Mesothelial cells and peritoneal homeostasis
2016; Elsevier BV; Volume: 106; Issue: 5 Linguagem: Inglês
10.1016/j.fertnstert.2016.09.005
ISSN1556-5653
AutoresSteven E. Mutsaers, Cecilia M. Prêle, Steven Pengelly, Sarah E. Herrick,
Tópico(s)Abdominal Surgery and Complications
ResumoThe mesothelium was traditionally thought to be a simple tissue with the sole function of providing a slippery, nonadhesive, and protective surface to allow easy movement of organs within their body cavities. However, our knowledge of mesothelial cell physiology is rapidly expanding, and the mesothelium is now recognized as a dynamic cellular membrane with many other important functions. When injured, mesothelial cells initiate a cascade of processes leading either to complete regeneration of the mesothelium or the development of pathologies such as adhesions. Normal mesothelial healing is unique in that, unlike with other epithelial-like surfaces, healing appears diffusely across the denuded surface, whereas for epithelium healing occurs solely at the wound edges. This is because of a free-floating population of mesothelial cells which attach to the injured serosa. Taking advantage of this phenomenon, intraperitoneal injections of mesothelial cells have been assessed for their ability to prevent adhesion formation. This review discusses some of the functions of mesothelial cells regarding maintenance of serosal integrity and outlines the mechanisms involved in mesothelial healing. In addition, the pathogenesis of adhesion formation is discussed with particular attention to the potential role of mesothelial cells in both preventing and inducing their development. The mesothelium was traditionally thought to be a simple tissue with the sole function of providing a slippery, nonadhesive, and protective surface to allow easy movement of organs within their body cavities. However, our knowledge of mesothelial cell physiology is rapidly expanding, and the mesothelium is now recognized as a dynamic cellular membrane with many other important functions. When injured, mesothelial cells initiate a cascade of processes leading either to complete regeneration of the mesothelium or the development of pathologies such as adhesions. Normal mesothelial healing is unique in that, unlike with other epithelial-like surfaces, healing appears diffusely across the denuded surface, whereas for epithelium healing occurs solely at the wound edges. This is because of a free-floating population of mesothelial cells which attach to the injured serosa. Taking advantage of this phenomenon, intraperitoneal injections of mesothelial cells have been assessed for their ability to prevent adhesion formation. This review discusses some of the functions of mesothelial cells regarding maintenance of serosal integrity and outlines the mechanisms involved in mesothelial healing. In addition, the pathogenesis of adhesion formation is discussed with particular attention to the potential role of mesothelial cells in both preventing and inducing their development. Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/11703-mesothelial-cell-and-peritoneal-homeostasis Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/11703-mesothelial-cell-and-peritoneal-homeostasis Mesothelial cells form a monolayer of cobblestone-like cells that line the peritoneal, pleural, and pericardial cavities and most internal organs. This monolayer is termed the mesothelium and is a barrier and first line of defense against microorganisms and invading tumor cells. Following injury or exposure to foreign organisms or tumor cells, mesothelial cells initiate defense mechanisms, including inflammatory and immune responses. Mesothelial cells also provide a slippery nonadhesive surface to facilitate free movement of internal organs (1Mutsaers S.E. Mesothelial cells: their structure, function and role in serosal repair.Respirology. 2002; 7: 171-191Crossref PubMed Scopus (296) Google Scholar). When the integrity of the mesothelium is lost, a rapid healing response is initiated with complete repair within a few days. If this repair mechanism is impeded in any way, pathologic changes can occur to the serosal membrane, with potentially severe clinical manifestations such as adhesion formation, fibrosis, endometriosis, cancer, and metastases. Embryologically, mesothelial cells are derived from the mesoderm, with cells gradually differentiating from round or cuboidal cells to elongated cells that line the celomic cavities (2Batra H. Antony V.B. The pleural mesothelium in development and disease.Front Physiol. 