TGF-β System: The Principal Profibrotic Mediator of Peritoneal Adhesion Formation

Whether induced by infection, inflammation, ischemia, and/or surgical injury, peritoneal adhesions are the leading cause of pelvic pain, bowel obstruction, and infertility. Although some patients develop limited scar tissues, others for unknown reasons develop severe adhesions from seemingly equal procedures. Additionally in the same patient, adhesions develop at one surgical site but not in another. The mechanisms underlying the predisposition to form scars as well as their site specificity are unknown. Because a large number of intraperitoneal surgical procedures are performed each day, many patients are at risk of developing postoperative adhesions. As such, understanding the nature of molecular events and their mechanisms of action is essential, and in the absence of such information, attempts to prevent patients from developing adhesions will remain an empirical process. An unprecedented advancement in surgical techniques have resulted in minimizing peritoneal tissue injury that cause adhesion formation. Increased understanding of the cellular and molecular events that lead to scar tissue formation has also led to the identification of many biologically active molecules with the potential of regulating inflammatory and immune responses, angiogenesis, and tissue remodeling, events that are central to normal peritoneal wound healing and adhesion formation. This article attempts to highlight some of the key molecules (i.e., the transforming growth factor family and its regulatory mechanisms) that are recognized to regulate peritoneal wound repair and adhesion formation. Such understanding of peritoneal biology not only will assist us to better manage patients with adhesions but also will assist those with endometriosis and malignant diseases that affect the peritoneal cavity.

Peritoneum - wound repair - adhesions - growth factors - cytokines - chemokines - proteases - clinical - molecular

- 1 Diamond M P, Schwartz L B. Prevention of Adhesion Development . In: Sutton C, Diamond MP Endoscopic Surgery for Gynecologists, 2nd ed. London, United Kingdom; W.B. Saunders 1994: 398-406 - 2 Lower A M, Hawthorn R J, Ellis H, O'Brien F, Buchan S, Crowe A M. The impact of adhesions on hospital readmissions over ten years after 8849 open gynaecological operations: an assessment from the Surgical and Clinical Adhesions Research Study. BJOG. 2000; 107 855-862 - 3 Lower A M, Hawthorn R J, Clark D Surgical and Clinical Research (SCAR) Group et al.. Adhesion-related readmissions following gynaecological laparoscopy or laparotomy in Scotland: an epidemiological study of 24 046 patients. Hum Reprod. 2004; 19 1877-1885 - 4 Diamond M P, Freeman M L. Clinical implications of postsurgical adhesions. Hum Reprod Update. 2001; 7 567-576 - 5 Practice Committee of the American Society for Reproductive Medicine . Control and prevention of peritoneal adhesions in gynecologic surgery. Fertil Steril. 2006; 86(Suppl 5) S1-S5 - 6 Zeng Q, Yu Z, You J, Zhang Q. Efficacy and safety of Seprafilm for preventing postoperative abdominal adhesion: systematic review and meta-analysis. World J Surg. 2007; 31 2125-2131 - 7 Al-Jaroudi D, Tulandi T. Adhesion prevention in gynecologic surgery. Obstet Gynecol Surv. 2004; 59 360-370 - 8 Johns A. Evidence-based prevention of post-operative adhesions. Hum Reprod Update. 