Acute pancreatitis: pathogenesis and emerging therapies.

The primary goals of AP therapy are multifaceted and aim to reduce the severity of the acute injury and its complications, shorten intensive care unit (ICU) and hospital stays, reduce mortality, and decrease the associated medical and quality of life costs. An unresolved question is whether limiting acute and short-term injury will reduce the emerging longer-term complications such as pancreatic exocrine insufficiency, diabetes, and pancreatic cancer. For example, research has highlighted the role of interleukin (IL)-6 as an early predictive marker for severe pancreatitis. [ 11 ] Other studies have underscored the importance of IL-6 in driving the progression of preneoplastic pancreatic lesions. [ 12 , 13 ] These findings prompt an intriguing question of whether therapies targeting IL-6 in the short-term could potentially reduce the risk of pancreatic cancer or other long-term complications in patients with AP and prompt the question of the timing and length of therapy needed to do so. The potential negative effects of treatments also need to be considered. For example, what is the risk of reducing acute inflammatory responses to an extent that might increase the risk of infection or change healing responses? Thus, the duration of treatment and balance between managing the acute phase and preventing short-term and long-term complications need to consider potential off-target effects of treatments.

Acute pancreatitis (AP), a sudden inflammatory disease of the pancreas, can range from mild discomfort to a severe, life-threatening illness. It is one of the most common causes of gastrointestinal disease-related hospitalizations in the United States. [ 1 ] Past AP annual expenditures in the United States were estimated to be $2.6 billion. [ 2 ] Globally, the pooled incidence of AP is approximately 34 cases per 100,000 general population, making it a significant concern for public health. [ 3 ] Moreover, the global incidence of AP is increasing, with an estimated average annual percent increase of approximately 3% between 1961 and 2016. [ 4 ] There is considerable morbidity and mortality as well as medical costs associated with AP. Globally, there were approximately 115,000 AP deaths in 2019. [ 5 ] In its most severe form, AP can result in systemic inflammatory response syndrome (SIRS), multiple organ failure (MOF), increased infection rates, and mortality rates of up to 30% in those with severe disease. [ 6 ] Though most AP patients survive the disease, they can experience long-term consequences, including recurrent AP, chronic pancreatitis, exocrine and endocrine insufficiency, and an increased risk of pancreatic cancer. [ 7 – 9 ] Although the risks associated with AP are well known, current treatment strategies for AP are supportive and include fluid resuscitation, pain management, and nutritional support. [ 10 ] Current treatment paradigms do not target the underlying pathophysiological mechanisms of this disease. Investigators have anticipated that understanding AP’s natural history and mechanisms will lead to new therapeutic strategies to reduce this debilitating disease’s short-term and long-term burden; these goals are just being met. This article aims to delve into the most foundational mechanisms underlying AP and explore related new potential treatments that could improve patient outcomes.

