Effect of antibody against integrin alpha4 on bleomycin-induced pulmonary fibrosis in mice.
Integrins are a family of transmembrane glycoproteins that can interact with components of the extracellular matrix. The alpha4beta1 and alpha4beta7 integrins are heterodimeric leukocyte cell surface molecules critical to their cell and matrix adhesive interactions. Evidence for a central role for the alpha4 integrins in leukocyte pathophysiology in the lung is well documented. In this study, we tested the hypothesis that neutralizing antibody for integrin alpha4 (PS2) may reduce bleomycin (BL)-induced lung fibrosis in vivo. Male C57BL/6 mice were injected intratracheally with saline (SA) or BL (0.08 U/mouse) followed by intraperitoneal injection of SA, isotype control antibody (1E6), or PS2 (100 microg) three times a week. Twenty-one days after the intratracheal instillation, mice were killed for bronchoalveolar lavage (BAL), biochemical, histopathological, and immunohistological analyses. Treatment with PS2 significantly reduced BL-induced increases in lung lipid 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 (alphaSMA), whereas treatment with PS2 minimized the BL-induced alphaSMA expression. Furthermore, treatment with PS2 reduced the BL-induced increase in the BAL total cell number, and attenuated the BL-induced increase in the BAL protein level. It is concluded that integrin alpha4 may play an important role in BL-induced pulmonary fibrosis, and the use of anti-alpha4 antibody offers therapeutic antifibrotic potential in vivo.
Wang
Q
Q
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. qwang@fibrogen.com
Wang
Y
Y
Hyde
D M
DM
Gotwals
P J
PJ
Lobb
R R
RR
Ryan
S T
ST
Giri
S N
SN
D000199:Actins / Q000032:analysis; D000818:Animals; D000900:Anti-Bacterial Agents; D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism*; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002454:Cell Differentiation; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D039441:Integrin alpha4; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*
D000199:Actins; D000900:Anti-Bacterial Agents; D000906:Antibodies; D015703:Antigens, CD; D001761:Bleomycin; D039441:Integrin alpha4; D011393:Procollagen-Proline Dioxygenase; D006909:Hydroxyproline