2001; 7 577-579 - 9 Chegini N. Peritoneal molecular environment, adhesion formation and clinical implication. Front Biosci. 2002; 7 e91-e115 - 10 Menke N B, Ward K R, Witten T M, Bonchev D G, Diegelmann R F. Impaired wound healing. Clin Dermatol. 2007; 25 19-25 - 11 Rivera A E, Spencer J M. Clinical aspects of full-thickness wound healing. Clin Dermatol. 2007; 25 39-48 - 12 Clark R FA. Wound repair. Overview and general consideration . In: Clark RAF The Molecular Biology of Wound Repair, 2nd ed. New York, NY; Plenum Press 1996: 3-50 - 13 Holmdahl L, Ivarsson L M. The role of cytokines, coagulation and fibrinolysis in peritoneal tissue repair. Eur J Surg. 1999; 165 1012-1019 - 14 Muller S A, Treutner K H, Tietze L et al.. Efficacy of adhesion prevention and impact on wound healing of intraperitoneal phospholipids. J Surg Res. 2001; 96 68-74 - 15 Furie B, Furie B C. Thrombus formation in vivo. J Clin Invest. 2005; 115 3355-3362 - 16 Gaffney P J. Fibrin degradation products. A review of structures found in vitro and in vivo. Ann N Y Acad Sci. 2001; 936 594-610 - 17 Lijnen H R. Elements of the fibrinolytic system. Ann N Y Acad Sci. 2001; 936 226-236 - 18 Herrick S, Blanc-Brude O, Gray A, Laurent G. Fibrinogen. Int J Biochem Cell Biol. 1999; 31 741-746 - 19 Bennett J S. Platelet-fibrinogen interactions. Ann N Y Acad Sci. 2001; 936 340-354 - 20 Clemetson K J, Clemetson J M. Platelet collagen receptors. Thromb Haemost. 2001; 86 189-197 - 21 Holly S P, Larson M K, Parise L V. Multiple roles of integrins in cell motility. Exp Cell Res. 2000; 261 69-74 - 22 Blobe G C, Schiemann W P, Lodish H F. Role of transforming growth factor beta in human disease. N Engl J Med. 2000; 342 1350-1358 - 23 Heldin C H. Development and possible clinical use of antagonists for PDGF and TGF-b. Ups J Med Sci. 2004; 109 165-178 - 24 Wynn T A. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007; 117 524-529 - 25 Li J, Chen J, Kirsner R. Pathophysiology of acute wound healing. Clin Dermatol. 2007; 25 9-18 - 26 Raja , Sivamani K, Garcia M S, Isseroff R R. Wound re-epithelialization: modulating keratinocyte migration in wound healing. Front Biosci. 2007; 12 2849-2868 - 27 Fitzpatrick F A, Soberman R. Regulated formation of eicosanoids. J Clin Invest. 2001; 107 1347-1351 - 28 Massague J, Gomis R R. The logic of TGF-beta signaling. FEBS Lett. 2006; 580 2811-2820 - 29 Feng X H, Derynck R. Specificity and versatility in TGF-b signaling through Smads. Annu Rev Cell Dev Biol. 2005; 21 659-693 - 30 ten Dijke P, Arthur H M. Extracellular control of TGF-b signalling in vascular development and disease. Nat Rev Mol Cell Biol. 2007; 8 857-869 - 31 Rifkin D B. Latent transforming growth factor-b (TGF-b) binding proteins: orchestrators of TGF-b availability. J Biol Chem. 2005; 280 7409-7412 - 32 Todorovic V, Jurukovski V, Chen Y, Fontana L, Dabovic B, Rifkin D B. Latent TGF-beta binding proteins. Int J Biochem Cell Biol. 2005; 37 38-41 - 33 Sterner-Kock A, Thorey I S, Koli K et al.. Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer. Genes Dev. 2002; 16 2264-2273 - 34 Chaudhry S S, Cain S A, Morgan A, Dallas S L, Shuttleworth C A, Kielty C M. Fibrillin-1 regulates the bioavailability of TGF-beta1. J Cell Biol. 2007; 176 355-367 - 35 Sheppard D. Integrin-mediated activation of latent transforming growth factor. Cancer Metastasis Rev. 2005; 24 395-402 - 36 Yang Z, Mu Z, Dabovic B et al.. Absence of integrin-mediated TGFbeta1 activation in vivo recapitulates the phenotype of TGFbeta1-null mice. J Cell Biol. 2007; 176 787-793 - 37 Sheppard D. Integrin-mediated activation of transforming growth factor-beta(1) in pulmonary fibrosis. Chest. 2001; 120 49S-53S - 38 Sime P J, O'Reilly K M. Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment. Clin Immunol. 2001; 99 308-319 - 39 Murphy-Ullrich J E, Poczatek M. Activation of latent TGF-b by thrombospondin-1: mechanisms and physiology. Cytokine Growth Factor Rev. 2000; 11 59-69 - 40 Hyytiainen M, Penttinen C, Keski-Oja J. Latent TGF-beta binding proteins: extracellular matrix association and roles in TGF-beta activation. Crit Rev Clin Lab Sci. 2004; 41 233-264 - 41 Barbara N P, Wrana J L, Letarte M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-b superfamily. J Biol Chem. 1999; 274 584-594 - 42 Yu L, Border W A, Huang Y, Noble N A. TGF-beta isoforms in renal fibrogenesis. Kidney Int. 2003; 64 844-856 - 43 Branton M H, Kopp J B. TGF-b and fibrosis. Microbes Infect. 1999; 1 1349-1365 - 44 Koch R M, Roche N S, Parks W T, Ashcroft G S, Letterio J J, Roberts A B. Incisional wound healing in transforming growth factor-b1 null mice. Wound Repair Regen. 2000; 8 179-191 - 45 Crowe M J, Doetschman T, Greenhalgh D G. Delayed wound healing in immunodeficient TGF-b1 knockout mice. J Invest Dermatol. 2000; 115 3-11 - 46 Tyrone J W, Marcus J R, Bonomo S R, Mogford J E, Xia Y, Mustoe T A. Transforming growth factor b3 promotes fascial wound healing in a new animal model. Arch Surg. 2000; 135 1154-1159 - 47 Ask K, Bonniaud P, Maass K, Eickelberg O, Margetts P J, Warburton D, Groffen J, Gauldie J, Kolb M. Progressive pulmonary fibrosis is mediated by TGF-beta isoform 1 but not TGF-beta3. Int J Biochem Cell Biol. 2008; 40 484-495 - 48 Freeman M L, Saed G M, Elhammady E F, Diamond M P. Expression of transforming growth factor beta isoform mRNA in injured peritoneum that healed with adhesions and without adhesions and in uninjured peritoneum. Fertil Steril. 2003; 80 708-713 - 49 Chegini N, Kotseos K, Zhao Y et al.. Differential expression of TGF-β1 and TGF-β3 in serosal tissues of human intraperitoneal organs and peritoneal adhesions. Hum Reprod. 2001; 6 1291-1300 - 50 Hobson K G, DeWing M, Ho H S, Wolfe B M, Cho K, Greenhalgh D G. Expression of transforming growth factor beta1 in patients with and without previous abdominal surgery. Arch Surg. 2003; 138 1249-1252 - 51 Chegini N, Rong H, Bennett B, Stone I K. Peritoneal fluid cytokine and eicosanoid levels and their relation to the incidence of peritoneal adhesion. J Soc Gynecol Investig. 1999; 6 153-157 - 52 Holmdahl L, Kotseos K, Bergström M, Falk P, Ivarsson M L, Chegini N. Overproduction of transforming growth factor-beta1 (TGF-b1) is associated with adhesion formation and peritoneal fibrinolytic impairment. Surgery. 2001; 129 626-632 - 53 Krause T J, Katz D, Wheeler C J, Ebner S, McKinnon R D. Increased levels of surgical adhesions in TGFb1 heterozygous mice. J Invest Surg. 1999; 12 31-38 - 54 Bonniaud P, Margetts P J, Ask K, Flanders K, Gauldie J, Kolb M. TGF-beta and Smad3 signaling link inflammation to chronic fibrogenesis. J Immunol. 