2014; 5: 284Crossref Scopus (37) Google Scholar). However, they share many properties of epithelial cells, such as apical/basal polarity, basement membrane adherence, junctional complexes, and surface microvilli. Their dual phenotypic characteristics influence the function of these cells, determining how they respond to environmental changes. The present review discusses some of the functions of mesothelial cells, how they regenerate an intact lining after injury, and the role they play in serosal pathologies, particularly the development of adhesions. We also discuss the potential use of mesothelial cells in tissue engineering applications to improve serosal repair and prevent adhesion formation. Mesothelial cells are metabolically active cells that play important roles in maintaining serosal homeostasis. They provide a nonadhesive protective surface through the production of phospholipids and a well developed surface glycocalyx (fuzzy coat on the external surface of their plasma membrane consisting of glycolipids and glycoproteins) to allow movement of organs within the serosal cavities. The mesothelium acts as a semipermeable membrane regulating transport of fluid and cells across the serosa and is in constant contact with serosal fluid containing immunoglobulin, complement, lysozyme, and other proteins that aid microorganism clearance. Mesothelial cells display multiple pattern-recognition receptors, including Toll-like receptors, nucleotide-binding oligomerization domain–like receptors, RIG-I–like receptors, and C-type lectin-like receptors, which recognize carbohydrates and lipopolysaccharides on the surface of microbial pathogens such as bacteria, fungi, and viruses and in response release inflammatory mediators to initiate inflammation and activate immunomodulatory pathways (3Jantz M.A. Antony V.B. Pathophysiology of the pleura.Respiration. 2008; 75: 121-133Crossref PubMed Scopus (93) Google Scholar). 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Mesothelial repair differs from other epithelial-like surfaces because repair occurs diffusely across the injured surface, whereas for epithelium healing occurs solely from the wound edge. Furthermore, the integrity of the mesothelium is restored relatively quickly regardless of wound size. These observations suggest a unique mechanism for healing, where cells not only migrate onto the wound surface from the wound edge but also detach from opposing surfaces and distant sites and settle on the wound surface (Fig. 1). These free-floating mesothelial cells, detected in serosal fluid, subsequently proliferate and scatter to repopulate the injured area (36Foley-Comer A.J. Herrick S.E. Al-Mishlab T. Prele C.M. Laurent G.J. Mutsaers S.E. Evidence for incorporation of free-floating mesothelial cells as a mechanism of serosal healing.J Cell Sci. 2002; 115: 1383-1389PubMed Google Scholar). Mesothelial cells are known to change phenotype in a process similar to epithelial-to-mesenchymal transition but termed mesothelial-mesenchymal transition (MMT) (37Li Y. Wang J. Asahina K. Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial-mesenchymal transition in liver injury.Proc Natl Acad Sci U S A. 2013; 110: 2324-2329Crossref PubMed Scopus (139) Google Scholar). TGF-β1, a key mediator of this process, induces the expression of the transcription factor SNAI1, with a dramatic down-regulation of epithelial markers, E-cadherin, and cytokeratins (38Yanez-Mo M. Lara-Pezzi E. Selgas R. Ramirez-Huesca M. Dominguez-Jimenez C. Jimenez-Heffernan J.A. et al.Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells.N Engl J Med. 2003; 348: 403-413Crossref PubMed Scopus (619) Google Scholar), resulting in a fibroblast-like and more motile phenotype. Mesothelial cells undergo MMT during continuous ambulatory peritoneal dialysis and up-regulate smooth muscle actin and type I collagen expression, which is consistent with a myofibroblast phenotype (38Yanez-Mo M. Lara-Pezzi E. Selgas R. Ramirez-Huesca M. Dominguez-Jimenez C. Jimenez-Heffernan J.A. et al.Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells.N Engl J Med. 2003; 348: 403-413Crossref PubMed Scopus (619) Google Scholar, 39Yang A.H. Chen J.Y. Lin J.K. Myofibroblastic conversion of mesothelial cells.Kidney Int. 2003; 63: 1530-1539Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). This suggests a fibrogenic role for mesothelial cells in conditions such as serosal fibrosis and adhesion formation. There is also emerging evidence to support a blood-borne precursor, possibly originating from the bone marrow, that is released into the serosal fluid and subsequently attaches onto the denuded wound surface (40Chen K.S. Wang C.H. Yen T.H. Chen J.R. Hung M.J. Lin C.Y. Potential role of bone marrow-derived cells in the turnover of mesothelium.Ren Fail. 2010; 32: 1081-1087Crossref Scopus (3) Google Scholar). The concept of a free-floating mesothelial cell has led researchers to investigate the potential of mesothelial cell transplantation to help in healing injured serosa, particularly for prevention of intra-abdominal adhesions, e.g., after surgery. Intra-abdominal adhesions are pathologic scars formed between intra-abdominal organs. Some are congenital, but they are more commonly formed in response to trauma. Adhesions can occur without surgery, for example, in the presence of intraperitoneal inflammation, such as appendicitis. The increased adhesiveness of the inflamed area causes peritoneal surfaces to adhere to each other. Although these adhesions can be helpful initially by, e.g., containing contamination should the appendix perforate, they can cause problems if the scarring limits the free movement of intestinal contents through the lumen, leading to bowel obstruction and eventually ischemia and necrosis (41Hill J. Williams N.S. Bulstrode C.J.K. O'Connell P.R. Bailey and Love’s short practice of surgery. 