Nitric oxide : biology and chemistry
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In human alveolar epithelial cell line, we investigated the binding activity of NF-kappaB induced by the bronchoalveolar lavage fluids (BALs) from ventilated patients with acute lung injury (ALI), in correlation with the concentrations of inflammatory cytokines, RNOS, and the severity of the ALI. In BALs obtained in 67 patients (16 bronchopneumonia, 14 infected ARDS, 20 ARDS, and 17 ALI patients without bronchopneumonia and no ARDS), we measured endotoxin, IL-1beta, IL-8, and nitrated proteins (NTP), the activity of myeloperoxidase, and the capacity to activate the NF-kappaB in alveolar A549 cells by electrophoretic mobility shift and supershift assays. The neutrophil counts and mean IL-1beta, IL-8, myeloperoxidase, and NTP values were increased in bronchopneumonia and infected ARDS groups compared to ARDS and ALI without bronchopneumonia and no ARDS groups (P<0.001). ⋯ BALs of bronchopneumonia and infected ARDS patients had increased inflammatory mediators (compared to ARDS and ALI without bronchopneumonia and no ARDS patients) that correlated to neutrophil counts and to the NF-kappaB-binding activity. These mediators and NF-kappaB activation may induce an amplification of inflammatory phenomena. By in vitro studies, we confirmed that NO-derived species (10(-6) to 10(-5)M peroxynitrite and 10(-5)M nitrites) and myeloperoxidase (at concentration equivalent to that found in BALs) can participate in the NF-kappaB activation.
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Monocyte chemoattractant protein 1 (MCP-1) is an important mediator of monocyte/macrophage recruitment and activation at the sites of chronic inflammation and neoplasia. In the current study, the role of nitrogen monoxide (NO) in the activation of murine peritoneal macrophages to the tumoricidal state in response to in vitro MCP-1 treatment and the regulatory mechanisms involved therein were investigated. Murine peritoneal macrophages upon activation with MCP-1 showed a dose- and time-dependent production of NO together with increased tumoricidal activity against P815 mastocytoma cells. ⋯ Various modulators of calcium and calmodulin (CaM) such as EGTA, nifedipine, TMB-8 (3,4,5-trimethoxybenzoic acid-8-(diethylamino)octyl ester), A23187, and W-7 (N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide) were also found to modulate the in vitro macrophage NO release in response to MCP-1. This observation indicated the regulatory role of calcium/CaM in the process of MCP-1-induced macrophage NO production. Similarly, the role of serine/threonine and protein tyrosine phosphatases in the above pathway was suggested using the specific inhibitors of these phosphatases, okadaic acid and sodium orthovanadate.
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Review
Nitric oxide synthase-independent generation of nitric oxide in muscle ischemia--reperfusion injury.
Nitric oxide (NO) is an important molecule in many physiological or pathophysiological processes including ischemia--reperfusion injury. The enzymatic nitric oxide synthase (NOS)-dependent pathway was universally accepted as the source of NO in ischemia-reperfusion injury. However, generation of NO that is independent of NOS has also been identified in ischemia--reperfusion injury to both cardiac and skeletal muscle. This review summarizes the evidence for the generation NOS-independent NO in ischemia--reperfusion injury to cardiac and skeletal muscle.
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The effects of taurine (T) and niacin (N) on the influx of inflammatory cells and nitric oxide (NO) levels in bronchoalveolar lavage fluid (BALF) and expression of inducible NO synthase (iNOS) mRNA and iNOS protein in lungs were evaluated in the bleomycin (BL)-mouse model of lung fibrosis. Mice were placed into four groups: saline-instilled (SA) with a control diet (CD) (SA + CD); saline-instilled with TN (1% taurine in water + 2.5% (w/w) niacin in diet) (SA + TN); BL-instilled with CD (BL + CD); and BL-instilled with TN treatment (BL + TN). There was no difference in differential cell counts in BALF between the SA + CD and SA + TN control groups. ⋯ The increases in NO levels in BALF from the BL + CD group were associated with elevated levels of iNOS gene expression and protein in the lungs. RT-PCR analysis of total RNA isolated from the lungs indicated that taurine and niacin treatment suppressed the BL-induced increases in iNOS message and iNOS protein. The ability of taurine and niacin to suppress the BL-induced increased production of NO secondary to decreases in iNOS mRNA and protein appears to be one of the mechanisms for their anti-inflammatory and antifibrotic effects.