Local congestion, edema, and adhesion of the small intestine were observed in the resveratrol intervention group rats. However, the degree of the lesion was lower than that in the HN group rats. The medium-dose resveratrol group rats had the lowest tissue scores of 1.20 ± 0.42, which was significantly lower than that in the HN group rats ( P < 0.01), show Fig. 1 . 3.3 Histopathological observations The results of HE staining revealed that the structure of small intestinal villi in the PC group rats was intact, with clear and undamaged layers, normal tissue morphology, and a pathological score of 0.20 ± 0.42. In the HC group rats, small intestinal villi exhibited edema accompanied by capillary congestion and lymphocyte infiltration while maintaining evident structural integrity in each layer, with a pathological score of 1.20 ± 0.79, significantly differing from that of the PC group rats (P < 0.05). Within the HN group rats, the lamina propria of the small intestine exhibited varying degrees of obvious edema, denatured and necrotic epithelial cells in the intestinal mucosa, occasional villi tip detachment, and significant infiltration of inflammatory cells, resulting in a pathological score of 2.9 ± 0.99, markedly higher than that of the HC group rats ( P < 0.001). The degree of pathological damage to the small intestinal mucosa was lower in the resveratrol intervention group (low, medium, or high) compared to the HN group rats. However, some rats exhibited villous edema, apical epithelial detachment with capillary congestion, and infiltration of inflammatory cells. The medium-dose resveratrol group rats had the lowest pathological score of 1.30 ± 0.48, demonstrating statistical significance in comparison to the HN group rats. ( P < 0.01)show Fig. 2. 3.4 Inflammatory factors ELISA results indicated a significant increase in the levels of IL-1 β and TNF-α in the small intestine tissue of the HC group rats compared to the PC group, while the level of IL-10 was notably decreased ( p < 0.01). Correspondingly, the levels of IL-1 β and TNF-α in the small intestine of rats in the HN group were significantly increased, while the level of IL-10 was significantly decreased, with a statistically significant difference compared to the HC group rats ( p < 0.01). Furthermore, in comparison to the HN group rats, the levels of IL-1 β and TNF-α in the small intestine tissue of rats in the resveratrol (low, medium, and high) intervention group were significantly reduced, and the IL-10 level was notably increased, with the most substantial difference observed in the resveratrol medium dose group rats ( P < 0.01). 3.5 Oxidative stress indicators In comparison to the PC group, the expression levels of both MOP and SOD in the intestinal mucosa of rats in the HC group showed a significant increase ( P < 0.05). Likewise, the expression levels of MOP and SOD in the intestinal mucosa of rats in the HN group exhibited a significant increase compared to the HC group ( P < 0.05). In contrast to the HN group, the expression levels of SOD and MOP protein in the small intestine tissue of rats in the resveratrol intervention groups (low, medium, and high doses) experienced a significant decrease, particularly notable in the medium resveratrol groups ( P < 0.01),show Fig. 3 . 3.6 Immunohistochemistry detect the expression of Ang-Ⅱand ICAM-1 Ang-Ⅱ positive protein was primarily localized to the cell plasma or cell membrane of the intestinal mucosa, exhibiting a brownish-yellow color, while ICAM-1-positive protein particles were predominantly expressed in the cell membrane or cell plasma of the epithelium of the intestinal mucosa and in the inflammatory cells of the mucous membrane lamina propria, displaying a yellowish-brown color. Immunohistochemistry analysis revealed that the expression level of Ang II protein in the intestinal mucosa of rats in the HC group was significantly higher ( P < 0.05) compared to the PC group, while there was no significant difference observed in the expression of ICAM-1 protein. In comparison to the HC group, the expression levels of AngⅡ and ICAM-1 protein in the intestinal mucosa of rats in the HN group were markedly elevated ( P < 0.05). Furthermore, in comparison to the HN group rats, the expression levels of AngⅡ and ICAM-1 protein in the intestinal mucosal tissues of rats in the resveratrol intervention groups (low, medium, and high) were notably reduced, with the most pronounced decrease observed in the middle-dose resveratrol grouprats ( P < 0.05)show Fig. 4.5. 3.7 Correlation Analysis The expressions of Ang-II and ICAM-1 were both positively correlated with the degree of histological damage to the small intestinal mucosa of rats, respectively (r = 0.795, 0.832, both P < 0.01),show Fig. 6 . Disscusion The high-altitude environment, characterized by low pressure, low oxygen, and cold, can lead to oxidative stress and inflammatory reactions due to ischemia and hypoxia in various organs, adversely affecting the normal organism, particularly leading to gastrointestinal adverse reactions [28–30] . The small intestine’s susceptibility to hypoxia arises from its complex blood supply and rapid mucosal surface cell turnover, leading to a heightened oxygen demand [31] 。 Persistent hypoxia readily induces pathological changes in the structure and function of intestinal tissues. In this study, rats in the HC group exhibited decreased appetite, slower weight gain, mild adhesion of the intestinal mucosa with edema in the intestinal tissues, and pathologically evident small intestinal villi edema, along with capillary congestion, lymphocyte infiltration, and other manifestations of damage, when compared to the PC group.The ELISA results indicated elevated levels of inflammatory factors including IL-1β and TNF-α, along with indicators of oxidative stress such as MPO and SOD, and a decrease in the protective inflammatory factor IL-10 within the intestinal tissues. These findings suggest that the high-altitude environment induces oxidative stress and an inflammatory response in the intestine, impacting the normal function and tissue structure of the gastrointestinal tract.This result is in line with the findings of previous relevant studies. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly utilized in clinical settings due to their anti-inflammatory, antipyretic, and analgesic properties, as well as their ability to inhibit platelet aggregation. Multiple studies have demonstrated that prolonged use of NSAIDs can compromise the integrity of the intestinal mucosal barrier and lead to the onset of NSAID-related intestinal disorders. [32–34] NSAIDs are recognized for their propensity to induce adverse effects in the upper gastrointestinal tract. Recent studies have highlighted the growing concern regarding NSAID-induced adverse reactions in the lower gastrointestinal tract, particularly the small bowel, following the introduction of capsule endoscopy and small colonoscopy, alongside the rising utilization of NSAIDs, including aspirin. [35] A study reported that Non-steroidal anti-inflammatory drugs cause small-bowel inflammation in about 60% of patients receiving these drugs long-term [36] . Severe small-bowel injury represents a prevalent complication associated with NSAID usage, contributing to one-third of all complication cases [37] .In this study, the rats in the HN group received 200 mg/kg aspirin by gavage daily for 3 weeks. During this period, they exhibited symptoms including anorexia, a sluggish reaction, and decreased stool volume. Both the macroscopic score and the pathological tissue damage score of intestinal tissue, as well as mucosal inflammatory factors and oxidative stress indexes, were notably higher in the HN group compared to the PC group rats. These findings suggest that NSAID drugs may can lead to small intestinal injuries. Studies have shown that short-term oral administration of low-dose aspirin may induce inflammation of the small intestinal mucosa, whereas prolonged use of aspirin can result in a range of small intestinal lesions, including multiple petechiae, villus shedding, and mucosal erosion, and may even lead to serious adverse effects such as ulcers and perforation [12, 38–40] . In the prevention and treatment of cardiovascular diseases, inflammatory conditions, a certain cancers, patients require long-term oral administration of aspirin. However, this therapeutic regimen may gradually result in low-dose drug-dependent intestinal injury in patients, subsequently impacting their intestinal health [40, 41] [40, 41] . The hypoxic environment at high altitudes has emerged as a significant risk factor for gastrointestinal injury in patients undergoing prolonged aspirin therapy.In our study, we simulated NSAID-induced intestinal injury at high altitude by administering aspirin at a loading dose of 200 mg/kg to rats. The results indicated that intestinal tissue damage in the HN group rats was characterized by significant adhesion of the intestinal mucosa with varying degrees of congestion and edema, and sections of the intestinal wall appeared necrotic and purplish-black. The small intestinal mucosa of the rats exhibited varying