Store-Operated Calcium Entry Associated Regulatory Factor (SARAF) regulates calcium signaling in pancreatic acinar cells. In mouse models of AP, SARAF levels initially increase but then decrease over time, leading to excessive calcium influx into acinar cells and worsening pancreatitis. SARAF knockout mouse models had more severe pancreatitis, while mice overexpressing SARAF were protected. [ 108 ] This suggests that strategies to stabilize or restore SARAF levels in acinar cells could be a potential new therapeutic approach for treating AP. MicroRNAs may serve as a critical target in the treatment of AP. The microRNA miR-26a is crucial in regulating calcium signaling and overload in pancreatic acinar cells. MiR-26a levels are reduced in experimental mouse models and human samples of AP. Mechanistically, miR-26a directly targets and inhibits the calcium channels TRPC3 and TRPC6, thereby restricting pathological calcium elevations and protecting against pancreatitis. miR-26a deficiency in mice worsened pancreatitis, while miR-26a overexpression, globally or in acinar cells, markedly reduced pancreatitis severity. Additionally, administering a miR-26a mimic mitigated cerulein-induced pancreatitis. [ 109 ] This work highlights miR-26a as an intrinsic checkpoint on acinar cell calcium overload. It demonstrates its therapeutic potential to alleviate AP by normalizing pathological calcium signaling, suggesting the need to investigate further other miRNAs that may be involved in calcium signaling or other mechanisms underlying AP development. Heparin and its non-anticoagulant derivatives can protect against SAP in mouse models. The drugs reduced pancreatic necrosis, inflammation, and macrophage infiltration in SAP, independent of anticoagulant function. [ 110 ] Release of high mobility group box 1 (HMGB-1) from pancreas macrophages, which can drive inflammation and multi-organ damage in SAP, is inhibited by this drug class and independent of their anticoagulant function. Reduced HMGB-1 release is associated with reduced intestinal barrier dysfunction and, lung injury and decreased mortality. [ 110 ] With regard to non-heparin anticoagulants, one group found that orally administered dabigatran etexilate (with anticoagulant and trypsin-inhibiting activities) could reduce trypsin activity and had therapeutic efficacy in a cerulein pancreatitis mouse model (T7K24R), but not in a more aggressive AP model. [ 111 ] This work demonstrates that benzamidine derivatives like dabigatran can be potent trypsin inhibitors. However, their efficacy may be limited by the severity of the pathology and drug concentrations in the pancreas. [ 111 ] Clinically, a retrospective study of 190,474 AP patients found that those on anticoagulation therapy before onset had lower risks of ICU admission, acute kidney injury, organ failure, and inpatient mortality, suggesting a therapeutic role in AP. [ 112 ] These results suggest that heparin, non-heparin anticoagulants, and non-anticoagulant heparin derivatives may be future options for AP treatment. Hormonal regulation plays a critical role in the body’s response to various forms of stress, including AP. In this context, hormones like ghrelin, leptin, and melatonin are metabolic regulators and are found to be protective roles in AP. By interacting with immune factors, these hormones may support innate defense mechanisms that reduce the severity of pancreatitis. Ghrelin has been shown to exert a protective effect in AP models by modulating inflammatory pathways. [ 113 , 114 ] Specifically, ghrelin decreases the expression of nuclear factor kappa B (NFκB) and the inflammatory signal transduction pathway, [ 115 ] leading to lower levels of inflammatory cytokines such as IL-1β and tumor necrosis factor-α (TNFα). [ 116 ] Furthermore, ghrelin’s protective influence extends to reducing pancreatitis-associated lung injury and neutrophil sequestration, showcasing its systemic anti-inflammatory potential. [ 116 , 117 ] When given intraperitoneal or intracerebroventricular, leptin, another hormone modulating immune response, can reduce experimental AP severity. [ 116 ] The underlying mechanism involves the engagement of sensory nerves and the neuropeptide calcitonin gene–related peptide (CGRP), essential for leptin’s protective action. [ 118 ] Leptin enhances pancreatic tissue repair and decreases lung injuries, similar to ghrelin. [ 119 ] Its therapeutic effects include the activation of the nitric oxide (NO) system, improvement in pancreatic microcirculation, and the potential release of glucocorticoids that attenuate inflammation. [ 120 , 121 ] Melatonin, commonly known for regulating circadian rhythms, also confers protection against acute pancreatic inflammation. [ 114 , 122 ] Its administration to animal models before inducing pancreatitis results in a marked reduction of inflammation markers, such as edema and leukocyte infiltration. It decreases proinflammatory cytokines while increasing anti-inflammatory IL-10 levels. [ 114 , 123 ] It also diminishes apoptosis and necrosis in pancreatic tissues and improves pancreatic blood flow, which aids in the clearance of inflammatory mediators. [ 113 , 124 , 125 ] These findings support that ghrelin, leptin, and melatonin could be integral components of the natural defense system against pancreatic inflammation. Their increased blood levels during the initial phase of pancreatic inflammation represent a physiological response to suppress or mitigate the inflammatory process within the pancreas, offering a promising avenue for therapeutic intervention in AP. An emerging interest in examining the utility of corticosteroids for severe AP treatment is reflected by a favorable meta-analysis. [ 126 ] The benefits of corticosteroids when used in selective coronavirus disease 2019 (COVID-19) patients may also be a factor. A 5-year prospective clinical trial based on the Beth Israel Deaconess Medical Center on corticosteroid use in severe AP is underway (completion date: 2027; gov ID: NCT05160506 ) in the United States. Recent research has underscored the gut microbiome’s influence on AP using experimental models. [ 127 ] Antibiotic therapy can improve the course of AP in rodents by reducing innate immune system activation. [ 128 , 129 ] However, we are unaware of findings that show similar benefits of antibiotics in clinical AP. A recent study has also shown how microbial imbalances may relate to the severity of necrotizing pancreatitis. In a study comparing the gut bacteria of healthy individuals with AP patients, marked differences were found in microbial diversity and composition. Specifically, patients with necrotizing pancreatitis demonstrated microbial species with altered ketone body and benzoate metabolism. [ 130 ] Enterococcus faecium and Finegoldia magna were identified as potential biomarkers for necrotizing pancreatitis and infected necrotizing pancreatitis, respectively. [ 130 ] These findings suggest that gut microbiota profiles could inform early necrotizing pancreatitis diagnosis and treatment, highlighting the microbiome’s potential as a target for AP management and intervention. However, probiotics’ role in treating AP remains controversial. A meta-analysis of 13 randomized controlled trials with 950 patients reveals that supplementing pre-, pro-, and synbiotics to standard enteral nutrition may reduce hospital stays for severe AP in Chinese cohorts. However, other clinical outcomes showed no significant improvement. [ 131 ] The Probiotics in Pancreatitis Trial (PROPATRIA), a multicenter, randomized, double-blind, placebo-controlled trial of 298 patients with severe AP, demonstrated that enteral probiotic prophylaxis did not decrease infectious complications in patients with severe AP and was linked to significantly increased mortality and gut ischemia in the probiotic arm of the trial. This has caused broad caution about their use in this patient population, though this may change with time and more information. [ 132 – 134 ] Notably, the authors cautioned against considering probiotics universally harmless, especially in critically ill patients. [ 135 ] The contrasting results from the prior studies and debate regarding the results of the PROPATRIA trial advocate for further large-scale, rigorously designed, and controlled studies to confirm the efficacy and safety of probiotic supplementation in AP treatment and whether any specific species of bacteria may have specific benefits in AP patients.

