Matrix metalloproteinase inhibitor (ONO-4817) attenuates ischemia-reperfusion injury in rat lung.
BACKGROUND
Ischemia-reperfusion injury of the lungs seems to be initiated by the activation of alveolar macrophages, and mediated by matrix metalloproteinases (MMP)s, although their roles have not been fully elucidated. Therefore, we used a novel MMP inhibitor (ONO-4817) with high affinities for MMP-2 and MMP-9 to investigate the roles of MMPs in reperfusion injury of the lungs.


METHODS
After 18 h of cold ischemia, isolated rat lungs were ventilated and reperfused. Lungs without ischemia served as controls. Lungs were reperfused with fresh blood with or without the MMP inhibitor for 120 min at 37 degrees C.


RESULTS
The oxygenation capacity of lungs after ischemia deteriorated progressively during 120 min of reperfusion, but was preserved by the MMP inhibitor (p<0.05). The histopathology of the lungs after ischemia-reperfusion showed interstitial edema accompanied by neutrophil migration, and the number of neutrophils, but not macrophages, in the broncho-alveolar lavage increased to more than two-fold the value in control lungs without ischemia (p<0.01). These changes were attenuated by the MMP inhibitor (p<0.01). Similarly, an increase in the tissue malondialdehyde level in lungs after ischemia-reperfusion was ameliorated by the MMP inhibitor (p<0.01). The expressions of CD11c and CD31 adhesion molecules in extracted alveolar macrophages increased in lungs after ischemia-reperfusion compared with control lungs without ischemia, and the MMP inhibitor had no obvious effect.


CONCLUSIONS
Our data show that ONO-4817 prevented neutrophil migration into the interstitial space and alveolus in the lungs, and reduced the production of oxygen free radicals, suggesting that this is an important mechanism in reperfusion injury.
Shimoyama
Takehiko
T
Department of Cardio-Thoracic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. t-shim.tsrg@tmd.ac.jp
Tabuchi
Noriyuki
N
Chung
Jihwa
J
Koyama
Takatoshi
T
Sunamori
Makoto
M
D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D055370:Lung Injury; D016676:Macrophages, Alveolar / Q000276:immunology / Q000473:pathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D009504:Neutrophils / Q000473:pathology; D010647:Phenyl Ethers / Q000494:pharmacology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
D039521:CD11c Antigen; D061965:Matrix Metalloproteinase Inhibitors; C414368:N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; D010647:Phenyl Ethers; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011480:Protease Inhibitors; D017382:Reactive Oxygen Species