2005; 175 5390-5395 - 55 Flanders K C. Smad3 as a mediator of the fibrotic response. Int J Exp Pathol. 2004; 85 47-64 - 56 Dooley S, Hamzavi J, Breitkopf K et al.. Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology. 2003; 125 178-191 - 57 Hou C C, Wang W, Huang X R et al.. Ultrasound-microbubble-mediated gene transfer of inducible Smad7 blocks transforming growth factor-beta signaling and fibrosis in rat remnant kidney. Am J Pathol. 2005; 166 761-771 - 58 Kopp J, Preis E, Said H et al.. Abrogation of transforming growth factor-beta signaling by SMAD7 inhibits collagen gel contraction of human dermal fibroblasts. J Biol Chem. 2005; 280 21570-21576 - 59 Guo H, Leung J C, Lam M F et al.. Smad7 transgene attenuates peritoneal fibrosis in uremic rats treated with peritoneal dialysis. J Am Soc Nephrol. 2007; 18 2689-2703 - 60 Wahab N A, Schaefer L, Weston B S et al.. Glomerular expression of thrombospondin-1, transforming growth factor beta and connective tissue growth factor at different stages of diabetic nephropathy and their interdependent roles in mesangial response to diabetic stimuli. Diabetologia. 2005; 48 2650-2660 - 61 Daniel C, Takabatake Y, Mizui M et al.. Antisense oligonucleotides against thrombospondin-1 inhibit activation of TGF-beta in fibrotic renal disease in the rat in vivo. Am J Pathol. 2003; 163 1185-1192 - 62 Streit M, Velasco P, Riccardi L et al.. Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice. EMBO J. 2000; 19 3272-3282 - 63 Kondou H, Mushiake S, Etani Y, Miyoshi Y, Michigami T, Ozono K. A blocking peptide for transforming growth factor-beta1 activation prevents hepatic fibrosis in vivo. J Hepatol. 2003; 39 742-748 - 64 Akhurst R J. Large- and small-molecule inhibitors of transforming growth factor-beta signaling. Curr Opin Investig Drugs. 2006; 7 513-521 - 65 Suzuki E, Kim S, Cheung H K et al.. A novel small-molecule inhibitor of transforming growth factor beta type I receptor kinase (SM16) inhibits murine mesothelioma tumor growth in vivo and prevents tumor recurrence after surgical resection. Cancer Res. 2007; 67 2351-2359 - 66 Moon J A, Kim H T, Cho I S, Sheen Y Y, Kim D K. IN-1130, a novel transforming growth factor-beta type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy. Kidney Int. 2006; 70 1234-1243 - 67 Tojo M, Hamashima Y, Hanyu A et al.. The ALK-5 inhibitor A-83–01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta. Cancer Sci. 2005; 96 791-800 - 68 DaCosta Byfield S, Major C, Laping N J, Roberts A B. SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol. 2004; 65 744-752 - 69 Kapoun A M, Gaspar N J, Wang Y et al. Transforming growth factor-beta receptor type 1 (TGFbetaRI) kinase activity but not p38 activation is required for TGFbetaRI-induced myofibroblasts differentiation and profibrotic gene expression. Mol Pharmacol. 2006; 70 518-531 - 70 Weng H L, Ciuclan L, Liu Y et al.. Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes. Hepatology. 2007; 46 1257-1270 - 71 Hui A Y, Dannenberg A J, Sung J J et al.. Prostaglandin E2 inhibits transforming growth factor beta 1-mediated induction of collagen alpha 1(I) in hepatic stellate cells. J Hepatol. 