ro-31-9790 and Asthma

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.

Topics: Aprotinin; Asthma; Autocrine Communication; Blood Proteins; Cell Division; Cells, Cultured; Chelating Agents; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Edetic Acid; Extracellular Matrix; Hemostatics; Humans; Hydroxamic Acids; Leucine; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Mitogens; Muscle, Smooth; Platelet-Derived Growth Factor; Protease Inhibitors; Serine Proteinase Inhibitors; Thrombin; Thymidine; Trachea