degrees of villous edema, necrotic detachment of the apical epithelium, disorganization of the glandular arrangement in the lamina propria, and a significant amount of inflammatory cell infiltration under electron microscopy, which differed significantly from that in the HC group rats. The dual stress conditions, such as the high altitude environment and NSAID drugs, were observed to cause increased intestinal mucosal injury in rats, with the high-altitude hypoxic environment potentially exacerbating NSAID drug-induced intestinal injury. Angiotensin II (Ang II), a peptide hormone primarily synthesized by the kidneys, serves not only to regulate blood pressure, water-salt balance, and renal function, but also acts as a pro-inflammatory mediator [42] . Angiotensin II (Ang II) receptors are distributed across various organs including the kidneys, brain, heart, lung tissue, intestine, blood vessels, and immune cells [43] . Within the intestine, the colon exhibits the highest density of these receptors, followed by the ileum, duodenum, and jejunum [44] . Angiotensin II (Ang-II) mediates the effects of the angiotensin system in the intestine by activating angiotensin receptors, notably AT1 receptors. This activation can result in heightened intestinal vascular permeability and modifications in tight junctions of the vascular endothelium, thereby fostering the development of exudate and edema in intestinal inflammation [45] .It can regulate the activation state of immune cells, promote inflammatory cell infiltration, boost leukocyte rolling and adhesion [46–48] , and can also bind with receptors to activate signal transduction pathways. It can stimulate the activation of a variety of signal pathways through NF-κ B, which is also the hub of the intestinal inflammatory response, and produce adhesion molecules and chemokines such as IL-1 β, IL-6, IL-10, TNF-α, ICAM-1, etc., resulting in further development of the inflammatory response and damage to the corresponding tissue structure [49, 50] . ICAM-1 (intercellular adhesion molecule-1) is a cell surface glycoprotein and adhesion receptor that participates in the regulation of inflammatory responses and tissue damage by mediating leukocyte adhesion and migration [51, 52] . The expression of ICAM-1 can be induced by a variety of stimulatory factors, such as cytokines, inflammatory mediators, etc., to enhance the adhesion of immune cells and vascular endothelial cells and subsequently secrete a large quantity of pro-inflammatory cytokines, exacerbating inflammatory injury [53, 54] .Studies have shown that Ang II can increase the expression of ICAM-1 to promote the occurrence and development of an inflammatory response [55] . In this study, the small intestinal mucosa of rats in the HN group was damaged to varying degrees. The levels of IL-1β, TNF-α, MPO, and SOD in intestinal tissue were significantly higher than those in other groups. The level of IL-10, a protective inflammatory factor, was significantly reduced. The expression of Ang II and ICAM-1 proteins was up-regulated. The expression of Ang II and ICAM-1 was positively correlated with the degree of histological damage to the small intestinal mucosa. It can be seen that Ang II may mediate the intestinal inflammatory response, and the inflammatory factors and oxidative stress products may stimulate the production of ICAM-1. When ICAM-1 binds to its receptor, it mediates the adhesion and aggregation of more inflammatory cells to release inflammatory mediators, further producing an inflammatory cascade reaction and aggravating intestinal injury. It has been shown that Ang-II promotes apoptosis of intestinal epithelial cells in an AT2 receptor-dependent manner through the GATA-6 and Bax pathways, thereby increasing mucosal barrier permeability and generating intestinal inflammatory injury [56] . Touyz et al. demonstrated that Ang-II primarily activates multiple pathways via reactive oxygen species (ROS) produced by NAD(P)H oxidase to drive smooth muscle cell growth, proliferation, hypertrophy, and pro-inflammatory effects [57] . Additionally, Zhang et al. showed that Ang II plays a crucial role in NSAID-associated small bowel injury in rats and indicated that the RAS-p38MARPK signaling pathway is implicated in the pathogenesis of such injuries, suggesting that Ang II may act pro-inflammatory through this signaling pathway and contribute to intestinal inflammatory damage [58] .Several studies have suggested that hypoxic conditions induce inflammation, oxidative stress, and vascular dysfunction, leading to increased expression levels of Ang II [59, 60] . In this study, HC group rats intestinal tissues exhibited elevated levels of pro-inflammatory factors, including IL-1β and TNF-α, oxidative stress indicators like MPO and SOD, decreased levels of the anti-inflammatory factor serum IL-10, and increased expression of both Ang-II and ICAM-1 compared to the PC group. This highlights a significant association between organismic hypoxia, increased expression levels of Ang II, and intestinal inflammation, which aligns with previous findings. In summary, Ang II likely contributes to intestinal inflammatory injury by initiating inflammatory cascade responses via various signaling pathways. Additionally, the regulation of Ang II expression may be associated with the mechanism of NSAID-induced small intestinal injury in rats exposed to plateau environments. Studies have shown that, to date, there is no effective and safe strategy to prevent or treat lower gastrointestinal injuries associated with NSAIDs [61] . Resveratrol is widely found in natural plants such as Polygonum cuspidatum, grapes, and pines [62, 63] . Resveratrol can regulate intestinal mucosal barrier damage and dysfunction, providing a protective effect against intestinal injury through various pathways, such as anti-inflammatory and antioxidant mechanisms [64] . It shows promise as a natural remedy for preventing intestinal injury. It can enhance cytochrome oxidase activity in the intestinal mucosal epithelium, thereby reducing oxygen-free radical production [65] 。In this study, the levels of MPO and SOD in the intestinal tissue of rats in the resveratrol intervention group were reduced compared to the HN group, with the most significant difference observed in the middle dose of the resveratrol intervention group. Based on the aforementioned results, it can be concluded that resveratrol can alleviate intestinal mucosal damage by exerting antioxidant effects. The anti-inflammatory effect of resveratrol is achieved by regulating the initiation and termination of the inflammatory response. Studies have shown that the anti-inflammatory effect of resveratrol on the intestine is primarily accomplished by inhibiting NF-κB activity and downregulating proinflammatory factors and inflammatory mediators [66] . In this study, compared with the HN group, the levels of pro-inflammatory factors such as IL-1β and TNF-α in the intestinal tissue of rats in the resveratrol intervention group were significantly decreased, while the anti-inflammatory factor IL-10 was increased. A significant difference was observed in the middle dose of the resveratrol intervention group, suggesting that resveratrol can mitigate the intestinal injury induced by NSAIDs in the high-altitude hypoxia environment by decreasing the intestinal mucosal inflammatory response and modulating the pro-inflammatory and anti-inflammatory. There are Studies have shown that resveratrol can inhibit the apoptosis of intestinal epithelial cells to protect the integrity of the intestinal barrier, thus reducing intestinal injury [67, 68] . In our study, compared with the HN group, the resveratrol intervention group reduced the histopathology and tissue damage of the small intestinal mucosa. Moreover, the microscopic score of the resveratrol medium dose intervention group was lower than that of the HN group. This significant difference suggests that resveratrol can protect intestinal function by reducing intestinal cell death and apoptosis, as well as regulating intestinal permeability. Additionally, our study found that, compared with the HN group, the expression of Ang-Ⅱ and ICAM-1 proteins in the intestinal mucosa of rats in the resveratrol intervention group was significantly reduced. This suggests that resveratrol may alleviate intestinal inflammation and injury by down-regulating the expression of Ang-Ⅱ and ICAM in intestinal tissue. conclusion The dual stress conditions of a high-altitude environment and NSAID drugs can lead to the exacerbation of intestinal mucosal injury in rats. The expression level of Ang Ⅱ may be associated with the mechanism of NSAID-induced small intestinal injury in rats at high altitude. Our study found that resveratrol can effectively mitigate intestinal injury induced by NSAIDs in a high-altitude environment. The mechanism may involve downregulating the expression of Ang Ⅱ and ICAM-1, alleviating oxidative stress and the inflammatory response of the intestinal mucosa, and preserving intestinal barrier function. Declarations Data availability statement Data is provided within the manuscript or supplementary information files A