Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia decreases plasma aldosterone in vivo without a decrease in PRA, angiotensin II (ANG II), ACTH, or cortisol. The present study evaluated whether this could be due to a direct, specific inhibitory effect on the zona glomerulosa related to the magnitude of the decrease in oxygen (O2). Bovine adrenocortical cells were dispersed with collagenase and studied in vitro within 48 h. Cells were stimulated for 2 h with ANG II (0.1-1000 nM) or (Bu)2cAMP (0.3-3 mM) under oxygen levels ranging from 0 to 100% O2 (PO2 from 66 +/- 4 to 561 +/- 46 torr) vs. a reference gas mixture (21% O2 PO2 approximately 140 torr). Exposure to 123 +/- 8, 110 +/- 12, 100 +/- 16, and 66 +/- 4 torr led to 27%, 30%, 40% and 70% inhibition, respectively, of 3 nM ANG II-stimulated aldosterone secretion as compared to 140 +/- 16 torr (reference). Exposure to hyperoxia (288 +/- 36 to 561 +/- 46 torr) led to a small (10%) increase in ANG II-stimulated aldosterone secretion which was not statistically significant. The P50 (half-maximal PO2) for aldosteronogenesis was approximately 95 torr. The results for other doses of ANG II and for cAMP were similar. The inhibitory effect of low O2 was reversed by returning the cells to reference conditions (140 +/- 16 torr). Cortisol secretion was not significantly affected by changes in oxygen tension. We conclude that small changes in O2 within the physiological range directly and specifically inhibit aldosteronogenesis in a dose-dependent manner with a P50 of approximately 95 torr. Inhibition of cAMP-stimulated aldosterone secretion suggests a postreceptor site of action. This direct, reversible, and specific effect on the zona glomerulosa of the adrenal cortex may account for the dissociation of renin and aldosterone during hypoxia in vivo.
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PMID:The effect of oxygen on aldosterone release from bovine adrenocortical cells in vitro: PO2 versus steroidogenesis. 216 17

Oxygen toxicity is attributed to the reaction of oxygen metabolites with cellular components leading to cell destruction. Activation of latent human neutrophil interstitial collagenase by reactive oxygen species has been demonstrated. The potential role of collagenases in hyperoxic lung injury has not been investigated. We studied the effect of hyperoxia on newborn rat lung water content, morphology and ultrastructure, interstitial (type I) and type IV collagenase gene expression and type I and IV collagenolytic activity. We observed that hyperoxia causes pulmonary edema, alters newborn rat lung morphology in a sequential manner and produces ultrastructural alterations, induces type I and increases type IV collagenase mRNA expression, and increases type I and IV collagenolytic activity. A role for type I and IV collagenase in hyperoxic newborn lung injury or in the recovery following the injury is proposed.
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PMID:Hyperoxia induces interstitial (type I) and increases type IV collagenase mRNA expression and increases type I and IV collagenolytic activity in newborn rat lung. 799 51

The influence of 12, 24 and 48 hrs of normobaric hyperoxia on hydroxyproline content and both collagenase and elastase activities in rat lung was investigated. The rise in hydroxyproline level in lung after only 24 hrs of hyperoxia was observed. In bronchoalveolar lavage, however, the level of this amino acid remains unchanged during the whole time of the experiment. Collagenase activity decreased significantly after 12 hrs of hyperoxia, and then decreased gradually. Elastase activity was diminished after 48 hrs of hyperoxia. It is suggested that breathing with pure oxygen induce changes in collagenase activity long before the changes in elastase activity or hydroxyproline content.
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PMID:The influence of normobaric hyperoxia on hydroxyproline content and collagenase and elastase activities in rat lung. 805 48

Hyperoxic lung injury is commonly encountered in patients who require treatment with high concentrations of inspired oxygen. To determine whether interleukin (IL)-6 is protective in oxygen toxicity, we compared the effects of 100% O(2) in transgenic mice that overexpress IL-6 in the lung and transgene (-) controls. IL-6 markedly enhanced survival, with 100% of transgene (-) animals dying within 72 to 96 h, 100% of transgene (+) animals living for more than 8 d and more than 90% of transgene (+) animals living longer than 12 d. This protection was associated with markedly diminished alveolar-capillary protein leak, endothelial and epithelial membrane injury, and lung lipid peroxidation. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene (-) animals and IL-6 markedly diminished this cytopathic response. The protective effects of IL-6 were not associated with significant alterations in the activities of copper/ zinc superoxide dismutase (SOD) or manganese SOD. They were, however, associated with the enhanced accumulation of the cell-death inhibitor Bcl-2, but not the cell-death stimulator BAX, and with the heightened accumulation of the cell-death regulator tissue inhibitor of metalloproteinase-1 (TIMP-1). These studies demonstrate that IL-6 markedly diminishes hyperoxic lung injury and that this protection is associated with a marked diminution in hyperoxia-induced cell death and DNA fragmentation. They also demonstrate that this protection is not associated with significant alterations in SOD activity, but is associated with the induction of Bcl-2 and TIMP-1.
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PMID:Interleukin-6-induced protection in hyperoxic acute lung injury. 1078 24