2004; 41 251-258 - 72 Peng H, Cheung A K, Reimer L G, Kamerath C D, Leypoldt J K. Effect of indomethacin on peritoneal protein loss in a rabbit model of peritonitis. Kidney Int. 2001; 59 44-51 - 73 Tager A M, Dufour J H, Goodarzi K, Bercury S D, von Andrian U H, Luster A D. BLTR mediates leukotriene B(4)-induced chemotaxis and adhesion and plays a dominant role in eosinophil accumulation in a murine model of peritonitis. J Exp Med. 2000; 192 439-446 - 74 Haribabu B, Verghese M W, Steeber D A, Sellars D D, Bock C B, Snyderman R. Targeted disruption of the leukotriene B(4) receptor in mice reveals its role in inflammation and platelet-activating factor-induced anaphylaxis. J Exp Med. 2000; 192 433-438 - 75 Saed G M, Al-Hendy A, Salama S A, Diamond M P. Adenovirus-mediated expression of cyclooxygenase-2 antisense reverse abnormal genetic profile of human adhesion fibroblasts. Fertil Steril. 2008; 89(5 Suppl) 1455-1460 - 76 Mehrad B, Keane M P, Strieter R M. Chemokines as mediators of angiogenesis. Thromb Haemost. 2007; 97 755-762 - 77 Frangogiannis N G. Chemokines in ischemia and reperfusion. Thromb Haemost. 2007; 97 738-747 - 78 Braunersreuther V, Mach F, Steffens S. The specific role of chemokines in atherosclerosis. Thromb Haemost. 2007; 97 714-721 - 79 Ludwig A, Weber C. Transmembrane chemokines: versatile ‘special agents’ in vascular inflammation. Thromb Haemost. 2007; 97 694-703 - 80 Gerard C, Rollins B J. Chemokines and disease. Nat Immunol. 2001; 2 108-115 - 81 Horuk R. Chemokine receptors. Cytokine Growth Factor Rev. 2001; 12 313-335 - 82 Hoshino A, Kawamura Y I, Yasuhara M et al.. Inhibition of CCL1–CCR8 interaction prevents aggregation of macrophages and development of peritoneal adhesions. J Immunol. 2007; 178 5296-5304 - 83 Berkkanoglu M, Zhang L, Ulukus M et al.. Inhibition of chemokines prevents intraperitoneal adhesions in mice. Hum Reprod. 2005; 20 3047-3052 - 84 El-Hakim A, Chiu K Y, Sherry B, Bhuiya T, Smith A D, Lee B R. Peritoneal and systemic inflammatory mediators of laparoscopic bowel injury in a rabbit model. J Urol. 2004; 172 1515-1519 - 85 Motomura Y, Kanbayashi H, Khan W I et al.. The gene transfer of soluble VEGF type I receptor (Flt-1) attenuates peritoneal fibrosis formation in mice but not soluble TGF-beta type II receptor gene transfer. Am J Physiol Gastrointest Liver Physiol. 2005; 288 G143-G150 - 86 Holsti M A, Chitnis T, Panzo R J et al.. Regulation of postsurgical fibrosis by the programmed death-1 inhibitory pathway. J Immunol. 2004; 172 5774-5781 - 87 Gao Y, Luo L, He F. Effect of monocyte chemotactic protein-1 on the intraperitoneal adhesion formation. J Tongji Med Univ. 2000; 20 340-342 - 88 Larbi K Y, Dangerfield J P, Culley F J et al.. P-selectin mediates IL-13-induced eosinophil transmigration but not eotaxin generation in vivo: a comparative study with IL-4-elicited responses. J Leukoc Biol. 2003; 73 65-73 - 89 Matsukawa A, Hogaboam C M, Lukacs N W, Lincoln P M, Strieter R M, Kunkel S L. Endogenous monocyte chemoattractant protein-1 (MCP-1) protects mice in a model of acute septic peritonitis: cross-talk between MCP-1 and leukotriene B4. J Immunol. 1999; 163 6148-6154 - 90 Mrstik M, Kotseos K, Ma C, Chegini N. Increased expression of interferon-inducible protein-10 during surgically induced peritoneal injury. Wound Repair Regen. 