funding statement This work was supported by [Host-gut microbial interaction regulates intestinal metabolism and influences intestinal mucosal barrier function in cealiac disease in the Xinjiang region: a study on the mechanism of action] grant number [82260116] Ethics approval All experiments were approved by the Institutional Animal Protection and Use Committee of Xinjiang medical University (Ethics no. KY20230209135), and the methods were conducted in accordance with the guidelines for the Animal Experiments of Xinjiang medical University. Acknowledgments The authors acknowledge the contribution of the team of individuals in the data collection process. Conflict of Interest All authors declare no conflict of interest. Author Contributions: Paziliya Abulaiti: Investigation; Conceptualization; Methodology; Validation; Formal analysis ; Writing - original draft. Wen hui Shi Investigation; Conceptualization; Methodology; Validation; Formal analysis ; Writing - original draft;Huan Liu : Conceptualization; Investigation; Writing - review & editing; Formal analysis. Ailifeire Tuerxuntayi: Methodology; Validation; Formal analysis. Sheng long Xue: Software; Methodology; Formal analysis; Validation. Kailibinuer Nuermaimaiti: Conceptualization; Investigation. Zhuo shuyi Liu: Investigation; Validation; Yingying Xing:Investigation; Validation; Najimangu Remutula:Investigation; Conceptualization;Kudelaiti Abdukelimu:Investigation; Validation; Weidong Liu: Validation; Formal analysis. 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Angiotensin II in inflammation, immunity and rheumatoid arthritis[J]. Clin Exp Immunol, 2015,179(2):137-145. Geara A S, Azzi J, Jurewicz M, et al. The renin-angiotensin system: an old, newly discovered player in immunoregulation[J]. Transplant Rev (Orlando), 2009,23(3):151-158. Krejcy K, Eichler H G, Jilma B, et al. Influence of angiotensin II on circulating adhesion molecules and blood leukocyte count in vivo[J]. Can J Physiol Pharmacol, 1996,74(1):9-14. Lakshmanan A P, Thandavarayan R A, Watanabe K, et al. Modulation of AT-1R/MAPK cascade by an olmesartan treatment attenuates diabetic nephropathy in streptozotocin-induced diabetic mice[J]. Mol Cell Endocrinol, 2012,348(1):104-111. Wang Y, Hong C, Wu Z, et al. Resveratrol in Intestinal Health and Disease: Focusing on Intestinal Barrier[J]. Front Nutr, 2022,9:848400. Bui T M, Wiesolek H L, Sumagin R. ICAM-1: A master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis[J]. 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Touyz R M, Yao G, Viel E, et al. Angiotensin II and endothelin-1 regulate MAP kinases through different redox-dependent mechanisms in human vascular smooth muscle cells[J]. J Hypertens, 2004,22(6):1141-1149. ZHANG Yanhong, MENG Lina, CHEN Shanshan. Mechanism of RAS-p38MAPK signaling pathway-mediated non-steroidal anti-inflammatory drug-associated small bowel injury in rats, Nanchang, 2013[C].. Kou Y, Zhang P, Wang H, et al. [Changes of angiotensin II and oxidation stress during the development of chronic intermittent-induced pulmonary injury in rats][J]. Zhonghua Jie He He Hu Xi Za Zhi, 2015,38(8):612-616. Liu S S, Wang H Y, Tang J M, et al. Hypoxia-induced collagen synthesis of human lung fibroblasts by activating the angiotensin system[J]. Int J Mol Sci, 2013,14(12):24029-24045. Guo C G, Leung W K. Potential Strategies in the Prevention of Nonsteroidal Anti-inflammatory Drugs-Associated Adverse Effects in the Lower Gastrointestinal Tract[J]. Gut Liver, 2020,14(2):179-189. Kalantari H, Das D K. Physiological effects of resveratrol[J]. Biofactors, 2010,36(5):401-406. Salehi B, Mishra A P, Nigam M, et al. Resveratrol: A Double-Edged Sword in Health Benefits[J]. Biomedicines, 2018,6(3). Zhang L X, Li C X, Kakar M U, et al. Resveratrol (RV): A pharmacological review and call for further research[J]. Biomed Pharmacother, 2021,143:112164. Ozkan O V, Yuzbasioglu M F, Ciralik H, et al. Resveratrol, a natural antioxidant, attenuates intestinal ischemia/reperfusion injury in rats[J]. Tohoku J Exp Med, 2009,218(3):251-258. Manna S K, Mukhopadhyay A, Aggarwal B B. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation[J]. J Immunol, 2000,164(12):6509-6519. Dong W, Li F, Pan Z, et al. Resveratrol ameliorates subacute intestinal ischemia-reperfusion injury[J]. J Surg Res, 2013,185(1):182-189. Garcia P, Schmiedlin-Ren P, Mathias J S, et al. Resveratrol causes cell cycle arrest, decreased collagen synthesis, and apoptosis in rat intestinal smooth muscle cells[J]. Am J Physiol Gastrointest Liver Physiol, 2012,302(3):G326-G335. Additional Declarations No competing interests reported. Supplementary Files table.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4607078","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":323782558,"identity":"9a4775ff-19d6-4f7f-a0cc-df5414f54427","order_by":0,"name":"Paziliya Abulaiti","email":"","orcid":"","institution":"Xinjiang Medical University","correspondingAuthor":false,"prefix":"","firstName":"Paziliya","middleName":"","lastName":"Abulaiti","suffix":""},{"id":323782559,"identity":"8941b885-9a3c-486a-84eb-4524c072a81c","order_by":1,"name":"hui Shi Wen","email":"","orcid":"","institution":"General Hospital of Xinjiang Military Region of 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with HC group\u003csup\u003e△\u003c/sup\u003eP\u0026lt;0. 05，\u003csup\u003e△△\u003c/sup\u003eP\u0026lt;0.01or\u003csup\u003e△△△\u003c/sup\u003eP\u0026lt;0.001； Compared with HNgroup: # \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, ## \u003cem\u003eP\u003c/em\u003e\u0026lt;0.01 . \u0026nbsp;(PC:plain blank control group，HC：high-altitude blank group，HN：high-altitude NSAIDs injury group，RES-L：resveratrol intervention low dose group，RES-M：resveratrol intervention medium dose group，RES-H：resveratrol intervention medium dose group）. The arrows (↓) indicate intestinal mucosal congestion and edema, (↓) indicates intestinal mucosal adhesion, and (↓) indicates intestinal wall necrosis, and the intestinal wall is purple-black.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4607078/v1/8b2e82806177214b17d20983.png"},{"id":60294339,"identity":"b0b34c6b-d61a-4780-8d12-2110895dc5f9","added_by":"auto","created_at":"2024-07-15 09:21:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":616601,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA.\u003c/strong\u003eHE staining appearance \u003cstrong\u003eB. \u003c/strong\u003eintestinal histological injury score of\u0026nbsp; rat（n=10）。Compared with PC group:* \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, ** \u003cem\u003eP\u003c/em\u003e\u0026lt;0.01 or *** \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001;Compared with HC group\u003csup\u003e△\u003c/sup\u003eP\u0026lt;0. 05，\u003csup\u003e△△\u003c/sup\u003eP\u0026lt;0.01or\u003csup\u003e△△△\u003c/sup\u003eP\u0026lt;0.001； Compared with HNgroup: # \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, ## \u003cem\u003eP\u003c/em\u003e\u0026lt;0.01 . The arrows (\u003cstrong\u003e↓\u003c/strong\u003e) in each figure, from left to right, HC group:indicate capillary congestion, lymphocytic infiltration, and small intestinal villous edema in the small intestinal mucosa . HN group :indicates massive lymphocytic infiltration, small intestinal lamina propria edema, and apical detachment of intestinal mucosal villi ;RES-L group: indicates villous edema with lymphocytic infiltration, capillary congestion, and partial epithelial detachment of the apical villi;RES-M group: indicates apical partial epithelial detachment of villi; RES-H group indicates partial epithelial detachment of villi\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4607078/v1/90b1b37b075f20969fe4b848.png"},{"id":60294672,"identity":"4ef20f71-8321-4ba3-98f4-251c751b7610","added_by":"auto","created_at":"2024-07-15 09:29:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":208901,"visible":true,"origin":"","legend":"\u003cp\u003eLevels of inflammation factor and Oxidative stress indicators in serum of rat .(x±s,n = 10)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003e.Serum IL-1β level \u003cstrong\u003e(B)\u003c/strong\u003e.Serum IL-10 level\u003cstrong\u003e (C)\u003c/strong\u003e.Serum TNF-α level \u003cstrong\u003e(D).\u003c/strong\u003e Serum MOP level \u003cstrong\u003e(E). \u003c/strong\u003eSerum MOP level ; Compared with PC group: * \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, ** \u003cem\u003eP\u003c/em\u003e\u0026lt;0.01 or *** \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001；Compared with HC group：\u003csup\u003e△\u003c/sup\u003eP\u0026lt;0. 05，\u003csup\u003e△△\u003c/sup\u003eP\u0026lt;0.01or\u003csup\u003e△△△\u003c/sup\u003eP\u0026lt;0.001；Compared with HN group: # \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, ## \u003cem\u003eP\u003c/em\u003e\u0026lt;0.01 ，### \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4607078/v1/35f9f4f1bbeff433438ecae5.png"},{"id":60293260,"identity":"46d3ed77-f864-4535-b0c7-df88c15257e8","added_by":"auto","created_at":"2024-07-15 09:13:55","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":753072,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA.\u003c/strong\u003eImmunohistochemical staining of AngⅡ protein expression\u003cstrong\u003e B\u003c/strong\u003e.H-score of AngⅡ protein expression in the intestinal tissues of rat\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4607078/v1/d75f1f0c09fa3c826b555f56.png"},{"id":60293263,"identity":"f31f80c2-3802-421e-a8f2-ad0dd7ec6bd9","added_by":"auto","created_at":"2024-07-15 09:13:55","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":736107,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA.\u003c/strong\u003eImmunohistochemical staining of ICAM-1 protein expression\u003cstrong\u003eB\u003c/strong\u003e.H-score of ICAM-1 protein expression in the intestinal tissues of rat\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4607078/v1/cdd52079c44119b098991ae7.png"},{"id":60293256,"identity":"c0fc7603-2b31-4606-8c0e-f3fe54663c58","added_by":"auto","created_at":"2024-07-15 09:13:55","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":22005,"visible":true,"origin":"","legend":"\u003cp\u003ePearson correlation analysis correlation between \u003cstrong\u003eA\u003c/strong\u003e.Ang-II histopathological score of the intestinal mucosa of rats\u003cstrong\u003eB.\u003c/strong\u003e ICAM-1 and histopathological score of the intestinal mucosa of rats\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-4607078/v1/b4c9576f0854282aabd368af.png"},{"id":62574506,"identity":"d9b9bdc9-ff5b-441e-814e-f51e61806ea9","added_by":"auto","created_at":"2024-08-16 04:34:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3450763,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4607078/v1/37a8425d-d91d-4387-b197-f7f328184cb5.pdf"},{"id":60294343,"identity":"98fc5efa-c370-449f-8605-2e8036274cc0","added_by":"auto","created_at":"2024-07-15 09:21:55","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19208,"visible":true,"origin":"","legend":"","description":"","filename":"table.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4607078/v1/7f72715677b6b7acab7ecd3f.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Resveratrol mitigates NSAIDs-induced intestinal injury in rats exposed to high altitude hypoxia by reducing the expression levels of Ang- II","fulltext":[{"header":"STRENGTHS AND LIMITATIONS OF THIS STUDY","content":"\u003cp\u003eThe characterization of the modified intestinal injury resulting from the extended oral intake of non-steroidal anti-inflammatory drugs in highland environments has not yet been definitively documented.\u003c/p\u003e\n\u003cp\u003eResveratrolshows promise as a natural remedy for preventing\u0026nbsp;NSAIDs drug-related intestinal injury.\u003c/p\u003e\n\u003cp\u003eThis study is that it only relies on animal models and lacks the validation of in vitro cellular experiments. Our study only relies on animal models and lacks the validation of in vitro cellular experiments. Therefore, the results of animal experiments may not be directly applicable to humans, and the feasibility of clinical application has not been verified.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis experiment was conducted in a controlled, special laboratory environment. However, people living at high altitudes are affected by many factors in their living environment, which may lead to a deviation of the experimental results from the actual situation. Therefore, the results may need to be further verified by long-term, repeated experiments.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eThe main characteristics of the high-altitude environmentt include low air pressure, hypoxia, low temperature, strong ultraviolet rays, and climatic variability, which exert different degrees of adverse effects on the human body \u003csup\u003e[1, 2]\u003c/sup\u003e. As the altitude increases, the partial pressure of arterial blood oxygen decreases, leading to progressive hypoxia in human tissues. Inflammatory factors and oxygen-free radicals are produced when the oxygen supply to human tissues and cells becomes insufficient, and these factors can induce damage to cells and lead to dysfunction or apoptosis \u003csup\u003e[2, 3]\u003c/sup\u003e. Due to these special conditions at high altitude, individuals entering high-altitude areas are prone to plateau adverse reactions, with gastrointestinal reactions being more significant, including nausea, vomiting, diarrhea, peptic ulcers, gastrointestinal hemorrhage, and even perforation and other injuries\u003csup\u003e[4]\u003c/sup\u003e. Wu et al. demonstrated that the incidence of gastrointestinal hemorrhage in workers who had operated for an extended period at high altitude was 0.49%, and that incidence increased with altitude \u003csup\u003e[5]\u003c/sup\u003e. It has been demonstrated that the hypoxic environment at high altitudes activates the inflammatory pathway and the oxidative stress process in the human body and promotes the production of inflammatory factors, thereby triggering a cascade of inflammatory responses leading to intestinal damage \u003csup\u003e[6, 7]\u003c/sup\u003e. These oxidative stress products increase intestinal permeability, allowing harmful microorganisms and antigens from the luminal environment to enter the circulation and increasing the risk of systemic reaction syndrome \u003csup\u003e[8]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNonsteroidal anti-inflammatory drugs (NSAIDs) cause gastroduodenal adverse effects \u003csup\u003e[9]\u003c/sup\u003e. Recently, attention has been drawn to NSAID-induced small bowel injuries. Current evidence suggests that NSAIDs increase the risk of bleeding and perforation in the lower gastrointestinal (GI) tract to a comparable degree as in the upper GI tract \u003csup\u003e[10]\u003c/sup\u003e. Aspirin is a non-steroidal anti-inflammatory drug with favorable anti-inflammatory, antipyretic, and analgesic effects and is widely used in clinical practice \u003csup\u003e[11]\u003c/sup\u003e. Studies have shown that the incidence of small intestinal mucosal erosions, ulcers, and mucosal bleeding can be as high as 70% in patients undergoing video capsule endoscopy following long-term oral administration of nonsteroidal anti-inflammatory drugs, such as aspirin \u003csup\u003e[12, 13]\u003c/sup\u003e. However, the characteristics of altered intestinal damage caused by prolonged oral administration of nonsteroidal anti-inflammatory drugs in high-altitude environments are rarely reported. In this study, we simulated and observed NSAID-induced intestinal injury in a high-altitude environment by administering aspirin through gavage to rats in a specialized hypoxic chamber. Our objective was to investigate the potential exacerbating impact of the high-altitude hypoxic environment on NSAID-related intestinal injury.\u003c/p\u003e \u003cp\u003eAngiotensin II, a peptide hormone, is produced by the kidney. Numerous studies have demonstrated its crucial role in regulating blood pressure, hydrosalinity balance, and kidney function \u003csup\u003e[14]\u003c/sup\u003e. It participates in the regulation of gastrointestinal physiological functions through various means and significantly affects gastrointestinal blood flow, motility, secretion, and other aspects \u003csup\u003e[15]\u003c/sup\u003e. Recent research has shown that angiotensin II may also contribute to the inflammatory response, particularly in intestinal inflammation \u003csup\u003e[16\u0026ndash;18]\u003c/sup\u003e. It can modulate the process of apoptosis in intestinal epithelial cells \u003csup\u003e[19]\u003c/sup\u003e. Research has indicated that the angiotensin 2 receptor (AT2 receptor) is widely distributed in the intestine, and its activity may correlate with the onset and progression of intestinal inflammation \u003csup\u003e[20]\u003c/sup\u003e. It has been observed that the renin-angiotensin system (RAS) is activated in the body during hypoxia, leading to the increase of circulating renin activity, Ang II, and ACE activity, resulting in hypoxic diseases in local tissues and organs \u003csup\u003e[21]\u003c/sup\u003e.However, further research is necessary to verify the precise relationship between hypoxia, angiotensin II expression levels, and intestinal inflammation. Our study focuses on the alteration of Ang II expression levels in intestinal tissues in high-altitude hypoxic environments and NSAID drugs through animal models to further clarify the mechanism of intestinal injury generation induced by plateau badlands and NSAID drugs.Our study focuses on the alteration of Ang II expression levels in intestinal tissues in high-altitude hypoxic environments and NSAID drugs, using animal models to elucidate the mechanism of intestinal injury caused by high altitudes and NSAIDs.