In this study, we examined the sequential expression of several matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and growth factors as well as the presence of apoptosis in a model of pulmonary fibrosis induced in rats with paraquat and hyperoxia. Animals showing neither clinical nor morphological changes with this double aggression were classified as "resistant". Rats were killed at 1, 2, 3, and 6 wk, and lungs were used for collagen content, gene expression by real-time PCR, gelatinolytic activity by zymography, apoptosis by in situ DNA fragmentation, and protein localization by immunohistochemistry. Our results showed a significant decrease of collagenases MMP-8 and MMP-13, with an increase of TIMP-1 and transforming growth factor-beta. Immunoreactive TIMP-1 was increased in experimental rats and primarily localized in alveolar macrophages. Expression of gelatinases MMP-2 and MMP-9 mRNAs was not affected, but lung zymography revealed an increase in progelatinase B, progelatinase A, and its active form. Epithelial apoptosis was evident from the first week, whereas at later periods, interstitial cell apoptosis was also noticed. Resistant animals behave as controls. These findings suggest that an imbalance between collagenases and TIMPs, excessive gelatinolytic activity, and epithelial apoptosis participate in the fibrotic response in this experimental model.
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PMID:Unbalanced collagenases/TIMP-1 expression and epithelial apoptosis in experimental lung fibrosis. 1288 63

We examined the effects of prolonged hyperoxia (75% O(2)) on lung structure and collagen metabolism in the subacute phase of lung injury induced by continuous infusion of endotoxin (LPS) in a rat model. Experimental groups included control, endotoxin alone, endotoxin plus hyperoxia, and hyperoxia alone. Endotoxin-treated rats received a bolus of LPS (10 mg/kg i.v.) followed by 500 microg.kg(-1).day(-1) in continuous infusion for 10 days. The bronchoalveolar lavage (BAL) fluid/plasma albumin concentration ratio, an index of capillary permeability, and neutrophil and macrophage counts in BAL fluid were highest in the endotoxin plus hyperoxia group. On pathological examination, prolonged hyperoxia exacerbated destruction of the alveolar wall and caused most prominent emphysematous changes in the endotoxin plus hyperoxia group. Lung tissue hydroxyproline concentration was significantly decreased in the hyperoxia group and increased in the endotoxin group. The latent forms of MMP-2 and MMP-9 increased in BAL fluid of the endotoxin- and/or hyperoxia-treated groups, whereas the activities of collagenase and gelatinase, and the active form of MMP-2 were all increased in the hyperoxia-treated groups. Added to endotoxin, prolonged hyperoxia degraded collagen, the major structural component of basement membranes, and caused emphysematous changes associated with activation of collagenase and MMP-2. Our observations suggest that, in the subacute phase of endotoxin-induced lung injury, prolonged hyperoxia causes pulmonary emphysematous changes with persistent injury to the alveolar capillary barrier. Collagenase and MMP-2 activated by hyperoxia, together with MMP-9, may play prominent roles in disruption of the alveolar basement membranes and degradation of collagen lining the alveolar walls.
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PMID:Hyperoxia-induced emphysematous changes in subacute phase of endotoxin-induced lung injury in rats. 1500 27

Matrix metalloproteinases (MMPs) regulate the formation of normal lung architecture. Extremely premature infants exposed to hyperoxia and mechanical ventilation often develop lung inflammation and injury. We hypothesized that an imbalance between MMPs and their tissue inhibitors plays a key role. Our hypothesis was tested to: 1) examine the ontogeny of lung MMPs and tissue inhibitors of metalloproteinases (TIMPs); and 2) determine the effects of hyperoxia and mechanical ventilation on lung MMPs and TIMPs in premature newborn baboons developing chronic lung disease/bronchopulmonary dysplasia (CLD/BPD). Lung specimens were obtained from five groups of gestational controls (GCs) sacrificed at 125, 140, 160, 175, and 185 (term) days of gestation, one fetal baboon model of CLD/BPD delivered at 125 days, and two at 140 days of gestation. Paraffin-embedded lung tissue sections were examined for pathological changes, and frozen lung specimens were analyzed for MMPs-1, -2, -8, and -9; TIMPs-1 and -2; and messenger RNA expression of type I collagen. In GCs, MMP-1 and -9 were elevated in the last trimester, whereas MMP-2 and -8 levels were decreased. Significant changes in lung architecture were noted in the BPD models. MMP-1 was increased in the 125-day model, but decreased in both 140-day models. MMP-8 and collagen mRNA levels were decreased, while MMP-9 and MMP-9 to TIMP-1 ratios were increased in all BPD models. We conclude that an imbalance between MMP-9 and TIMP-1 leading to excessive MMP-9 activity contributes to lung inflammation and edema in CLD/BPD.
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PMID:Increased lung matrix metalloproteinase-9 levels in extremely premature baboons with bronchopulmonary dysplasia. 1552 Oct 85

