GELATINASE-A AND GELATINASE-B ARE UP-REGULATED IN RAT LUNGS BY SUBACUTE HYPEROXIA - PATHOGENETIC IMPLICATIONS

Subacute hyperoxia may cause basement membrane disruption and subseque nt fibrosis. To test the role of extracellular matrix degradation in h yperoxic damage, we analyzed the expression of gelatinases A and B and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 in rats e xposed to 85% O-2. Oxygen-exposed rats were studied at 1, 3, 5, and 7 days, and compared with air-breathing rats. Lung mRNAs assayed by Nort hern and in situ hybridization showed an up-regulation of lung gelatin ases A and B from the 3rd day on. Gelatinase A was localized in alveol ar macrophages and in interstitial and alveolar epithelial cells. Gela tinase B mRNA and protein were localized in macrophages and bronchiola r and alveolar epithelial cells. Increased gelatinase A and B activiti es were demonstrated in bronchoalveolar lavage. TIMP-1 and TIMP-2 were constitutively expressed, and only TIMP-1 displayed a moderate increa se with hyperoxia. To elucidate transcriptional mechanisms for increas ed gelatinase B expression after hyperoxia, nuclear transcription fact or-kappa beta activation was explored. Oxidative stress significantly increased the lung expression of nuclear transcription factor-kappa be ta (p65) protein, and nuclear transcription factor-kappa beta activati on and increased levels of gelatinases A and B were found in isolated type II alveolar cells obtained from hyperoxic rats. Conceivably, suba cute hyperoxia induces excessive gelatinase activity, which may contri bute to lung damage.