SZ: Project administration; writing - review & editing. FG: Project administration; resources; supervision; writing - review & editing.

Our review did not involve any clinical or animal experiments and was analyzed only using published open-source studies, therefore did not involve the approval of the Institutional Review Board.

FG’s research is supported by a Veterans Administration Senior Clinical Scientist Merit Award ( BX003250 ), a Department of Defense Investigator Initiated Award (PR220457), and the Henry and Joan Binder Endowment.

Our mechanistic knowledge of pancreatitis comes largely from in vivo rodent studies and ex vivo studies in rodent and human pancreatic tissue slices and isolated pancreatic cells. Confirmation of mechanisms described in rodents in human tissues has been limited. In brief, the initiating event most often occurs in the pancreatic acinar cell, where multiple forms of injury can lead to abnormal intracellular calcium signaling. [ 14 ] Though less studied, injury responses also occur in the pancreatic duct and endothelial cells early in the disease and contribute to disease initiation and perpetuation. [ 15 ] Changes in acinar cell calcium signaling can coordinate pathologic responses in mitochondria and autophagic pathways, [ 16 ] activate digestive enzymes within the acinar cell, misdirect secretion, and drive the production of inflammatory mediators. A complex-ordered inflammatory cascade follows in the pancreas, likely beginning with platelets, then neutrophils and inflammatory macrophages. The resolution of AP requires suppressing the acute inflammatory cells and activating an anti-inflammatory cascade. Other factors, such as reduced blood flow, vascular injury, vessel occlusion, tissue hypoxia, and neurogenic inflammation, can modulate the injury’s severity and recovery effectiveness. Less is known about the factors regulating the AP recovery phase than those mediating early phases of injury or how the acute therapies discussed below might affect recovery and long-term AP sequelae. However, in addition to the mechanisms previously described, one key aspect of tissue recovery is the clearance of necrotic debris and revascularization. [ 17 ] This process is mediated by macrophages, which phagocytize necrotic tissue and facilitate recovery. [ 18 ] One group has demonstrated that M1 macrophages dominate during the proinflammatory phase of AP, while M2-like macrophages dominate during pancreas repair and regeneration. Depletion of M2-like macrophages during the recovery phase delayed inflammation resolution. [ 19 ] The precise mechanisms and signaling pathways governing the regenerative processes in the pancreas following AP remain incompletely understood. Furthermore, the long-term consequences of AP, such as the development of new-onset diabetes and pancreatic insufficiency, are areas of growing concern and active research. [ 20 ] In a review of 24 prospective clinical studies involving 1102 patients with a first episode of AP, newly diagnosed diabetes mellitus developed in 15% of individuals within 12 months after the first episode of AP. [ 21 ] One meta-analysis of 1795 patients from 39 studies demonstrated that 35% of patients studied had exocrine pancreatic insufficiency after AP on follow-up after hospital discharge. [ 9 ] It remains unclear how early intervention in AP, particularly strategies aimed at avoiding SIRS, might influence long-term outcomes such as these. This has led to initiatives like the Diabetes RElated to Acute Pancreatitis and its Mechanisms (DREAM) Study, a prospective cohort study designed to investigate and provide the evidence needed to screen for, prevent, and treat DM after AP. [ 22 ] There remains a need for continued research into the immediate management of AP and the long-term monitoring and treatment of patients to mitigate these secondary complications.