2003; 11 120-126 - 91 Fine J S, Jackson J V, Rojas-Triana A, Bober L A. Evaluation of chemokine- and phlogistin-mediated leukocyte chemotaxis using an in vivo sponge model. Inflammation. 2000; 24 331-346 - 92 Call D R, Nemzek J A, Ebong S J et al.. Differential local and systemic regulation of the murine chemokines KC and MIP2. Shock. 2001; 15 278-284 - 93 Kopydlowski K M, Salkowski C A, Cody M J et al.. Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo. J Immunol. 1999; 163 1537-1544 - 94 Gautam S C, Noth C J, Janakiraman N, Pindolia K R, Chapman R A. Induction of chemokine mRNA in bone marrow stromal cells: modulation by TGF-b1 and IL-4. Exp Hematol. 1995; 23 482-491 - 95 Sakata Y, Chancey A L, Divakaran V G, Sekiguchi K, Sivasubramanian N, Mann D L. Transforming growth factor-beta receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor. Basic Res Cardiol. 2008 Jan; 103 60-68 - 96 Nakaya I, Wada T, Furuichi K et al.. Blockade of IP-10/CXCR3 promotes progressive renal fibrosis. Nephron Exp Nephrol. 2007; 107 e12-e21 - 97 Kampfer H, Paulukat J, Muhl H, Wetzler C, Pfeilschifter J, Frank S. Lack of interferon-gamma production despite the presence of interleukin-18 during cutaneous wound healing. Mol Med. 2000; 6 1016-1027 - 98 Witowski J, Thiel A, Dechend R et al.. Synthesis of C–X-C and C–C chemokines by human peritoneal fibroblasts: induction by macrophage-derived cytokines. Am J Pathol. 2001; 158 1441-1450 - 99 Visser C E, Tekstra J, Brouwer-Steenbergen J J et al.. Chemokines produced by mesothelial cells: huGRO-α, IP-10, MCP-1 and RANTES. Clin Exp Immunol. 1998; 112 270-275 - 100 McColl S R, Clark-Lewis I. Inhibition of murine neutrophil recruitment in vivo by CXC chemokine receptor antagonists. J Immunol. 1999; 163 2829-2835 - 101 Haslinger B, Mandl-Weber S, Sellmayer A, Sitter T. Hyaluronan fragments induce the synthesis of MCP-1 and IL-8 in cultured human peritoneal mesothelial cells. Cell Tissue Res. 2001; 305 79-86 - 102 Zeyneloglu H B, Seli E, Senturk L M, Gutierrez L S, Olive D L, Arici A. The effect of monocyte chemotactic protein 1 in intraperitoneal adhesion formation in a mouse model. Am J Obstet Gynecol. 1998; 179 438-443 - 103 Rachfal A W, Brigstock D R. Structural and functional properties of CCN proteins. Vitam Horm. 2005; 70 69-103 - 104 Ihn H. Pathogenesis of fibrosis: role of TGF-b and CTGF. Curr Opin Rheumatol. 2002; 14 681-685 - 105 Leask A, Abraham D J. The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology. Biochem Cell Biol. 2003; 81 355-363 - 106 Perbal B. CCN proteins: multifunctional signalling regulators. Lancet. 2004; 363 62-64 - 107 Kelly M, Kolb M, Bonniaud P, Gauldie J. Re-evaluation of fibrogenic cytokines in lung fibrosis. Curr Pharm Des. 2003; 9 39-49 - 108 Gressner O A, Weiskirchen R, Gressner A M. Biomarkers of hepatic fibrosis, fibrogenesis and genetic pre-disposition pending between fiction and reality. J Cell Mol Med. 2007; 11 1031-1051 - 109 Gressner O A, Lahme B, Demirci I, Gressner A M, Weiskirchen R. Differential effects of TGF-beta on connective tissue growth factor (CTGF/CCN2) expression in hepatic stellate cells and hepatocytes. J Hepatol. 2007; 47 699-710 - 110 Luo X, Ding L, Chegini N. CCNs, fibulin-1C and S100A4 expression in leiomyoma and myometrium: inverse association with TGF-beta and regulation by TGF-beta in leiomyoma and myometrial smooth muscle cells. Mol Hum Reprod. 