Gelatinases A and B are up-regulated in rat lungs by subacute hyperoxia: pathogenetic implications.
Subacute hyperoxia may cause basement membrane disruption and subsequent fibrosis. To test the role of extracellular matrix degradation in hyperoxic damage, we analyzed the expression of gelatinases A and B and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 in rats exposed to 85% O2. Oxygen-exposed rats were studied at 1, 3, 5, and 7 days, and compared with air-breathing rats. Lung mRNAs assayed by Northern and in situ hybridization showed an up-regulation of lung gelatinases A and B from the 3rd day on. Gelatinase A was localized in alveolar macrophages and in interstitial and alveolar epithelial cells. Gelatinase B mRNA and protein were localized in macrophages and bronchiolar and alveolar epithelial cells. Increased gelatinase A and B activities were demonstrated in bronchoalveolar lavage. TIMP-1 and TIMP-2 were constitutively expressed, and only TIMP-1 displayed a moderate increase with hyperoxia. To elucidate transcriptional mechanisms for increased gelatinase B expression after hyperoxia, nuclear transcription factor-kappabeta activation was explored. Oxidative stress significantly increased the lung expression of nuclear transcription factor-kappabeta (p65) protein, and nuclear transcription factor-kappabeta activation and increased levels of gelatinases A and B were found in isolated type II alveolar cells obtained from hyperoxic rats. Conceivably, subacute hyperoxia induces excessive gelatinase activity, which may contribute to lung damage.
Pardo
A
A
Facultad de Ciencias, UNAM, Coyoacán, México, México DF. aps@hp.fciencias.unam.mx
Barrios
R
R
Maldonado
V
V
Meléndez
J
J
Pérez
J
J
Ruiz
V
V
Segura-Valdez
L
L
Sznajder
J I
JI
Selman
M
M
D000208:Acute Disease; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D018496:Hyperoxia / Q000201:enzymology* / Q000473:pathology; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D015854:Up-Regulation
D016328:NF-kappa B; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9