26th ed. CRC Press, Boca Raton, FL2013Google Scholar). Adhesions can also be induced mechanically, for example, after surgical trauma. Some gynecologic operations, such as myomectomy, endometriosis surgery, and ovarian and tubal surgery, are high-risk procedures concerning adhesion development (42de Wilde R.L. Bakkum E.A. Brolmann H. Crowe A. Koninckx P. 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The role of fibrinolysis in adhesion formation.Eur J Surg Suppl. 1997; : 24-31PubMed Google Scholar). Trauma also induces release of cytokines and chemokines such as TNF-α, IL-6, and IL-8, within the peritoneal cavity (48Badia J.M. Whawell S.A. Scott-Coombes D.M. Abel P.D. Williamson R.C. Thompson J.N. Peritoneal and systemic cytokine response to laparotomy.Br J Surg. 1996; 83: 347-348Crossref PubMed Scopus (85) Google Scholar). These are chemotactic for neutrophils and activate mesothelial cells and macrophages, leading to secretion of vasodilatory factors that in turn lead to the leakage of more fibrin (45Pados G. Venetis C.A. Almaloglou K. Tarlatzis B.C. Prevention of intra-peritoneal adhesions in gynaecological surgery: theory and evidence.Reprod Biomed Online. 2010; 21: 290-303Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). The fibrinous exudate allows adjacent surfaces to adhere to each other and, if the fibrin is not cleared, provides a scaffold for infiltration of endothelial cells and fibroblasts (49Hellebrekers B.W. Trimbos-Kemper T.C. Trimbos J.B. Emeis J.J. Kooistra T. Use of fibrinolytic agents in the prevention of postoperative adhesion formation.Fertil Steril. 2000; 74: 203-212Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 50Milligan D.W. Raftery A.T. Observations on the pathogenesis of peritoneal adhesions: a light and electron microscopical study.Br J Surg. 1974; 61: 274-280Crossref PubMed Scopus (160) Google Scholar). The fibrin mesh then begins to be replaced by ECM, increasing the tensile strength of the adhesion. Thus, adhesion formation is controlled by the balance of fibrin deposition and degradation. Excessive deposition and delayed clearance of fibrin is thought to be due to a compromised fibrinolytic system (Fig. 1) (47Holmdahl L. The role of fibrinolysis in adhesion formation.Eur J Surg Suppl. 1997; : 24-31PubMed Google Scholar). During normal repair, fibrin is lysed principally through the action of plasmin. Plasmin is stored as an inactive substrate plasminogen which is converted to its active form by tPA and urokinase PA. In contrast, fibrinolysis is inhibited by specific fast-acting serine protease inhibitors PAI-1, PAI-2, and α-2 antiplasmin, which are induced by stimuli such as endotoxin, trauma, or infection (47Holmdahl L. The role of fibrinolysis in adhesion formation.Eur J Surg Suppl. 1997; : 24-31PubMed Google Scholar). Exudative pleural effusions are characterized by shed mesothelial cells (51Strange C. Tomlinson J.R. Wilson C. Harley R. Miller K.S. Sahn S.A. 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Reduced fibrinolytic activity correlates with increased adhesion formation (47Holmdahl L. The role of fibrinolysis in adhesion formation.Eur J Surg Suppl. 1997; : 24-31PubMed Google Scholar) suggesting that it is an important early biochemical event in the pathogenesis of adhesions in humans. We have shown that tPA-deficient mice had increased numbers of peritoneal adhesions after injury compared with wild-type control mice (54Sulaiman H. Dawson L. Laurent G.J. Bellingan G.J. Herrick S.E. Role of plasminogen activators in peritoneal adhesion formation.Biochem Soc Trans. 2002; 30: 126-131Crossref PubMed Google Scholar), confirming that reduced PA activity is important for adhesion formation. Mesothelial cells are the main source of PA and PAI in serosal tissues and regulate the fine balance between fibrin deposition and breakdown. If mesothelial repair is impaired or delayed, this balance is lost and adhesions form (Fig. 2). It is clear that adhesion prevention requires reestablishing an intact mesothelial monolayer as quickly as possible. Peritoneal injury is reduced by good surgical technique and avoiding unnecessary trauma, tissue drying and hypoxia, and foreign bodies. Laparoscopy generally results in fewer adhesions than laparotomy but does not eliminate them entirely (55Pismensky S.V. Kalzhanov Z.R. Eliseeva M.Y. Kosmas I.P. Mynbaev O.A. Severe inflammatory reaction induced by peritoneal trauma is the key driving mechanism of postoperative adhesion formation.BMC Surg. 2011; 11: 30Crossref Scopus (41) Google Scholar). Attempts have been made to limit peritoneal adhesion formation by removing deposited fibrin by means of administration of tPA, but the effectiveness of this approach is limited (49Hellebrekers B.W. Trimbos-Kemper T.C. Trimbos J.B. Emeis J.J. Kooistra T. 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