\u003c/p\u003e \u003cp\u003eResveratrol, a plant polyphenol isolated from grape seeds and peel \u003csup\u003e[22]\u003c/sup\u003e, possesses antioxidant, anti-inflammatory, anti-apoptotic, and other pharmacological effects \u003csup\u003e[23]\u003c/sup\u003e. It shows promise as a natural drug for preventing and treating intestinal diseases. Studies have demonstrated that resveratrol can protect against intestinal injury by reducing oxidative stress, inhibiting the inflammatory response, and regulating apoptosis, among other pathways \u003csup\u003e[24, 25]\u003c/sup\u003e. This study administered resveratrol at various doses to assess its protective effect on intestinal injury and to investigate whether resveratrol can mitigate non-steroidal anti-inflammatory drug-induced intestinal injury in rats by regulating the expression level of Ang Ⅱ in a high-altitude hypoxic environment. This research aims to provide insights into the prevention and treatment of intestinal injury in patients on long-term oral NSAIDs in clinical high-altitude environments\u003c/p\u003e"},{"header":"Methods and Materials","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e1.1Chemicals and reagents\u003c/h2\u003e \u003cp\u003eThe aspirin was acquired from Shanghai Yuanye Biotechnology Co. The resveratrol standard, sourced from Sigma Aldrich (Shanghai) Trading Co. Ltd., was prepared as a suspension using distilled water for the experiments. The pentobarbital sodium was procured from Shanghai Sinopharm Chemical Reagent Co. The Ang-II polyclonal antibody and monoclonal antibody targeting intercellular adhesion molecule-1 (ICAM-1) were obtained from Shanghai Snowdance Biotechnology Co. Ltd. The measurement kits for myeloperoxidase (MPO) and superoxide dismutase (SOD), interleukin (IL)-10, interleukin (IL)-1β, and tumor necrosis factor-α (TNF-α) were procured from Shanghai Wei Ao Biotechnology Co.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e1.2 Animal grouping and drug administration\u003c/h2\u003e \u003cp\u003e All experiments were approved by the Institutional Animal Protection and Use Committee of Xinjiang medical University (ethics no. KY20230209135), and the methods were conducted in accordance with the guidelines for the Animal Experiments of Xinjiang medical University and ARRIVE guidelines.Sixty male SD rats, aged 6 weeks, weighing 250 ± 50 g, were obtained from the Animal Experiment Centre of Xinjiang Medical University. Rats for this experimental modeling and drug intervention will be accommodated in a specialized hypoxia chamber in the northwest region (SPF-grade clean laboratory) of Urumqi General Hospital of Lanzhou Military Region.With the parameters adjusted to an altitude of 5500 m, the atmospheric pressure to 93.2 KPa (699.1 mmHg), and the partial pressure of oxygen to 19.54 KPa (146.6 mmHg). Every 5 rats were housed in standard rat experimental cages (485*350*200mm),and provided with standard mouse feed ad libitum throughout the experiment, maintained at a controlled temperature of 22 ± 2°C, with a relative humidity of 40–60%, and subjected to an alternating daily and diurnal cycle of 12 hours.\u003c/p\u003e \u003cp\u003eAll the rat were subjected to acclimation for 1 week and assigned randomly to six groups with different treatments: plain blank control group (PC group, n = 10), high-altitude blank group (HC group), high-altitude NSAIDs injury group (HN group), resveratrol intervention low dose (RES-L group), medium dose (RES-M group), and high dose (RES-H group), with 10 rats in each group. The daily oral dose of each drug was converted from the human oral dose by reference. The plain blank control group was exposed to the conventional atmospheric environment, while the other groups were placed in the hypoxia chamber in a special environment.\u003c/p\u003e \u003cp\u003eThe control group received daily gavage with saline (1 ml/100 g), while the remaining rats were administered aspirin at a dosage of 200 mg/kg daily. The resveratrol intervention group received resveratrol at doses of 25 mg/kg, 50 mg/kg, and 100 mg/kg in the low, medium, and high dose groups, respectively, for 2 hours following the 200 mg/kg aspirin administration,continuously for 3 weeks. All drugs were ground into powder and dissolved in a 5% carboxymethyl Na solution at a ratio of 1:1 to prepare a suspension, The liquid volume for each gavage was given at 10 ml/kg。In order to minimize potential confounders, treatments, measurements, and animal/cage locations were randomized. During the experiment, all experimenters excepting the designer were blinded to group assignment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e1.3 Physical Evaluation of rats\u003c/h2\u003e \u003cp\u003eRecord and observe specific general symptoms of rats in each group, including their mental state, eating habits, activity levels, defecation patterns, and other relevant indicators.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e1.4Tissue sample collection\u003c/h2\u003e \u003cp\u003eFollowing the last administration, the rats underwent a 24-hour fasting period and were anesthetized with a 3% sodium pentobarbital solution at a dosage of 40 mg/kg via intraperitoneal injection. With adherence to strict aseptic procedures, the abdominal cavity was promptly opened to observe its contents. Subsequently, the intestinal segments were carefully dissected to assess damage, with the most severely affected 3cm segment of the small intestine excised and placed in a 10% formaldehyde solution for 24 hours for fixation. Following fixation, the tissue slices were embedded in paraffin wax for subsequent microscopic scoring and immunohistochemical staining. Additionally, intestinal tissue located 5 cm from the proximal jejunum was isolated, and the homogenization medium from the test box was added and ground on ice to produce a 5% tissue homogenate.The activities of TNF-α, IL-1β, IL-10, MPO, and SOD in rat jejunal tissues were detected by the Enzyme-Linked Immunosorbent Assay (ELISA) method, following the instructions provided by the kit in strict accordance with the prescribed steps.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e1.5 Histological Analysis\u003c/h2\u003e \u003cp\u003eThe severity of intestinal mucosal tissue damage was observed, and the degree of intestinal injury was macroscopically scored according to the Reuten score \u003csup\u003e[26]\u003c/sup\u003e. The cut intestinal tissue was fixed in a 10% formaldehyde solution and then embedded in paraffin for routine sectioning. Three pathologists observed the histopathological changes of the small intestine under a light microscope using a blind method and then scored the intestinal injury histology according to Chiu's scoring method \u003csup\u003e[27]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e1.6 Immunohistochemical Analysis\u003c/h2\u003e \u003cp\u003esmall intestinal tissues were fixed in 10% formalin buffer, embedded in paraffin, and cut into 4 µm-thick sections. They were then deparaffinized in xylene and rehydrated with gradient ethanol. Thermal antigen repair was performed twice in high fire using EDTA antigen repair solution (50X). Sections were incubated in 5% BSA for 35 minutes and washed well in PBS. Then, the sections were incubated with angiotensinogen antibody (1:200 dilution) and Icam-1 antibody overnight at 4°C, followed by incubation with goat anti-rabbit secondary antibody HRP Polymer Quanto at 37°C for 35 min. They were then visualized by DAB horseradish peroxidase color solution (brownish-yellow staining), and the nuclei of the cells were restained with hematoxylin. Finally, the sections were dehydrated, sealed, scanned with a digital scanner, and analyzed with Visiopharm AI pathology analysis software.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.Statistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using the GraphPad Prism 9 software (GraphPad, San Diego, CA, USA). The results were presented as the mean ± standard deviation (SD). One-way ANOVA and the least significant difference (LSD-t) method were used to assess statistical significance between multiple groups. Pearson correlation analysis was employed to determine the correlation between Ang-II and ICAM-1 and the degree of pathological damage to the intestinal mucosa of rats, respectively. p \u0026lt; 0.05 was considered statistically significant (two-tailed).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003cp\u003e \u003c/p\u003e\u003c/div\u003e "},{"header":"Result","content":"\u003ch2\u003e3.1Physical stiuation of Rats\u003c/h2\u003e\u003cp\u003eDuring the experimental period, no rats died. The rats in the PC group demonstrated a sensitive response, had shiny fur, displayed a healthy appetite, passed well-formed stools. The rats in the HC group showed a slightly reduced response, a minor decrease in appetite, well-formed stools. The rats in the HN group demonstrated decreased appetite, loss of hair luster, delayed response, dull quietness, irregular stools, and reduced urine volume. The rats in the resveratrol intervention groups displayed average reactions, exercise, and appetite, with no significant abnormalities observed in their bowel movements.