Autocrine production of matrix metalloproteinase-2 is required for human airway smooth muscle proliferation.
Airway smooth muscle proliferation is important in asthma and is dependent on pro- and antimitogenic factors and cell-matrix interactions. Here we show an antiproliferative effect of protease inhibitors on human airway smooth muscle due to inhibition of autocrine-derived matrix metalloproteinase (MMP)-2. Proliferation in response to fetal bovine serum, thrombin, and platelet-derived growth factor was inhibited by the broad-spectrum protease inhibitor Complete and the MMP inhibitors EDTA and Ro-31-9790 but not by cysteine or serine protease inhibitors. Conditioned medium from airway smooth muscle cells contained 72-kDa gelatinase that was secreted by growth-arrested cells and increased by fetal bovine serum but not by thrombin or platelet-derived growth factor. Immunostaining of cultured human airway smooth muscle cells and normal lung biopsies confirmed this gelatinase to be MMP-2. Our results suggest a novel role for MMP-2 as an important autocrine factor required for airway smooth muscle proliferation. Inhibition of MMPs could provide a target for the prevention of smooth muscle hyperplasia and airway remodeling in asthma.
Johnson
S
S
Division of Respiratory Medicine, City Hospital, University of Nottingham, Nottingham NG5 1PB, United Kingdom.
Knox
A
A
D007611:Aprotinin / Q000494:pharmacology; D001249:Asthma / Q000378:metabolism; D019898:Autocrine Communication / Q000502:physiology; D001798:Blood Proteins / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D005109:Extracellular Matrix / Q000201:enzymology; D006490:Hemostatics / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008934:Mitogens / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology* / Q000201:enzymology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism / Q000494:pharmacology; D014132:Trachea / Q000166:cytology*
D001798:Blood Proteins; D002614:Chelating Agents; D015853:Cysteine Proteinase Inhibitors; D006490:Hemostatics; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D011480:Protease Inhibitors; C097661:Ro 31-9790; D015842:Serine Proteinase Inhibitors; C095477:platelet-derived growth factor AB; D007611:Aprotinin; D004492:Edetic Acid; D013917:Thrombin; D020778:Matrix Metalloproteinase 2; D007930:Leucine; C024974:E 64; D013936:Thymidine