Am. J. Respir. Cell Mol. Biol., Volume 23, Number 2, August, 2000 204-212

A CD36 Synthetic Peptide Inhibits Bleomycin-Induced Pulmonary Inflammation and Connective Tissue Synthesis in the Rat

Teshome Yehualaeshet, Robert O'Connor, Asher Begleiter, Joanne E. Murphy-Ullrich, Roy Silverstein, and Nasreen Khalil

Departments of Internal Medicine and Pathology, and the Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Mannitoba; BC Cancer Agency and Vancouver Hospital, Vancouver, British Columbia, Canada; Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; and Division of Hematology/Oncology, Cornell Medical Center, New York, New York

Transforming growth factor (TGF)-1 is an important regulator of inflammation and fibrosis. TGF-1 is usually secreted as a biologically latent protein called latent TGF-1 (L-TGF-1). L-TGF-1 has no biologic effect unless L-TGF-1 is converted to its active form. Using a well-recognized model of lung injury induced by the antineoplastic antibiotic bleomycin (Blm), we demonstrated that 7 d after intratracheal Blm administration, total lung TGF- was maximally increased. This induction was due to TGF-1 production by alveolar macrophages that, when explanted, generated increased quantities of L-TGF-1 complexed with the glycoprotein thrombospondin (TSP)-1. The TSP-1/L-TGF-1 complex was associated with CD36, a receptor for TSP-1. The association of TSP-1/L-TGF-1 to CD36 was critical for plasmin-mediated release of mature TGF-1. In this paper we show that, compared with administration of Blm by itself, when a synthetic peptide of CD36 between amino acids 93 and 110 is given concomitantly with Blm to rats, alveolar macrophages generate markedly less active TGF-1, the rats gain weight more rapidly, and there is less inflammation, collagen I and III, and fibronectin synthesis. These findings demonstrate a novel in vivo mechanism of activation of L-TGF-1 in lung injury and the importance of alveolar macrophage- derived active TGF-1 in the pathogenesis of pulmonary inflammation and fibrosis.

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