\u003c/p\u003e\u003ch2\u003e3.2 macroscopic appearance\u003c/h2\u003e\u003cp\u003eNo macroscopic damage, adhesion, or ulcers were observed in the rats in the PC group. Mild adhesion and edema of the intestinal mucosa were observed in the rats in the HC group without any ulcers or bleeding points; the tissue injury score was 1.15 ± 0.34 points. The HN group of rats showed severe intestinal mucosal adhesion with varying degrees of congestion and edema, and some exhibited necrosis of the intestinal wall, which appeared purple-black in color. No intestinal perforation or ulcer was observed, and the tissue injury score was 2.00 ± 0.62 points, significantly higher than that of the HC group rats(\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001). Local congestion, edema, and adhesion of the small intestine were observed in the resveratrol intervention group rats. However, the degree of the lesion was lower than that in the HN group rats. The medium-dose resveratrol group rats had the lowest tissue scores of 1.20 ± 0.42, which was significantly lower than that in the HN group rats (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01), show Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003ch2\u003e3.3 Histopathological observations\u003c/h2\u003e\u003cp\u003eThe results of HE staining revealed that the structure of small intestinal villi in the PC group rats was intact, with clear and undamaged layers, normal tissue morphology, and a pathological score of 0.20 ± 0.42. In the HC group rats, small intestinal villi exhibited edema accompanied by capillary congestion and lymphocyte infiltration while maintaining evident structural integrity in each layer, with a pathological score of 1.20 ± 0.79, significantly differing from that of the PC group rats \u003cem\u003e(P\u003c/em\u003e \u0026lt; 0.05). Within the HN group rats, the lamina propria of the small intestine exhibited varying degrees of obvious edema, denatured and necrotic epithelial cells in the intestinal mucosa, occasional villi tip detachment, and significant infiltration of inflammatory cells, resulting in a pathological score of 2.9 ± 0.99, markedly higher than that of the HC group rats (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001). The degree of pathological damage to the small intestinal mucosa was lower in the resveratrol intervention group (low, medium, or high) compared to the HN group rats. However, some rats exhibited villous edema, apical epithelial detachment with capillary congestion, and infiltration of inflammatory cells. The medium-dose resveratrol group rats had the lowest pathological score of 1.30 ± 0.48, demonstrating statistical significance in comparison to the HN group rats. (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01)show Fig.\u0026nbsp;2.\u003c/p\u003e\u003ch2\u003e3.4 Inflammatory factors\u003c/h2\u003e\u003cp\u003eELISA results indicated a significant increase in the levels of IL-1 β and TNF-α in the small intestine tissue of the HC group rats compared to the PC group, while the level of IL-10 was notably decreased (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01). Correspondingly, the levels of IL-1 β and TNF-α in the small intestine of rats in the HN group were significantly increased, while the level of IL-10 was significantly decreased, with a statistically significant difference compared to the HC group rats (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01). Furthermore, in comparison to the HN group rats, the levels of IL-1 β and TNF-α in the small intestine tissue of rats in the resveratrol (low, medium, and high) intervention group were significantly reduced, and the IL-10 level was notably increased, with the most substantial difference observed in the resveratrol medium dose group rats (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01).\u003c/p\u003e\u003ch2\u003e3.5 Oxidative stress indicators\u003c/h2\u003e\u003cp\u003eIn comparison to the PC group, the expression levels of both MOP and SOD in the intestinal mucosa of rats in the HC group showed a significant increase (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05). Likewise, the expression levels of MOP and SOD in the intestinal mucosa of rats in the HN group exhibited a significant increase compared to the HC group (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05). In contrast to the HN group, the expression levels of SOD and MOP protein in the small intestine tissue of rats in the resveratrol intervention groups (low, medium, and high doses) experienced a significant decrease, particularly notable in the medium resveratrol groups (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01),show Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003ch2\u003e3.6 Immunohistochemistry detect the expression of Ang-Ⅱand ICAM-1\u003c/h2\u003e \u003cp\u003eAng-Ⅱ positive protein was primarily localized to the cell plasma or cell membrane of the intestinal mucosa, exhibiting a brownish-yellow color, while ICAM-1-positive protein particles were predominantly expressed in the cell membrane or cell plasma of the epithelium of the intestinal mucosa and in the inflammatory cells of the mucous membrane lamina propria, displaying a yellowish-brown color. Immunohistochemistry analysis revealed that the expression level of Ang II protein in the intestinal mucosa of rats in the HC group was significantly higher (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05) compared to the PC group, while there was no significant difference observed in the expression of ICAM-1 protein. In comparison to the HC group, the expression levels of AngⅡ and ICAM-1 protein in the intestinal mucosa of rats in the HN group were markedly elevated (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05). Furthermore, in comparison to the HN group rats, the expression levels of AngⅡ and ICAM-1 protein in the intestinal mucosal tissues of rats in the resveratrol intervention groups (low, medium, and high) were notably reduced, with the most pronounced decrease observed in the middle-dose resveratrol grouprats (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05)show Fig.\u0026nbsp;4.5.\u003c/p\u003e\u003ch2\u003e3.7 Correlation Analysis\u003c/h2\u003e\u003cp\u003eThe expressions of Ang-II and ICAM-1 were both positively correlated with the degree of histological damage to the small intestinal mucosa of rats, respectively (r = 0.795, 0.832, both \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01),show Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e"},{"header":"Disscusion","content":"\u003cp\u003eThe high-altitude environment, characterized by low pressure, low oxygen, and cold, can lead to oxidative stress and inflammatory reactions due to ischemia and hypoxia in various organs, adversely affecting the normal organism, particularly leading to gastrointestinal adverse reactions \u003csup\u003e[28–30]\u003c/sup\u003e. The small intestine’s susceptibility to hypoxia arises from its complex blood supply and rapid mucosal surface cell turnover, leading to a heightened oxygen demand \u003csup\u003e[31]\u003c/sup\u003e。 Persistent hypoxia readily induces pathological changes in the structure and function of intestinal tissues. In this study, rats in the HC group exhibited decreased appetite, slower weight gain, mild adhesion of the intestinal mucosa with edema in the intestinal tissues, and pathologically evident small intestinal villi edema, along with capillary congestion, lymphocyte infiltration, and other manifestations of damage, when compared to the PC group.The ELISA results indicated elevated levels of inflammatory factors including IL-1β and TNF-α, along with indicators of oxidative stress such as MPO and SOD, and a decrease in the protective inflammatory factor IL-10 within the intestinal tissues. These findings suggest that the high-altitude environment induces oxidative stress and an inflammatory response in the intestine, impacting the normal function and tissue structure of the gastrointestinal tract.This result is in line with the findings of previous relevant studies.\u003c/p\u003e\u003cp\u003eNonsteroidal anti-inflammatory drugs (NSAIDs) are commonly utilized in clinical settings due to their anti-inflammatory, antipyretic, and analgesic properties, as well as their ability to inhibit platelet aggregation. Multiple studies have demonstrated that prolonged use of NSAIDs can compromise the integrity of the intestinal mucosal barrier and lead to the onset of NSAID-related intestinal disorders. \u003csup\u003e[32–34]\u003c/sup\u003eNSAIDs are recognized for their propensity to induce adverse effects in the upper gastrointestinal tract. Recent studies have highlighted the growing concern regarding NSAID-induced adverse reactions in the lower gastrointestinal tract, particularly the small bowel, following the introduction of capsule endoscopy and small colonoscopy, alongside the rising utilization of NSAIDs, including aspirin.\u003csup\u003e[35]\u003c/sup\u003e A study reported that Non-steroidal anti-inflammatory drugs cause small-bowel inflammation in about 60% of patients receiving these drugs long-term\u003csup\u003e[36]\u003c/sup\u003e. Severe small-bowel injury represents a prevalent complication associated with NSAID usage, contributing to one-third of all complication cases\u003csup\u003e[37]\u003c/sup\u003e.In this study, the rats in the HN group received 200 mg/kg aspirin by gavage daily for 3 weeks. During this period, they exhibited symptoms including anorexia, a sluggish reaction, and decreased stool volume. Both the macroscopic score and the pathological tissue damage score of intestinal tissue, as well as mucosal inflammatory factors and oxidative stress indexes, were notably higher in the HN group compared to the PC group rats. These findings suggest that NSAID drugs may can lead to small intestinal injuries.