Fat cells and their triglyceride content can modulate AP severity. Specifically, hypertriglyceridemia can cause severe pancreatitis. Blood levels of triglycerides directly relate to the risk of developing AP. [ 97 ] Lipases hydrolyze triglycerides to generate free fatty acids, which can vary in their ability to damage the pancreas. Unsaturated fatty acids are particularly harmful and can cause mitochondrial dysfunction, calcium overload, and the generation of inflammatory mediators in pancreatic acinar cells. [ 98 – 100 ] Additionally, hypertriglyceridemia worsens outcomes in AP, regardless of the initial cause. [ 101 ] This effect appears to be increased in obese patients and mice, likely due to lipolysis of intrapancreatic fat. [ 98 ] One group found that during AP, pancreatic triglyceride lipase (PNLIP) leaks into visceral adipose tissue, causing excessive lipolysis independent of adipocyte-autonomous adipose triglyceride lipase, leading to increased non-esterified fatty acids, more severe organ failure, and reduced survival. In contrast, this mechanism does not occur in acute diverticulitis, indicating a specific role of PNLIP-induced lipolysis in the pathogenesis of organ failure during pancreatitis. [ 99 ] These results suggest that treatments that lower triglycerides or inhibit relevant lipases could potentially reduce the severity of AP. Insights into the mechanisms of lipid toxicity are appearing. In human patients and mouse models, increased free unbound fatty acids, especially unsaturated fatty acids like linoleic and oleic acid, can enter and damage immune cells by interacting with cell membrane phospholipids and mitochondrial membranes. This impairs immune cell functions like phagocytosis, reduces bacterial clearance, and increases susceptibility to infections during pancreatitis. [ 102 ] Additionally, some work has suggested lipotoxicity from peri-pancreatic fat necrosis is a key factor in converting mild to severe AP in obesity. [ 103 ] These studies suggest that preventing an increase in unbound fatty acids or promoting their binding to albumin could reduce infections in and severity of AP. Inhibition of lipolysis using the lipase inhibitor orlistat in an obese mouse model of pancreatitis reduced pancreatic necrosis, systemic inflammation, lung and kidney injury, hypocalcemia, and mortality. [ 98 ] These findings suggest that lipotoxicity mediated by UFAs contributes to the severe outcomes in obese patients with pancreatitis and that treatment modalities that reduce lipolysis could reduce AP severity. Pancreatic triacylglycerol lipase and pancreatic lipase-related protein 2 (PNLIPRP2) may be suitable targets for drug development. These 2 proteins are present in fat necrosis in human and experimental pancreatitis and can efficiently hydrolyze triglycerides to toxic unsaturated free fatty acids that cause injury. In cell models, pancreatic triacylglycerol lipase and PNLIPRP2 caused lipotoxic injury. [ 104 ] In mouse models, PNLIP activity increased during AP, generating excess non-esterified fatty acids. [ 99 ] These findings suggest pancreatic triacylglycerol lipase and PNLIPRP2 contribute to local and systemic lipotoxic injury in severe AP. This further supports pancreatic lipase inhibition as a potential therapeutic approach in AP and that pancreatic triacylglycerol lipase and PNLIPRP2 may be suitable drug targets for this strategy. Previous studies have examined the potential effects of dietary factors on AP. Obese individuals who consume more saturated fat have more saturated visceral fat triglycerides that are resistant to hydrolysis by pancreatic lipase. This reduces the generation of free fatty acids that can cause lipotoxic injury. In contrast, in leaner individuals who consume more unsaturated fat, the more unsaturated visceral triglycerides are readily hydrolyzed by lipase. This generates high lipotoxic-free fatty acid levels that worsen inflammation and organ failure. [ 100 ] The findings provide a potential explanation for the “obesity paradox” in AP, where obesity sometimes seems protective. The results suggest dietary fat saturation, not just the amount of body fat, contributes to pancreatitis severity through effects on lipotoxicity. Although the role of triglycerides in AP pathogenesis is well established, the impact of the removal of circulating triglycerides in treating AP remains unclear. In a recent multicenter cohort study of patients with hypertriglyceridemia-associated AP (HTG-AP), plasmapheresis, while effective in lowering plasma triglycerides, was not linked to reduced incidence or duration of AP-associated organ failure but was associated with increased ICU admissions. [ 105 ] Other studies have highlighted the lack of advantages of apheresis compared to insulin infusion. In a study comparing continuous insulin infusion and apheresis in 48 patients, apheresis resulted in a rapid 78.5% reduction in triglyceride levels after the first session. In contrast, insulin infusion led to a 44.4% reduction in the first 24 hours. However, despite the effectiveness of apheresis treatments, they did not offer a distinct advantage over insulin infusion in terms of prognosis and associated complications for HTG-associated pancreatitis. [ 106 ] As such, the optimal treatment for lowering triglyceride levels in patients with HTG-AP is undetermined. There may be negative consequences, such as ICU admissions, associated with apheresis and systemic issues, including the lack of widespread availability of apheresis. Larger clinical trials are currently being conducted to help resolve these questions. The EarLy Elimination of Fatty Acids iN hypertriglyceridemia-induced acuTe pancreatitis (ELEFANT) trial is an open-label, multicenter, adaptive randomized clinical trial that is investigating early elimination of triglycerides and free fatty acids in hypertriglyceridemia-induced AP in a minimum of 495 patients. The ELEFANT trial will randomize patients to plasmapheresis, insulin-heparin treatment, or standard fluid therapy within 48 hours of symptom onset. The primary endpoint is a composite of severe AP or mortality. [ 107 ] The results will provide high-quality evidence on whether early removal of triglycerides and free fatty acids improves outcomes in hypertriglyceridemia-induced pancreatitis. This could establish a new treatment approach targeting the inciting factors in this subset of patients.

