Effect of antibody against integrin alpha 4 on bleomycin-induced pulmonaryfibrosis in mice

Integrins are a family of transmembrane glycoproteins that can interact wit h components of the extracellular matrix. The alpha4 beta1 and alpha4 beta7 integrins are heterodimeric leukocyte cell surface molecules critical to t heir cell and matrix adhesive interactions. Evidence for a central role for the alpha4 integrins in leukocyte pathophysiology in the lung is well docu mented. In this study, we tested the hypothesis that neutralizing antibody for integrin alpha4 (PS2) may reduce bleomycin (BL)-induced lung fibrosis i n vivo. Male C57BL/6 mice were injected intratracheally with saline (SA) or BL (0.08 U/mouse) followed by intraperitoneal injection of SA, isotype con trol antibody (1E6), or PS2 (100 mug) three times a week. Twenty-one days a fter the intratracheal instillation mice were killed for bronchoalveolar la vage (BAL), biochemical, histopathological, and immunohistological analyses . Treatment with PS2 significantly reduced BL-induced increases in lung lip id peroxidation and hydroxyproline content. Lung histopathology also showed reduced fibrotic lesions in the BL-treated lungs by treatment with PS2. BL -treated mouse lungs also showed induction of cells with the myofibroblast phenotype, as indicated by the increased expression of alpha -smooth muscle actin (alpha SMA), whereas treatment with PS2 minimized the BL-induced alp ha SMA expression. Furthermore, treatment with PS2 reduced the BL-induced i ncrease in the BAL total cell number, and attenuated the BL-induced increas e in the BAL protein level. It is concluded that integrin alpha4 may play a n important role in BL-induced pulmonary fibrosis, and the use of anti-alph a4 antibody offers therapeutic antifibrotic potential in vivo. BIOCHEM I PH ARMACOL 60;12:1949 -1958, 2000. (C) 2000 Elsevier Science Inc.