\u003c/p\u003e\u003cp\u003eStudies have shown that short-term oral administration of low-dose aspirin may induce inflammation of the small intestinal mucosa, whereas prolonged use of aspirin can result in a range of small intestinal lesions, including multiple petechiae, villus shedding, and mucosal erosion, and may even lead to serious adverse effects such as ulcers and perforation\u003csup\u003e[12, 38–40]\u003c/sup\u003e. In the prevention and treatment of cardiovascular diseases, inflammatory conditions, a certain cancers, patients require long-term oral administration of aspirin. However, this therapeutic regimen may gradually result in low-dose drug-dependent intestinal injury in patients, subsequently impacting their intestinal health [40, 41]\u003csup\u003e[40, 41]\u003c/sup\u003e. The hypoxic environment at high altitudes has emerged as a significant risk factor for gastrointestinal injury in patients undergoing prolonged aspirin therapy.In our study, we simulated NSAID-induced intestinal injury at high altitude by administering aspirin at a loading dose of 200 mg/kg to rats. The results indicated that intestinal tissue damage in the HN group rats was characterized by significant adhesion of the intestinal mucosa with varying degrees of congestion and edema, and sections of the intestinal wall appeared necrotic and purplish-black. The small intestinal mucosa of the rats exhibited varying degrees of villous edema, necrotic detachment of the apical epithelium, disorganization of the glandular arrangement in the lamina propria, and a significant amount of inflammatory cell infiltration under electron microscopy, which differed significantly from that in the HC group rats. The dual stress conditions, such as the high altitude environment and NSAID drugs, were observed to cause increased intestinal mucosal injury in rats, with the high-altitude hypoxic environment potentially exacerbating NSAID drug-induced intestinal injury.\u003c/p\u003e\u003cp\u003eAngiotensin II (Ang II), a peptide hormone primarily synthesized by the kidneys, serves not only to regulate blood pressure, water-salt balance, and renal function, but also acts as a pro-inflammatory mediator\u003csup\u003e[42]\u003c/sup\u003e. Angiotensin II (Ang II) receptors are distributed across various organs including the kidneys, brain, heart, lung tissue, intestine, blood vessels, and immune cells \u003csup\u003e[43]\u003c/sup\u003e. Within the intestine, the colon exhibits the highest density of these receptors, followed by the ileum, duodenum, and jejunum \u003csup\u003e[44]\u003c/sup\u003e. Angiotensin II (Ang-II) mediates the effects of the angiotensin system in the intestine by activating angiotensin receptors, notably AT1 receptors. This activation can result in heightened intestinal vascular permeability and modifications in tight junctions of the vascular endothelium, thereby fostering the development of exudate and edema in intestinal inflammation \u003csup\u003e[45]\u003c/sup\u003e.It can regulate the activation state of immune cells, promote inflammatory cell infiltration, boost leukocyte rolling and adhesion \u003csup\u003e[46–48]\u003c/sup\u003e, and can also bind with receptors to activate signal transduction pathways. It can stimulate the activation of a variety of signal pathways through NF-κ B, which is also the hub of the intestinal inflammatory response, and produce adhesion molecules and chemokines such as IL-1 β, IL-6, IL-10, TNF-α, ICAM-1, etc., resulting in further development of the inflammatory response and damage to the corresponding tissue structure\u003csup\u003e[49, 50]\u003c/sup\u003e. ICAM-1 (intercellular adhesion molecule-1) is a cell surface glycoprotein and adhesion receptor that participates in the regulation of inflammatory responses and tissue damage by mediating leukocyte adhesion and migration \u003csup\u003e[51, 52]\u003c/sup\u003e. The expression of ICAM-1 can be induced by a variety of stimulatory factors, such as cytokines, inflammatory mediators, etc., to enhance the adhesion of immune cells and vascular endothelial cells and subsequently secrete a large quantity of pro-inflammatory cytokines, exacerbating inflammatory injury \u003csup\u003e[53, 54]\u003c/sup\u003e.Studies have shown that Ang II can increase the expression of ICAM-1 to promote the occurrence and development of an inflammatory response\u003csup\u003e[55]\u003c/sup\u003e. In this study, the small intestinal mucosa of rats in the HN group was damaged to varying degrees. The levels of IL-1β, TNF-α, MPO, and SOD in intestinal tissue were significantly higher than those in other groups. The level of IL-10, a protective inflammatory factor, was significantly reduced. The expression of Ang II and ICAM-1 proteins was up-regulated. The expression of Ang II and ICAM-1 was positively correlated with the degree of histological damage to the small intestinal mucosa. It can be seen that Ang II may mediate the intestinal inflammatory response, and the inflammatory factors and oxidative stress products may stimulate the production of ICAM-1. When ICAM-1 binds to its receptor, it mediates the adhesion and aggregation of more inflammatory cells to release inflammatory mediators, further producing an inflammatory cascade reaction and aggravating intestinal injury.\u003c/p\u003e\u003cp\u003eIt has been shown that Ang-II promotes apoptosis of intestinal epithelial cells in an AT2 receptor-dependent manner through the GATA-6 and Bax pathways, thereby increasing mucosal barrier permeability and generating intestinal inflammatory injury \u003csup\u003e[56]\u003c/sup\u003e. Touyz et al. demonstrated that Ang-II primarily activates multiple pathways via reactive oxygen species (ROS) produced by NAD(P)H oxidase to drive smooth muscle cell growth, proliferation, hypertrophy, and pro-inflammatory effects\u003csup\u003e[57]\u003c/sup\u003e. Additionally, Zhang et al. showed that Ang II plays a crucial role in NSAID-associated small bowel injury in rats and indicated that the RAS-p38MARPK signaling pathway is implicated in the pathogenesis of such injuries, suggesting that Ang II may act pro-inflammatory through this signaling pathway and contribute to intestinal inflammatory damage\u003csup\u003e[58]\u003c/sup\u003e.Several studies have suggested that hypoxic conditions induce inflammation, oxidative stress, and vascular dysfunction, leading to increased expression levels of Ang II \u003csup\u003e[59, 60]\u003c/sup\u003e. In this study, HC group rats intestinal tissues exhibited elevated levels of pro-inflammatory factors, including IL-1β and TNF-α, oxidative stress indicators like MPO and SOD, decreased levels of the anti-inflammatory factor serum IL-10, and increased expression of both Ang-II and ICAM-1 compared to the PC group. This highlights a significant association between organismic hypoxia, increased expression levels of Ang II, and intestinal inflammation, which aligns with previous findings. In summary, Ang II likely contributes to intestinal inflammatory injury by initiating inflammatory cascade responses via various signaling pathways. Additionally, the regulation of Ang II expression may be associated with the mechanism of NSAID-induced small intestinal injury in rats exposed to plateau environments.\u003c/p\u003e\u003cp\u003eStudies have shown that, to date, there is no effective and safe strategy to prevent or treat lower gastrointestinal injuries associated with NSAIDs \u003csup\u003e[61]\u003c/sup\u003e. Resveratrol is widely found in natural plants such as Polygonum cuspidatum, grapes, and pines \u003csup\u003e[62, 63]\u003c/sup\u003e. Resveratrol can regulate intestinal mucosal barrier damage and dysfunction, providing a protective effect against intestinal injury through various pathways, such as anti-inflammatory and antioxidant mechanisms \u003csup\u003e[64]\u003c/sup\u003e. It shows promise as a natural remedy for preventing intestinal injury. It can enhance cytochrome oxidase activity in the intestinal mucosal epithelium, thereby reducing oxygen-free radical production \u003csup\u003e[65]\u003c/sup\u003e。In this study, the levels of MPO and SOD in the intestinal tissue of rats in the resveratrol intervention group were reduced compared to the HN group, with the most significant difference observed in the middle dose of the resveratrol intervention group. Based on the aforementioned results, it can be concluded that resveratrol can alleviate intestinal mucosal damage by exerting antioxidant effects. The anti-inflammatory effect of resveratrol is achieved by regulating the initiation and termination of the inflammatory response. Studies have shown that the anti-inflammatory effect of resveratrol on the intestine is primarily accomplished by inhibiting NF-κB activity and downregulating proinflammatory factors and inflammatory mediators \u003csup\u003e[66]\u003c/sup\u003e. In this study, compared with the HN group, the levels of pro-inflammatory factors such as IL-1β and TNF-α in the intestinal tissue of rats in the resveratrol intervention group were significantly decreased, while the anti-inflammatory factor IL-10 was increased. A significant difference was observed in the middle dose of the resveratrol intervention group, suggesting that resveratrol can mitigate the intestinal injury induced by NSAIDs in the high-altitude hypoxia environment by decreasing the intestinal mucosal inflammatory response and modulating the pro-inflammatory and anti-inflammatory.