Acute lung injury is marked by damage to alveolar-capillary barrier. High pulmonary levels of matrix-degrading serine proteinase trypsin and matrix metalloproteinases (MMP)-2, -8, and -9 have been shown in preterm infants with respiratory distress syndrome (RDS). We studied expression of trypsin and MMP-2, -8, and -9 in rats exposed to >95% oxygen for 24, 48, or 60 h. As demonstrated by zymography and Western immunoblotting, levels of trypsin and MMP-2, -8, and -9 in bronchoalveolar lavage fluid (BALF) sharply increased after 48 h of hyperoxia relative to normoxia controls. This coincided with increase in alveolar-capillary permeability, as indicated by increased protein concentration in BALF. Both neutrophil-derived 80-kD and mesenchymal cell-derived 60-kD MMP-8 isoforms were detected in BALF. Of them, mesenchymal-type MMP-8 predominated. In immunohistochemistry, alveolar epithelium showed strong trypsin expression at 48 and 60 h of hyperoxia, whereas it was predominantly negative in controls. MMP-8 was mostly expressed in macrophages. Marked up-regulation of trypsin and MMP-8 early during hyperoxic lung injury suggests that these enzymes play a role in the pathogenesis of acute lung injury and may therefore be potential targets for therapy of lung injury.
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PMID:Up-regulation of trypsin and mesenchymal MMP-8 during development of hyperoxic lung injury in the rat. 1694 Feb 37

Prematurely born infants who require oxygen therapy often develop bronchopulmonary dysplasia (BPD), a debilitating disorder characterized by pronounced alveolar hypoplasia. Hyperoxic injury is believed to disrupt critical signaling pathways that direct lung development, causing BPD. We investigated the effects of normobaric hyperoxia on transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP) signaling in neonatal C57BL/6J mice exposed to 21% or 85% O(2) between postnatal days P1 and P28. Growth and respiratory compliance were significantly impaired in pups exposed to 85% O(2), and these pups also exhibited a pronounced arrest of alveolarization, accompanied by dysregulated expression and localization of both receptor (ALK-1, ALK-3, ALK-6, and the TGF-beta type II receptor) and Smad (Smads 1, 3, and 4) proteins. TGF-beta signaling was potentiated, whereas BMP signaling was impaired both in the lungs of pups exposed to 85% O(2) as well as in MLE-12 mouse lung epithelial cells and NIH/3T3 and primary lung fibroblasts cultured in 85% O(2). After exposure to 85% O(2), primary alveolar type II cells were more susceptible to TGF-beta-induced apoptosis, whereas primary pulmonary artery smooth muscle cells were unaffected. Exposure of primary lung fibroblasts to 85% O(2) significantly enhanced the TGF-beta-stimulated production of the alpha(1) subunit of type I collagen (Ialpha(1)), tissue inhibitor of metalloproteinase-1, tropoelastin, and tenascin-C. These data demonstrated that hyperoxia significantly affects TGF-beta/BMP signaling in the lung, including processes central to septation and, hence, alveolarization. The amenability of these pathways to genetic and pharmacological manipulation may provide alternative avenues for the management of BPD.
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PMID:Hyperoxia modulates TGF-beta/BMP signaling in a mouse model of bronchopulmonary dysplasia. 1707 23

To determine the role of matrix metalloproteinase-8 (MMP-8) in acute lung injury (ALI), we delivered LPS or bleomycin by the intratracheal route to MMP-8(-/-) mice versus wild-type (WT) mice or subjected the mice to hyperoxia (95% O(2)) and measured lung inflammation and injury at intervals. MMP-8(-/-) mice with ALI had greater increases in lung polymorphonuclear neutrophils (PMNs) and macrophage counts, measures of alveolar capillary barrier injury, lung elastance, and mortality than WT mice with ALI. Bronchoalveolar lavage fluid (BALF) from LPS-treated MMP-8(-/-) mice had more MIP-1alpha than BALF from LPS-treated WT mice, but similar levels of other pro- and anti-inflammatory mediators. MIP-1alpha(-/-) mice with ALI had less acute lung inflammation and injury than WT mice with ALI, confirming that MIP-1alpha promotes acute lung inflammation and injury in mice. Genetically deleting MIP-1alpha in MMP-8(-/-) mice reduced the increased lung inflammation and injury and mortality in MMP-8(-/-) mice with ALI. Soluble MMP-8 cleaved and inactivated MIP-1alpha in vitro, but membrane-bound MMP-8 on activated PMNs had greater MIP-1alpha-degrading activity than soluble MMP-8. High levels of membrane-bound MMP-8 were detected on lung PMNs from LPS-treated WT mice, but soluble, active MMP-8 was not detected in BALF samples. Thus, MMP-8 has novel roles in restraining lung inflammation and in limiting alveolar capillary barrier injury during ALI in mice by inactivating MIP-1alpha. In addition, membrane-bound MMP-8 on activated lung PMNs is likely to be the key bioactive form of the enzyme that limits lung inflammation and alveolar capillary barrier injury during ALI.
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PMID:Matrix metalloproteinase-8 inactivates macrophage inflammatory protein-1 alpha to reduce acute lung inflammation and injury in mice. 2004 85


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