The Pathogenesis of Intraabdominal Adhesions: Similarities and Differences to Luminal Fibrosis

Essentially every organ in the human body, including the intestine, can be affected by fibrotic reactions. Under normal homeostatic conditions these reactions are self-limited and constitute an important reparative process aimed at the restoration of the functional integrity of injured tissues. However, under pathologic circumstances the homeostatic regulatory mechanisms evolve into an uncontrolled fibrotic process characterized by the accumulation of large amounts of fibrotic tissue, which disrupts normal organ architecture and ultimately leads to organ failure. Even though their etiology varies greatly, all fibrotic reactions share common features. It is universally accepted that myofibroblasts are the cells ultimately responsible for the pathologic fibrotic process. Myofibroblasts, expressing α-smooth muscle actin (α-SMA), comprise a distinctive population of mesenchymal cells. When activated, they markedly increase the production of fibrillar collagens (types I, III, V, and VI) and other extracellular matrix (ECM) macromolecules coupled with an increased inhibition of ECM-degradative enzymes which may result in the production of injurious scar tissue in the intestine. While abdominal adhesions may be caused by infection, inflammation or ischemia, surgical procedures are the primary cause. Unfortunately, adequate therapeutic solutions have proven elusive. The peritoneal surfaces, both visceral and parietal, are covered by a monolayer of mesothelial cells bound to a basement membrane. Because the mesothelial cells are weakly connected, the peritoneal surface is delicate and easily injured, resulting in a series of events, which can be broken down into coagulation cascade and inflammatory stages leading to a fibrous adhesion stage. TGF-β, IL-6 and likely other cytokines and growth factors play critical roles in adhesion formation by mediating the formation of myofibroblasts and stimulating the production of ECM. In the pathogenesis of fibrosis in inflammatory bowel disease (IBD), many factors need to be considered, including a much more sustained inflammatory response, a clear if still poorly understood genetic predisposition, the potential involvement of multiple mesenchymal cells, exposure of the mucosa to intestinal bacteria and the involvement of the immune system. In IBD, the normal wound healing process triggered by injury and inflammation fails and, instead of resolution, there is continued ECM production by myofibroblasts. Because of a protracted inflammatory response, one could imagine that anti-inflammatory therapy might be an effective approach. Unfortunately, this has not been the case, and it appears that once the damaging fibrotic reaction has been initiated in fibrosis-prone individuals, it is self-propagating. Thus, as in other fibrotic situations, the aberrant myofibroblast becomes the ultimate target. However, unlike adhesions in which the potential instigators can be anticipated and candidate drugs given over a fairly short time, in IBD the pathogenesis is much more protracted. There are a number of FDA—approved drugs capable of intercepting pathways potentially critical in the fibrotic reaction. TGF-β signaling is, of course, the primary target. However, because of the manifold activities of TGF-β, one or more downstream events in the signaling pathways must be judiciously selected so as not to elicit toxic responses. The same caution must be applied when dealing with other potential targets. Because of the inherent redundancy in signaling from multiple cytokines/growth factors involved in fibrotic reactions, it is likely that more than one drug must be administered simultaneously to obtain effective beneficial inhibition.