\u003c/p\u003e\u003cp\u003eThere are Studies have shown that resveratrol can inhibit the apoptosis of intestinal epithelial cells to protect the integrity of the intestinal barrier, thus reducing intestinal injury\u003csup\u003e[67, 68]\u003c/sup\u003e. In our study, compared with the HN group, the resveratrol intervention group reduced the histopathology and tissue damage of the small intestinal mucosa. Moreover, the microscopic score of the resveratrol medium dose intervention group was lower than that of the HN group. This significant difference suggests that resveratrol can protect intestinal function by reducing intestinal cell death and apoptosis, as well as regulating intestinal permeability. Additionally, our study found that, compared with the HN group, the expression of Ang-Ⅱ and ICAM-1 proteins in the intestinal mucosa of rats in the resveratrol intervention group was significantly reduced. This suggests that resveratrol may alleviate intestinal inflammation and injury by down-regulating the expression of Ang-Ⅱ and ICAM in intestinal tissue.\u003c/p\u003e "},{"header":"conclusion","content":"\u003cp\u003eThe dual stress conditions of a high-altitude environment and NSAID drugs can lead to the exacerbation of intestinal mucosal injury in rats. The expression level of Ang Ⅱ may be associated with the mechanism of NSAID-induced small intestinal injury in rats at high altitude. Our study found that resveratrol can effectively mitigate intestinal injury induced by NSAIDs in a high-altitude environment. The mechanism may involve downregulating the expression of Ang Ⅱ and ICAM-1, alleviating oxidative stress and the inflammatory response of the intestinal mucosa, and preserving intestinal barrier function.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is provided within the manuscript or supplementary information files\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA funding statement\u0026nbsp;\u003c/strong\u003eThis work was supported by [Host-gut microbial interaction regulates intestinal metabolism and influences intestinal mucosal barrier function in cealiac disease in the Xinjiang region: a study on the mechanism of action] grant number [82260116]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll experiments were approved by the Institutional Animal Protection and Use Committee of Xinjiang medical University (Ethics no.\u0026nbsp;KY20230209135), and the methods were conducted in accordance with the guidelines for the Animal Experiments of Xinjiang medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge the contribution of the team of individuals in the data collection process.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;All authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePaziliya Abulaiti: Investigation; Conceptualization; Methodology; Validation; Formal analysis ; Writing - original draft. Wen hui Shi Investigation; Conceptualization; Methodology; Validation; Formal analysis ; Writing - original draft;Huan Liu : Conceptualization; Investigation; Writing - review \u0026amp; editing; Formal analysis. Ailifeire Tuerxuntayi: Methodology; Validation; Formal analysis. Sheng long Xue: Software; Methodology; Formal analysis; Validation. Kailibinuer Nuermaimaiti: Conceptualization; Investigation. Zhuo shuyi Liu: Investigation; Validation; Yingying Xing:Investigation; Validation; Najimangu Remutula:Investigation; Conceptualization;Kudelaiti Abdukelimu:Investigation; Validation; \u0026nbsp; \u0026nbsp;Weidong Liu: Validation; Formal analysis. \u0026nbsp;Jiang wei Liu:Formal analysis; Validation; \u0026nbsp; \u0026nbsp;Feng Gao: Writing - review \u0026amp; editing; Project administration; Resources; Supervision; Data curation; Conceptualization; Funding acquisition.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHui L, Rong W, Zheng-Ping J, et al. 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Am J Physiol Gastrointest Liver Physiol, 2012,302(3):G326-G335.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"NSAIDs, High altitude hypoxic environment, Resveratrol, Angiotensin II, Intercellular adhesion molecule-1","lastPublishedDoi":"10.21203/rs.3.rs-4607078/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4607078/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cb\u003eObjective\u003c/b\u003e The study aimed to investigate the protective effects of resveratrol against NSAIDs drug-related intestinal injury in rats by regulating the expression of Ang II, as well as mitigating oxidative stress and inflammatory reactions in the intestinal mucosa.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethod\u003c/b\u003e 60 male Sprague-Dawley rats were randomly assigned to five groups. The control group received a daily gavage of saline (1 ml/100 g/d) in a standard plain-air environment. The rest were housed in a hypoxic chamber, and gavage aspirin at a dosage of 200 mg/kg daily was used to induce NSAID-related intestinal injury in rats. The resveratrol intervention group received resveratrol at varying doses (25, 50, and 100 mg/kg) 2 hours post-aspirin gavage for 3 weeks. Behaving activities, macroscopic appearance, and histological injury of the small intestinal mucosa were assessed and scored in each group. Oxidative stress indicators MPO and SOD, along with inflammatory factors IL-1β, IL-10, and TNF-α, were quantified using ELISA. Immunohistochemistry was employed to detect the expressions of Ang II and ICAM-1 in small intestinal tissues, and their correlation with the degree of intestinal pathology was analysed.\u003c/p\u003e \u003cp\u003e \u003cb\u003eResult\u003c/b\u003e The small intestine mucosa of rats in the PC group did not show significant macroscopic or pathological injury, whereas other groups exhibited varying degrees of damage. The overall morphology and pathological damage scores were significantly higher than those in the PC group rats (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In comparison with the HN group, intervention with resveratrol led to a reduction in the overall morphology and histopathological injury score of rats (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). (1)ELISA test results indicated that, in contrast to the PC group, levels of MPO, SOD, IL-1β, and TNF-α were increased in the HC group rats, while IL-10 levels were notably reduced (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Similarly, compared to the HC group, levels of IL-1β and TNF-α in the HN group rats were elevated, with decreased IL-10 levels (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The resveratrol intervention group rats exhibited significantly lower levels of IL-1 β and TNF-α than the HN group rats (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01), alongside higher levels of IL-10 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Notably, the most difference was observed in the medium-dose resveratrol group. (2)Immunohistochemical results revealed a significant increase in Ang II levels in both the HC group and HN group rats (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), with ICAM-1 levels significantly elevated in the HN group rats (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). (3)The expression of Ang II and ICAM-1 correlates positively with the histological injury to the small intestine mucosa. Following intervention with resveratrol, the expression of Ang II and ICAM-1 was notably lower than that in the HN group rats (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cb\u003eConclusion\u003c/b\u003e Resveratrol can effectively mitigate intestinal injury induced by NSAIDs in a high-altitude environment. The mechanism may involve downregulating the expression of Ang Ⅱ and ICAM-1, alleviating oxidative stress and the inflammatory response of the intestinal mucosa, and preserving intestinal barrier function.\u003c/p\u003e","manuscriptTitle":"Resveratrol mitigates NSAIDs-induced intestinal injury in rats exposed to high altitude hypoxia by reducing the expression levels of Ang- II","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-15 09:13:50","doi":"10.21203/rs.3.rs-4607078/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6b73af6a-f7d7-4136-a0d0-e3a66e0af1e8","owner":[],"postedDate":"July 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":34239713,"name":"Biological sciences/Drug discovery"},{"id":34239714,"name":"Health sciences/Gastroenterology"}],"tags":[],"updatedAt":"2024-08-16T04:26:14+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-15 09:13:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4607078","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4607078","identity":"rs-4607078","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}