2006; 12 245-256 - 111 Page-McCaw A, Ewald A J, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007; 8 221-233 - 112 Hobeika M J, Thompson R W, Muhs B E, Brooks P C, Gagne P J. Matrix metalloproteinases in peripheral vascular disease. J Vasc Surg. 2007; 45 849-857 - 113 Hemmann S, Graf J, Roderfeld M, Roeb E. Expression of MMPs and TIMPs in liver fibrosis—a systematic review with special emphasis on anti-fibrotic strategies. J Hepatol. 2007; 46 955-975 - 114 Vartak D G, Gemeinhart R A. Matrix metalloproteases: underutilized targets for drug delivery. J Drug Target. 2007; 15 1-20 - 115 Yan C, Boyd D D. Regulation of matrix metalloproteinase gene expression. J Cell Physiol. 2007; 211 19-26 - 116 Medcalf R L. Fibrinolysis, inflammation, and regulation of the plasminogen activating system. J Thromb Haemost. 2007; 5(Suppl 1) 132-142 - 117 Paraskevas K I, Baker D M, Vrentzos G E, Mikhailidis D P. The role of fibrinogen and fibrinolysis in peripheral arterial disease. Thromb Res. 2008; 122 1-12 - 118 Schouten M, Wiersinga W J, Levi M, van der Poll T. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol. 2008; 83 536-545 - 119 Balsara R D, Xu Z, Ploplis V A. Targeting plasminogen activator inhibitor-1: role in cell signaling and the biology of domain-specific knock-in mice. Curr Drug Targets. 2007; 8 982-995 - 120 Bertolino P, Deckers M, Lebrin F, ten Dijke P. Transforming growth factor-beta signal transduction in angiogenesis and vascular disorders. Chest. 2005; 128 585S-590S - 121 Saed G, Zhang W, Wie K A, Yelian F D, Diamond M P. The effect of TGF-β and hypoxia on fibronectin expression. Reproductive Sciences. 2000; 7 348-354 - 122 Ma C, Tarnuzzer R W, Chegini N. Expression of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases in mesothelial cells and their regulation by transforming growth factor-beta1. Wound Repair Regen. 1999; 7 477-485 - 123 Chegini N, Kotseos K, Zhao Y et al.. The expression of matrix metalloproteinase (MMP-1) and tissue inhibitor of MMP (TIMP-1) in serosal tissue of intraperitoneal organs and adhesions. Fertil Steril. 2001; 76 1212-1219 - 124 Chegini N, Kotsesos K, Bennett B et al.. Matrix metalloproteinase (MMP-1) and tissue inhibitor of MMP (TIMP-1) in peritoneal fluids and sera, and correlation with peritoneal adhesions. Fertil Steril. 2001; 76 1207-1211 - 125 Sharpe-Timms K L, Zimmer R L, Jolliff W J, Wright J W, Nothnick W B, Curry T E. Gonadotropin-releasing hormone agonist (GnRH-a) therapy alters activity of plasminogen activators, matrix metalloproteinases, and their inhibitors in rat models for adhesion formation and endometriosis: potential GnRH-a-regulated mechanisms reducing adhesion formation. Fertil Steril. 1998; 69 916-923 - 126 Agren M S, Werthén M. The extracellular matrix in wound healing: a closer look at therapeutics for chronic wounds. Int J Low Extrem Wounds. 2007; 6 82-97 - 127 Diamond M P, El-Hammady E, Wang R, Saed G. Regulation of matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1 by dichloroacetic acid in human fibroblasts from normal peritoneum and adhesions. Fertil Steril. 2004; 81 185-190 Nasser CheginiPh.D. Division of Reproductive Endocrinology and Infertility, Institute for Wound Research, Department of Obstetrics and Gynecology University of Florida, Gainesville, FL 32610 Email: [email protected]