A CD36 synthetic peptide inhibits bleomycin-induced pulmonary inflammation and connective tissue synthesis in the rat.
Transforming growth factor (TGF)-beta1 is an important regulator of inflammation and fibrosis. TGF-beta1 is usually secreted as a biologically latent protein called latent TGF-beta1 (L-TGF-beta1). L-TGF-beta1 has no biologic effect unless L-TGF-beta1 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-beta was maximally increased. This induction was due to TGF-beta1 production by alveolar macrophages that, when explanted, generated increased quantities of L-TGF-beta1 complexed with the glycoprotein thrombospondin (TSP)-1. The TSP-1/L-TGF-beta1 complex was associated with CD36, a receptor for TSP-1. The association of TSP-1/L-TGF-beta1 to CD36 was critical for plasmin-mediated release of mature TGF-beta1. 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-beta1, 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-beta1 in lung injury and the importance of alveolar macrophage- derived active TGF-beta1 in the pathogenesis of pulmonary inflammation and fibrosis.
Departments of Internal Medicine and Pathology, and the Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Mannitoba, British Columbia, Canada.
T
T
Yehualaeshet
R
R
O'Connor
A
A
Begleiter
J E
JE
Murphy-Ullrich
R
R
Silverstein
N
N
Khalil
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018955:CD36 Antigens / Q000737:chemistry / Q000494:pharmacology*; D002452:Cell Count / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D003238:Connective Tissue / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D058575:Decorin; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000187:drug effects*; D005260:Female; D005353:Fibronectins / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D011509:Proteoglycans / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018955:CD36 Antigens; C546880:Dcn protein, rat; D058575:Decorin; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D009842:Oligopeptides; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D003094:Collagen