1 Department of Obstetrics and Gynaecology and 2 Centre for Surgical Technologies, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. e-mail: MariaMercedes.Binda{at}uz.kuleuven.ac.be
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Abstract |
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Key words: adhesion formation/antioxidants/free radical scavengers/pneumoperitoneum/reactive oxygen species
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Introduction |
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Pathophysiology of intraperitoneal adhesions |
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The fibrinous exudate and fibrin deposition is an essential part of normal tissue repair, but its complete resolution is required for normal healing. The degradation of fibrin is regulated by the plasminogen system. The inactive proenzyme plasminogen is converted into plasmin by tissue-type plasminogen activator (tPA) and/or urokinase-type plasminogen activator (uPA), which are inhibited by the plasminogen activator inhibitors 1 (PAI-1) and 2 (PAI-2). Plasmin is a serine protease which degrades fibrin into fibrin degradation products. Plasmin has, in addition, a role in other stages of tissue repair, e.g. extracellular matrix (ECM) degradation, activation of proenzymes of the matrix metalloprotease (MMP) family, and activation of growth factors. Plasmin can be directly inhibited by plasmin inhibitors, i.e. 2-macroglobulin,
2-antiplasmin and
1-antitrypsin, but their role in peritoneal fibrinolysis is not well defined (Holmdahl, 2000
).
The balance between fibrin deposition and degradation is critical in determining normal peritoneal healing or adhesion formation. If fibrin is completely degraded, normal peritoneal healing will occur. In contrast, if fibrin is not completely degraded, it will serve as a scaffold for fibroblasts and capillary ingrowth. Fibroblasts will invade the fibrin matrix and ECM will be produced and deposited. This ECM is normally completely degraded by MMPs, leading to normal healing. If this process is inhibited by tissue inhibitors of MMPs (TIMPs), peritoneal adhesions will be formed. In addition to fibroblast invasion and ECM deposition, the formation of new blood vessels has been universally claimed to be important in adhesion formation.
During peritoneal healing, cellcell interactions between mesothelial cells, macrophages and also fibroblasts contribute to the healing of the peritoneum. Adhesion fibroblasts have developed a specific phenotype. Compared with normal peritoneal fibroblasts, adhesion fibroblasts have increased basal levels of collagen I, fibronectin, MMP-1, tissue MMP-1, TGF, PA-1, IL-10 and decreased levels of tPA (Saed et al., 2001
).
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Pneumoperitoneum-enhanced adhesion formation |
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Reactive oxygen species |
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ROS inhibit cellular proliferation and produce cellular senescence (Honda et al., 2001, 2002), induce molecular damage of molecules such as DNA, proteins and lipids (Wei and Lee, 2002
), and cause ageing (Wei and Lee, 2002
) and apoptosis (Taglialatela et al., 1998
). ROS are also involved in a variety of diseases such as in the inflammatory reaction associated with endometriosis (Ota et al., 1999
; Van Langendonckt et al., 2002
), in neurodegenerative diseases as Alzheimers (Nourooz-Zadeh et al., 1999
), in autoimmune diseases as systemic lupus erythematosus (Ahsan et al., 2003
) and in the pathogenesis of diabetic nephropathy (Ha and Lee, 2001
). ROS have also been associated with surgery and postoperative adhesion formation (Tsimoyiannis et al., 1989
; Portz et al., 1991
; Hemadeh et al., 1993
; Galili et al., 1998
; Taskin et al., 1999
).
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Surgery and reactive oxygen species |
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Adhesion formation and reactive oxygen species |
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Indirectly, a role for ROS in adhesion formation is derived from the observation that ROS scavengers reduce adhesion formation following open surgery in different animal models. Indeed, CAT, SOD and trimetazidine reduce adhesion formation induced by vascular obstruction/reperfusion of an ileal segment in rats (Tsimoyiannis et al., 1989, 1990); CAT and SOD also reduce adhesion formation in an endometriosis model in rabbits (Portz et al., 1991
). In addition, intraperitoneal administration of methylene blue reduces adhesion formation induced by scraping the uterus in rats (Galili et al., 1998
); intraperitoneal administration of melatonin also prevents adhesion formation induced by monopolar cautery in rats (Özçelik et al., 2003
). Similarly, oral supplements of vitamin E reduce adhesion formation created by scraping the caecum with mesh gauze in rats (Hemadeh et al., 1993
). This effect of vitamin E, however, was not confirmed by denuding the serous surface of the uterus in rats (Sanfilippo et al., 1995
).
Finally, the observation that adhesion formation decreases by adding 24% of oxygen to the CO2 pneumoperitoneum (Molinas and Koninckx, 2000; Molinas et al., 2001
) could be explained by the fact that this addition of oxygen prevents the decrease of ROS scavengers, and thus the increase of ROS activity.
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Discussion |
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The importance of these observations on ROS activity is that the traditional concepts of adhesion formation, involving tissue trauma, fibrin deposition and fibrinolysis, fibroblast invasion, ECM deposition and angiogenesis, have to incorporate the effect of the environment upon the peritoneal cells, e.g. mesothelial cells, macrophages, fibroblasts in order to understand the differences between laparotomy and laparoscopy. During laparotomy, the pO2 of the environment is clearly hyperoxic for the peritoneal cells. During laparoscopy, the CO2 pneumoperitoneum creates a hypoxic environment. Specifically relevant for adhesion formation is that a hypoxic environment induces irreversible molecular changes in peritoneal fibroblast, such as increases in cyclooxygenase 2 (COX-2) (Saed et al., 2003), ECM (Saed and Diamond, 2002
), and PAI-1 (Saed and Diamond, 2003
); moreover, hypoxia modulates the expression of TGF
1, -2 and -3 and their receptors (Saed et al., 2002
) and decreases tPA (Saed and Diamond, 2003
).
These concepts are fundamental for the clinically important problem of adhesion prevention. Until now, prevention has focused on good surgical techniques minimizing tissue trauma and fibrin deposition and on mechanical separation of surfaces and upon fibrinolysis. The understanding of the role of the pO2 in adhesion formation and of the mechanisms involving ROS, hypoxia during CO2 pneumoperitoneum and hyperoxia during laparotomy, and angiogenesis could open new possibilities in adhesion prevention. Recent new approaches in animals, such as the addition of 3% of oxygen to the pneumoperitoneum (Molinas and Koninckx, 2000; Molinas et al., 2001
), the neutralization of PlGF by monoclonal antibodies (Molinas et al., 2003c
) and the administration of ROS scavengers (Tsimoyiannis et al., 1989
, Portz et al., 1991
; Hemadeh et al., 1993
; Galili et al., 1998
; Özçelik et al., 2003
), open unexpected possibilities for postoperative adhesion prevention.
We fully realize that these concepts are provocative. Yet to stimulate thinking and discussiondu choc des idées jaillit la lumièrewe decided to write this introduction to a Debate.
Indeed, the relative importance of fundamental mechanisms as the fibrinolytic system, angiogenic factors and ROS in adhesion formation is still unclear. Moreover, the role of a fundamental process such as ROS activity is important for many other aspects in medicine e.g. the ischaemiareperfusion process and transplant surgery, embryo implantation, cell culture, and possibly IVF and embryo culture.
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