NO Inhibits Hyperoxia-Induced NF-κB Activation in Neonatal Pulmonary Microvascular Endothelial Cells

Abstract

Inhaled nitric oxide may be protective against hyperoxic injury in the premature lung, but the mechanism is unknown. We hypothesized that nitric oxide (NO) would prevent hyperoxia-induced NF-κB activation in neonatal pulmonary microvascular endothelial cells (HPMEC) and prevent the upregulation of target genes. Following hyperoxic exposure (O2> 95%), nuclear NF-κB consensus sequence binding increased and was associated with IκBα degradation. Both of these findings were prevented by exposure to NO. Furthermore, ICAM-1 mRNA and protein levels increased in cells exposed to hyperoxia, an effect abrogated by NO. To evaluate the potentially toxic effect of NO plus hyperoxia, cell viability and proliferation were assessed. Cells exposed to NO plus hyperoxia demonstrated improved survival as measured by trypan blue exclusion when compared to cells exposed to hyperoxia alone. These differences in cell death could not be attributed to apoptosis measured by caspase-3 activity. Finally, cellular proliferation inhibited by hyperoxia was rescued by concurrent exposure to NO. These data demonstrate that NO prevents hyperoxia-induced NF-κB activation in HPMEC and results in decreased expression of adhesion molecules and decreased cellular toxicity. This may help explain the protective effects of NO on hyperoxic injury in the developing lung vasculature.

Hydrocortisone Normalizes Phosphodiesterase‐5 Activity in Pulmonary Artery Smooth Muscle Cells from Lambs with Persistent Pulmonary Hypertension of the Newborn

“…Because IκB expression is an important regulator of NFκB activity, we sought to determine the effects of hyperoxia and hydrocortisone treatment on IκB expression. In contrast to previous studies in microvascular endothelial cells, which have shown decreased IκB expression in response to hyperoxia, 42 we found that 24 hours of hyperoxia did not alter IκB protein expression in PPHN FPASMC (Fig. 7).…”

Astragalus polysaccharides mediated preventive effects on bronchopulmonary dysplasia in rats

“…We detected that APS could suppress NF-κBp65 production through inhibited TNF-α in lung tissues (19). It has been reported that APS appears to exert an immune modulating effect by regulating the expression of cytokines such as TNF-α and IL-6 (21,22).…”

“…Elevated levels of TNF-α have been detected in the lungs of various animal and human trials (5,18,19). Besides, elevated TNF-α might be a positive feedback signal that triggered NF-κB reactivation.…”

Attenuation of hyperoxia-induced lung injury in neonatal rats by 1α,25-Dihydroxyvitamin D3

“…Liu YY et al showed that hyperoxic injury was attenuated when NF-κB activity was inhibited by SN-50 [36]. In an in vitro study, Wright CJ et al found that nitric oxide decreased cellular toxicity induced by hyperoxia through inhibiting NF-κB activation [37]. These findings suggested that inhibiting NF-κB activation would alleviate hyperoxic lung injury.…”