Abstract
BackgroundHyperoxic exposures are often found in clinical settings of respiratory insufficient patients, although oxygen therapy (>50% O2) can result in the development of acute hyperoxic lung injury within a few days. Upon hyperoxic exposure, the inducible nitric oxide synthase (iNOS) is activated by a variety of proinflammatory cytokines both in vitro and in vivo. In the present study, we used a murine hyperoxic model to evaluate the effects of iNOS deficiency on the inflammatory response.MethodsWild-type and iNOS-deficient mice were exposed to normoxia, 60% O2 or >95% O2 for 72 h.ResultsExposure to >95% O2 resulted in an increased iNOS mRNA and protein expression in the lungs from wild-type mice. No significant effects of iNOS deficiency on cell differential in bronchoalveolar lavage fluid were observed. However, hyperoxia induced a significant increase in total cell count, protein concentration, LDH activity, lipid peroxidation, and TNF-α concentration in the bronchoalveolar lavage fluid compared to iNOS knockout mice. Moreover, binding activity of NF-κB and AP-1 appeared to be higher in wild-type than in iNOS-deficient mice.ConclusionTaken together, our results provide evidence to suggest that iNOS plays a proinflammatory role in acute hyperoxic lung injury.
Highlights
Hyperoxic exposures are often found in clinical settings of respiratory insufficient patients, oxygen therapy (>50% O2) can result in the development of acute hyperoxic lung injury within a few days
Hyperoxia induced a significant increase in total cell count, protein concentration, lactate dehydrogenase (LDH) activity, lipid peroxidation, and TNF-α concentration in the bronchoalveolar lavage fluid compared to inducible nitric oxide synthase (iNOS) knockout mice
Binding activity of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) appeared to be higher in wild-type than in iNOS-deficient mice
Summary
Hyperoxic exposures are often found in clinical settings of respiratory insufficient patients, oxygen therapy (>50% O2) can result in the development of acute hyperoxic lung injury within a few days. The inducible nitric oxide synthase (iNOS) is activated by a variety of proinflammatory cytokines both in vitro and in vivo. Supplemental oxygen therapy is administered for the treatment of tissue hypoxia, most commonly in an intensive care setting of respiratory insufficient patients, though its potent toxicity is well described [1]. The pathophysiology of oxygen injury is characterized by lung inflammation including activation and recruitment of neutrophils and alveolar macrophages, tissue and alveolar edema, surfactant dysfunction, and excess production of free radicals and inflammatory cytokines [2,3,4]. The precise molecular mechanisms by which hyperoxia produces acute lung injury remain unclear
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