Halofuginone, an inhibitor of collagen type I synthesis, prevents postoperative adhesion formation in the rat uterine horn model,☆☆,

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Abstract

Objective: The objective of this study was to evaluate the effects of halofuginone—a specific inhibitor of collagen type I synthesis—in preventing uterine horn adhesion formation in rats. Study Design: Adhesions were induced by scraping the rat uterine horns until capillary bleeding occurred. Halofuginone was either injected intraperitoneally or administered orally. The number and severity of the adhesions were scored. Collagen α1(I) gene expression was evaluated by in situ hybridization; total collagen was estimated by sirius red staining. Collagen synthesis in response to halofuginone was evaluated in cells cultured from the adhesions. Results: Regardless of the administration procedure, halofuginone reduced significantly the number and severity of the adhesions in a dose-dependent manner. Halofuginone prevented the increase in collagen α1(I) gene expression observed in the rats that underwent this procedure, thus affecting only the newly synthesized collagen but not the resident collagen. In cells derived from rat uterine horn adhesions, halofuginone induced dose-dependent inhibition of collagen synthesis. Conclusions: Upregulation of collagen synthesis appears to play a critical role in the pathophysiologic mechanism of adhesion formation. Halofuginone could be used as an important means of understanding the role of collagen in adhesion formation and might become a novel and promising antifibrotic agent for preventing adhesion formation after pelvic surgery. (Am J Obstet Gynecol 1999;180:558-63.)

Section snippets

Materials

[2,3,4,5 3H]L-proline (122 Ci/mmol) was obtained from the Radiochemical Centre (Amersham, United Kingdom). Highly purified Clostridium histolyticum collagenase type VII free of nonspecific proteases, β-aminopropionitrile, Dulbecco’s modified Eagle’s medium, and trypsin–ethylenediaminetetra-acetic acid solution (0.25% and 0.02%, respectively) were obtained from Sigma (St. Louis, Mo). Fetal calf serum was obtained from Biochemical Industries (Bet-HaEmek, Israel). Sirius red F3B was obtained from

Effect of halofuginone on uterine horn adhesions

Three experiments were performed to evaluate the effects of halofuginone on the number and severity of rat uterine horn adhesions. In the first experiment adhesions were induced and halofuginone was given by intraperitoneal injection at a concentration of 40 μg/kg body weight every other day starting 1 week before operation (Table I).No adhesions were observed in the control, nonoperated, rats with or without halofuginone. All rats that underwent the operation procedures but did not receive

Comment

Postoperative pregnancy rates decline as a result of peritubular adhesions. In addition, adhesions may cause intestinal obstruction and chronic pelvic pain, especially during ovulation. The involvement of fibroblast proliferation and extracellular matrix deposition—especially collagen—in scar formation in general,19 and in adhesion formation in particular,14, 20 is well documented. Up-regulation of collagen type I synthesis appears to play a critical role in the pathophysiologic mechanism of

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    Supported by Collgard Biopharmaceuticals Ltd, Tel Aviv, Israel. Contribution No. 2337-E, 1997 series, from the Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel.

    ☆☆

    Reprint requests: Mark Pines, PhD, Institute of Animal Science, ARO, The Volcani Center, Bet Dagan 50250, Israel.

    0002-9378/99 $8.00 + 06/1/95569

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