Use of GT-002 to prevent bleomycin-induced pulmonary fibrosis in rats

Purpose: Using Bleomycin (6) to induce pulmonary fibrosis in rats, we determined the pulmonary distribution and antifibrotic potential of the antiscarring agent GT-002(G) (Gliatech, Inc., Cleveland, Oh). Methods: For distribution studies, male Sprague-Dawley rats (250gm; n=4) were given 0.3cc fluorescein-labeled GT-002 (FG) (20mg/ml) intratracheally (IT) and lungs fixed and examined after 1°, 24° and 7d. For inhibition studies, rats (n=9) were given B (1.5U in 0.3cc saline) IT on day 0, then 0.3cc G (20 or 40mg/ml), or sahne, daily for 3-13d. On day 14 post-B, left lungs were fixed in formalin and examined histologically to assess degree of fibrosis; right lungs were hydrolyzed and assayed for hydroxyproline (HP) to assess collagen content. Results: Distribution of FG was uniform and localized in alveoli and alveolar macrophages (AM) at 1° and 24°, and in AM and interstitium by 7d. In the inhibition group, no difference in B-induced fibrosis was seen in control versus G-treated rats at lower doses of G (20mg/ml). At higher doses (40mg/ml), G-treated lungs showed prominence of AM and qualitative reduction in B-induced fibrosis, compared with saline controls. HP content of B+G-treated lungs (mgHP/mg total protein) was reduced by 34%, compared with lungs treated with B only. Conclusion: G administered IT is evenly distributed in rat lung AM and interstitium, where it persists for at least 7d. Histologically and biochemically, G appears to reduce B-induced pulmonary fibrosis. Clinical Implications: G may be a potentially useful drug for attenuating the progressive fibrosis associated with a variety of lung disorders in humans.