Mechanical stretch induces MMP-2 release and activation in lung endothelium: role of EMMPRIN.
High-volume mechanical ventilation leads to ventilator-induced lung injury. This type of lung injury is accompanied by an increased release and activation of matrix metalloproteinases (MMPs). To investigate the mechanism leading to the increased MMP release, we systematically studied the effect of mechanical stretch on human microvascular endothelial cells isolated from the lung. We exposed cells grown on collagen 1 BioFlex plates to sinusoidal cyclic stretch at 0.5 Hz using the Flexercell system with 17-18% elongation of cells. After 4 days of cell stretching, conditioned media and cell lysate were collected and analyzed by gelatin, casein, and reverse zymograms as well as Western blotting. RT-PCR of mRNA extracted from stretched cells was performed. Our results show that 1) cyclic stretch led to increased release and activation of MMP-2 and MMP-1; 2) the activation of MMP-2 was accompanied by an increase in membrane type-1 MMP (MT1-MMP) and inhibited by a hydroxamic acid-derived inhibitor of MMPs (Prinomastat, AG3340); and 3) the MMP-2 release and activation were preceded by an increase in production of extracellular MMP inducer (EMMPRIN). These results suggest that cyclic mechanical stretch leads to MMP-2 activation through an MT1-MMP mechanism. EMMPRIN may play an important role in the release and activation of MMPs during lung injury.
Haseneen
Nadia A
NA
Department of Medicine and Research, Northport Veterans Affairs Medical Center, Northport, NY 11768, USA.
Vaday
Gayle G
GG
Zucker
Stanley
S
Foda
Hussein D
HD
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology; D051926:Basigin; D015153:Blotting, Western; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D004790:Enzyme Induction / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000098:blood supply; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000032:analysis; D061965:Matrix Metalloproteinase Inhibitors; D053504:Matrix Metalloproteinases, Membrane-Associated; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D009930:Organic Chemicals; D010507:Periodicity; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C497886:BSG protein, human; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins; D009930:Organic Chemicals; D012333:RNA, Messenger; C113282:prinomastat; D019716:Tissue Inhibitor of Metalloproteinase-2; D051926:Basigin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1