Release of biologically active TGF-beta from airway smooth muscle cells induces autocrine synthesis of collagen.
In severe or chronic asthma, there is an increase in airway smooth muscle cell (ASMC) mass as well as an increase in connective tissue proteins in the smooth muscle layer of airways. Transforming growth factor-beta (TGF-beta) exists in three isoforms in mammals and is a potent regulator of connective tissue protein synthesis. Using immunohistochemistry, we had previously demonstrated that ASMCs contain large quantities of TGF-beta1-3. In this study, we demonstrate that bovine ASMC-derived TGF-beta associates with the TGF-beta latency binding protein-1 (LTBP-1) expressed by the same cells. The TGF-beta associated with LTBP-1 localizes TGF-beta extracellularly. Furthermore, plasmin, a serine protease, regulates the secretion of a biologically active form of TGF-beta by ASMCs as well as the release of extracellular TGF-beta. The biologically active TGF-beta released by plasmin induces ASMCs to synthesize collagen I in an autocrine manner. The autocrine induction of collagen expression by ASMCs may contribute to the irreversible fibrosis and remodeling seen in the airways of some asthmatics.
Coutts
A
A
Department of Medicine and Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba R3E 0V9.
Chen
G
G
Stephens
N
N
Hirst
S
S
Douglas
D
D
Eichholtz
T
T
Khalil
N
N
D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D001249:Asthma / Q000150:complications / Q000378:metabolism; D019898:Autocrine Communication / Q000502:physiology*; D001681:Biological Assay; D002352:Carrier Proteins / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D005110:Extracellular Space / Q000378:metabolism; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D005355:Fibrosis / Q000209:etiology; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D008907:Mink; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011347:Procollagen / Q000096:biosynthesis; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014132:Trachea; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D011347:Procollagen; D015842:Serine Proteinase Inhibitors; D016212:Transforming Growth Factor beta; D003094:Collagen; D007611:Aprotinin; D005341:Fibrinolysin