Combined neuronal and inducible nitric oxide synthase inhibition in ovine acute lung injury*

Abstract

Objective Acute lung injury (ALI) with subsequent pneumonia and sepsis represents a major cause of morbidity and mortality in thermally injured patients. Production of nitric oxide (NO) by the neuronal and inducible NO synthase (nNOS, iNOS) may be critically involved in the pathophysiology of the disease process at different time points and thus specific inhibition at different times may represent an effective treatment regimen. Design Prospective, controlled, randomized trial. Setting University research laboratory. Subjects Eighteen chronically instrumented, adult, female sheep. Interventions Following baseline measurements, the animals were allocated to either sham-injured, non-treated controls (sham), injured, non-treated controls (control), or injured animals treated with continuous infusion of 7-nitroindazole, a specific nNOS inhibitor, during the first 12 hrs post-injury and infusion of BBS-2, a specific iNOS inhibitor, during the next 12 hrs. Injury was induced by 48 breaths of cotton smoke and subsequent instillation of Ps. aeruginosa into the lungs. All sheep were mechanically ventilated and fluid resuscitated for the entire duration of the 24-hour experiment. Measurements and Main Results The injury induced severe pulmonary dysfunction which was associated with increases in lung edema formation, airway obstruction, and vascular endothelial growth factor (VEGF), 3-nitrotyrosine (3-NT), and poly(ADP ribose) (PAR) expression in lung tissue. The treatment reduced the degree of airway obstruction and improved pulmonary gas exchange, whereas the development of lung edema was not affected. The increases in lung tissue VEGF, 3-NT, and PAR expression were attenuated by the treatment. Conclusions The combination of early nNOS and delayed iNOS inhibition shows potential benefit in ovine ALI by reducing nitrosative stress in the lung and limiting the degree of airway obstruction.

Naringin attenuates acute lung injury in LPS-treated mice by inhibiting NF-κB pathway

“…Wang LF and his colleagues found that both pulmonary parenchymal cells and inflammatory cells contribute to the increased lung iNOS activity in endotoxemia, pulmonary parenchymal cells contribute to a significantly greater degree [46]. Accumulating evidence suggest that inhibitors of iNOS may be potential therapeutic agents for clinical application in patients with ALI/ARDS because the inflammatory responses and ALI following infusion of LPS are due to the production of NO, free radicals and proinflammatory cytokines through the iNOS system [47][48][49][50]. Here, our finding revealed that naringin significantly reduced LPS-induced increment of iNOS activity.…”

Beneficial pulmonary effects of a metalloporphyrinic peroxynitrite decomposition catalyst in burn and smoke inhalation injury

“…MPO concentrations were evaluated on homogenized whole lungs with a commercially available assay (CytoStore, Calgary, AB, Canada). MPO activity was normalized to lung wet-to-dry weight ratio and reported as units per gram of dry tissue, as previously reported (16).…”

“…B-2, Santa Cruz Biotechnology, Santa Cruz, CA), and VEGF (mouse monoclonal VEGF antibody; catalog no. VG-1, Abcam) was measured in lung tissue homogenates using a Western blot protocol, as described previously (16). Blots were quantified by National Institutes of Health IMAGEJ scanning densitometry and normalized to total actin expression.…”

Time course of the inflammatory and oxidative stress response to pulmonary infection in mice

“…In addition, these studies investigated only a few time points during the initial phase after the onset of infection [12][13][14][15][16]. However, recent experimental evidence suggests that the initial phase may be critical [4,17].…”