HALOFUGINONE - AN INHIBITOR OF COLLAGEN TYPE-I SYNTHESIS - PREVENTS POSTOPERATIVE FORMATION OF ABDOMINAL ADHESIONS

Objective To evaluate the effects of halofuginone, a specific inhibito r of collagen type I synthesis, on the postoperative formation of abdo minal adhesions in rats. Summary Background Data Postoperative adhesio ns remain the leading cause of small bowel obstruction in the Western world. Surgical trauma causes the release of a serosanguineous exudate that forms a fibrinous bridge between two organs. This becomes ingrow n with fibroblasts, and subsequent collagen deposition leads to the fo rmation of a permanent adhesion. Most of the drugs used have been clin ically ineffective, and none has been specific to a particular extrace llular matrix molecule. Therefore, there are serious concerns about th e toxic consequences of interfering with the biosynthesis of other col lagens, other matrix proteins, or vital collagen-like molecules. Metho ds Adhesions were induced by scraping the cecum until capillary bleedi ng occurred. The adhesions were scored 21 days later. Halofuginone was either injected intraperitoneally (1 mu g/25 g body weight) every day , starting on the day of operation, or added orally at concentrations of 5 or 10 mg/kg, starting 4 days before the operation. Collagen alpha 1(I) gene expression was evaluated by in situ hybridization, total co llagen was estimated by Sirius red staining, and collagen type III was detected by immunohistochemistry: Results The adhesions formed betwee n the intestinal walls were composed of collagen and were populated wi th cells expressing the collagen alpha 1(I) gene. Regardless of the ad ministration procedure, halofuginone significantly reduced the number and severity of the adhesions. Halofuginone prevented the increase in collagen alpha 1(I) gene expression observed in the operated rats, thu s reducing collagen content to the control level. In fibroblasts deriv ed from abdominal adhesions, halofuginone induced dose-dependent inhib ition of collagen alpha 1(I) gene expression and collagen synthesis. C ollagen type III levels were not altered by adhesion induction or by h alofuginone treatment. Conclusions Upregulation of collagen synthesis appears to have a critical role in the pathophysiology of postoperativ e adhesions. Halofuginone, an inhibitor of collagen type I synthesis, could be used as an important tool in understanding the role of collag en in adhesion formations and it may become a novel and promising anti fibrotic agent for preventing postoperative adhesion formation.