AP remains a disease with significant morbidity and mortality despite improvements in supportive care. Pathologic calcium signaling, mitochondrial dysfunction, organelle stress, zymogen activation, lipotoxicity, and uncontrolled inflammation are key mechanisms that drive acinar cell injury and systemic AP complications. This review summarizes promising pharmacologic approaches that target these underlying disease processes, including inhibitors of calcium influx, boosters of calcium efflux, anti-inflammatory therapies, antioxidants, and strategies to lower circulating lipotoxic factors (Table 1 ). Summary of potential therapeutic targets and agents for AP based on current preclinical studies and early clinical trials The table lists general target categories, specific molecular targets or pathways within each category, and examples of pharmacological inhibitors, agonists, or other interventions that have shown potential benefits in experimental models or early human studies of AP. AP = acute pancreatitis, CXCL = chemokine (C-X-C) ligand, HMGB-1 = high mobility group box 1, IP3R = inositol 1,4,5-tris-phosphate receptor, MLKL = mixed lineage kinase domain-like protein, MPTP = mitochondrial permeability transition pore, NLRP3 = PMCA = plasma membrane calcium ATPase, PNLIP = pancreatic triacylglycerol lipase, PNLIPRP2 = pancreatic triacylglycerol lipase and pancreatic lipase-related protein 2, RYR = ryanodine receptor, SARAF = Store-Operated Calcium Entry Associated Regulatory Factor, SOCE = store-operated calcium entry, TNF = tumor necrosis factor, TRPV = transient receptor potential cation channel subfamily V. Early clinical trials demonstrate the safety and potential efficacy of interventions like TNF-α inhibition, reducing calcium entry with Orai1-inhibition, and tacrolimus in reducing the incidence and severity of pancreatitis. Further studies are needed to show definitively improved clinical outcomes. While additional basic research is still required to elucidate mechanisms fully, the translation of novel treatments from preclinical studies to human trials appears to be accelerating. Multifunctional therapies that simultaneously address several pathologic mechanisms may provide the greatest benefit. Further characterization of pathologic pathways and crosstalk between organelles and cell types will aid in developing combinatorial treatments. Improved early diagnosis and risk stratification will enable therapies to be administered quickly and targeted to patients most likely to benefit. With continued progress in understanding disease mechanisms and applying this knowledge to human trials, the management of AP is poised for major advances in the coming years. Ultimately, the goal is to move beyond supportive care toward therapeutic interventions interrupting the underlying disease process and improving short- and long-term patient outcomes.

The authors declare no conflicts of interest.

None.