Plasmin regulates the activation of cell-associated latent TGF-beta 1 secreted by rat alveolar macrophages after in vivo bleomycin injury.
Transforming growth factor beta s (TGF-beta s) are 25-kD multifunctional proteins that regulate inflammation and connective tissue synthesis. With rare exception TGF-beta 1 is secreted noncovalently bound to a latency-associated peptide (LAP) that renders the mature TGF-beta 1 biologically inactive. An important mechanism for the control of TGF-beta 1 action is the regulation of the post-translational processing that removes the LAP from the mature peptide and renders it biologically active. In a model of pulmonary inflammation and fibrosis induced by the antineoplastic antibiotic, bleomycin, we have demonstrated that explanted alveolar macrophages secrete progressively increasing quantities of a biologically active form of TGF-beta 1, the secretion of which was maximal 7 days after bleomycin administration. Thereafter, there was a rapid decline in the secretion of the active form of TGF-beta 1, whereas the latent form continued to be secreted in elevated quantities. Plasmin, a serine protease, was transiently generated by the same bleomycin-activated alveolar macrophages and paralleled the rise in active TGF-beta 1. When alpha 2-antiplasmin, an inhibitor of plasmin, was added to cultures of alveolar macrophages, the post-translational activation of L-TGF-beta 1, was totally abrogated. When plasmin was added to alveolar macrophages in culture, there was complete activation of the L-TGF-beta 1 that had been secreted during the culture period. However, there was no effect of plasmin on the same alveolar macrophage-derived L-TGF-beta 1 in cell-free conditioned media. Our findings suggest that the secretion of an active form of TGF-beta 1 by alveolar macrophages is regulated by the generation of plasmin and requires that the alveolar macrophages be present. Because the diminution of active TGF-beta 1 coincides with the resolution of inflammation, this suggests that the availability of plasmin regulates the biologically active form of TGF-beta 1, and thus, the inflammation seen after bleomycin-induced lung injury.
Khalil
N
N
Department of Medicine, Manitoba Institute of Cell Biology, Winnipeg, Canada.
Corne
S
S
Whitman
C
C
Yacyshyn
H
H
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001761:Bleomycin; D002460:Cell Line / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned; D004847:Epithelial Cells; D005260:Female; D005341:Fibrinolysin / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008907:Mink; D011014:Pneumonia / Q000139:chemically induced / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000979:alpha-2-Antiplasmin / Q000494:pharmacology
D017077:Culture Media, Conditioned; D016212:Transforming Growth Factor beta; D000979:alpha-2-Antiplasmin; D001761:Bleomycin; D005341:Fibrinolysin