Postoperative Adhesions: From Formation to Prevention

Zeynep Alpay, MD; Ghassan M. Saed, PhD; Michael P. Diamond, MD


Semin Reprod Med. 2008;26(4):313-321. 

In This Article


Adhesions develop after an injury to the normal peritoneal tissue. This injury can result from surgery, trauma, inflammation, infection, or foreign body placement in the peritoneal cavity. After injury to the normal mesothelial cells overlaying the peritoneal surface, the healing process starts. Vasoactive substances such as histamines and kinins are released by the disruption of stromal mast cells increasing vascular permeability, which contributes to the collection of a fibrin-rich exudate that covers the injured area. Two processes occur essentially simultaneously. In one, the fibrin polymers in this exudate interact with fibronectin to form the fibrin gel matrix, which consequently produces fibrin bands between the injured areas. At the same time, fibrinolysis starts. Fibrinolysis dominates at sites where healing occurs without adhesions. In contrast, if fibrinolysis is impaired, this imbalance may result in the persistence of the fibrinous mass. Subsequently, proliferating fibroblasts invade this area and deposit extracellular matrix material including collagen that contributes to the formation of adhesion. After elicitation of angiogenesis factors such as vascular endothelial growth factor (VEGF), proliferation of endothelial cells initiates the development of vascular structure within the adhesion tissue. Thus, different mechanistic steps, some of which have been described above, regulate the healing process, with imbalances in any of these potentially contributing to adhesion development. Furthermore, it is likely that these activities are more pronounced at sites with prior fibrosis, such as those undergoing adhesiolysis.

Ischemia has been proposed as the most important insult that leads to adhesion development.[2] It has been demonstrated that fibroblasts in the adhesion tissues have different phenotype (myofibroblasts) than do the normal peritoneal tissue fibroblasts. More importantly, it has been shown that conversion of these cells from the normal phenotype to the adhesion phenotype can be induced by hypoxia.[2] The adhesion phenotype has been thoroughly characterized at the molecular level.[2] Compared with peritoneal fibroblasts, adhesion fibroblasts have a significant increase in the basal mRNA levels for collagen I, fibronectin, matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), transforming growth factor (TGF)-β1, (TGF)-β1, cyclooxygenase-2 (COX-2), and interleukin (IL)-10.[3,4,5,6,7] Also, adhesion fibroblasts manifested lower apoptosis rate and higher protein nitration compared with that of normal peritoneal fibroblasts.[8]

Tissue plasminogen activator (tPA) and plasminogen activator inhibitor type-1 (PAI-1) are intracellular enzymes found in the peritoneal mesenchymal cells. These constitute the intrinsic protective fibrinolytic activity of fibroblasts. In fact, the ratio between these enzymes can be considered as a better marker of fibrinolytic potential than just using tPA or PAI-1 levels individually. The tPA/PAI-1 ratio has been shown to be 80% higher in normal peritoneal fibroblasts than in adhesion fibroblasts. Under hypoxic conditions, this ratio significantly decreases in normal fibroblasts (90%), with an even more exaggerated decrease observed in adhesion fibroblasts (98%).[4]

MMPs and TIMPs are crucial proteolytic enzymes in the extracellular matrix remodeling process of healing. Similarly, any imbalance in these systems may contribute to tissue fibrosis and adhesion development. Hypoxia has been shown to inhibit MMP-1 and MMP-9 and augment TIMP-1 expression.[9,10] This decrease in the MMP:TIMP ratio during hypoxia (98%) may favor the increase in extracellular matrix production and the decrease in turnover and degradation that eventually may lead to tissue fibrosis and adhesion development.[5,6,7]

COX-2 enzyme has been shown to have an important role in the regulation of inflammatory and angiogenesis steps of postoperative adhesions development. In adhesion fibroblasts, the expression of COX-2 is significantly increased compared with that of the normal fibroblasts.[11] Hypoxia enhances the level of COX-2 expression in normal fibroblasts whereas there is no change in adhesion fibroblasts.[11] It has been reported that the normal fibroblasts acquire adhesion phenotype after transfection with COX-2 sense adenovirus.[12] Furthermore, COX-2 antisense adenovirus transfection decreases the adhesion phenotype characteristics in adhesion fibroblasts.[12] COX-2 inhibitors, such as celecoxib, tenoxicam, and pentoxifylline, have been reported to reduce postoperative adhesions through their anti-angiogenic, anti-inflammatory, and antioxidant effects in animal studies.[13,14,15]

The surface expression of certain adhesion and costimulatory molecules on peritoneal fibroblasts differs among adhesion tissue and normal peritoneum. We have shown that elimination of adhesion fibroblasts by allogeneic lymphokine-activated killer (LAK) cells is more pronounced than is the effect of LAK cells on normal peritoneal fibroblasts.[16] This enhanced killing has also been shown in the hypoxia-treated normal peritoneal fibroblasts, supporting a contributory role of hypoxia in the adhesion phenotype development.[17] Furthermore, a deficient, suppressed, or overwhelmed natural immune system has been proposed as an underlying mechanism in adhesion development.[16]


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