The role of growth factors in peritoneal healing: transforming growth factor beta (TGF-beta)

Processes that result in either normal peritoneal tissue repair of fibrous adhesion formation have until recently been largely unexplored at the molecular level. Our group is investigating the molecular events underlying peritoneal healing and hypothesizes that peptide growth factors, cytokines, and their receptors, which are expressed by various cell types at the site of injury and are present in the peritoneal fluid, play key roles in regulating tissue repair processes. This regulation is highly complex, involving the individual action of and/or synergistic interactions among many substances. These include various members of the growth factor family, such as transforming growth factors alpha and beta (TGF-alpha and TGF-beta), and of the cytokine family. These growth factors and cytokines are synthesized and released by activated macrophages in the peritoneal fluid and in the wound and by other major cell types in the wound, suggesting that they have a role in an autocrine/paracrine mechanism. For normal peritoneal healing to occur, the availability of these signaling substances must be optimal, precise, and synchronized. Inhibition, interruption, or excess expression of these signals seems to be responsible for failure in normal healing, either impairment (nonhealing) or excess tissue formation (adhesion development). Evidence of the key role of TGF-beta in peritoneal healing and adhesiogenesis falls into four main categories: 1) the characteristics of TGF-beta in other settings; 2) the presence and 3) activity of TGF-beta and/or its receptors in peritoneal wounds and fluid; and 4) the effects of the application of excess TGF-beta and anti-TGF-beta antibody on adhesion formation. TGF-betas are chemotactic for fibroblasts and inflammatory cells and promote cell proliferation and differentiation and angiogenesis. They also regulate the expression of various components of extracellular matrix. In mice, subcutaneous TGF-beta induces the formation of granulation tissue, and in several animal models and in humans, excess TGF-beta activity has been linked to the development of kidney and liver fibrosis. TGF-betas and their receptors are expressed by various cells in peritoneal wounds and fluid and are present at higher levels in injured compared with uninjured tissues. In vitro studies in peritoneal wounds and fluid show that TGF-beta 1 significantly upregulates its own expression and the expression of several extracellular matrix components and of tissue inhibitors of matrix metalloproteinases (TIMPs) but downregulates the expression of matrix metalloproteinases (MMPs). Following uterine horn injury, rats given TGF-beta daily for five days developed adhesions in significantly greater number and severity than did untreated controls. Although anti-TGF-beta neutralizing antibody in rats failed to significantly reduce adhesion formation, it did reduce cellularity of fibrous tissue. Antisense oligonucleotides to TGF-beta effectively blocked macrophage expression of TGF-beta, indicating the possible use of this technique in adhesion prevention. Another potential clinical application of some of our findings includes targeted delivery of an anti-TGF-beta preparation by means of a suitable biodegradable barrier during the first five to seven days following peritoneal injury.