Effects of inhaled nitric oxide or inhibition of endogenous nitric oxide formation on hyperoxic lung injury.

Administration of inhaled nitric oxide (iNO) is a potential therapeutic strategy to prevent bronchopulmonary dysplasia (BPD) in premature newborns with respiratory distress syndrome. We evaluated this approach in a rat model, in which premature pups were exposed to room air, hyperoxia, or a combination of hyperoxia and NO (8.5 and 17 ppm). We investigated the anti-inflammatory effects of prolonged iNO therapy by studying survival, histopathology, fibrin deposition, and differential mRNA expression (real-time RT-PCR) of key genes involved in the development of BPD. iNO therapy prolonged median survival 1.5 days ( P = 0.0003), reduced fibrin deposition in a dosage-dependent way up to 4.3-fold ( P < 0.001), improved alveolar development by reducing septal thickness, and reduced the influx of leukocytes. Analysis of mRNA expression revealed an iNO-induced downregulation of genes involved in inflammation (IL-6, cytokine-induced neutrophilic chemoattractant-1, and amphiregulin), coagulation, fibrinolysis (plasminogen activator inhibitor 1 and urokinase-type plasminogen activator receptor), cell cycle regulation (p21), and an upregulation of fibroblast growth factor receptor-4 (alveolar formation). We conclude that iNO therapy improves lung pathology and prolongs survival by reducing septum thickness, inhibiting inflammation, and reducing alveolar fibrin deposition in premature rat pups with neonatal hyperoxic lung injury.

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Hypothermia attenuates iNOS, CAT-1, CAT-2, and nitric oxide expression in lungs of endotoxemic rats

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00102.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. L1231-L1238 ◽

Cited By ~ 31

Author(s):

Philip O. Scumpia ◽

Paul J. Sarcia ◽

Vincent G. DeMarco ◽

Bruce R. Stevens ◽

Jeffrey W. Skimming

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Lung Injury ◽

Lung Tissue ◽

Inos Mrna ◽

Amino Acid Transporters ◽

Oxide Formation ◽

Cationic Amino Acid ◽

Nitric Oxide Formation ◽

Oxide Synthase

Endotoxemia stimulates endogenous nitric oxide formation, induces transcription of arginine transporters, and causes lung injury. Hypothermia inhibits nitric oxide formation and is used as a means of organ preservation. We hypothesized that hypothermia inhibits endotoxin-induced intrapulmonary nitric oxide formation and that this inhibition is associated with attenuated transcription of enzymes that regulate nitric oxide formation, such as inducible nitric oxide synthase (iNOS) and the cationic amino acid transporters 1 (CAT-1) and 2 (CAT-2). Rats were anesthetized and randomized to treatment with hypothermia (18–24°C) or normothermia (36–38°C). Endotoxin was administered intravascularly. Concentrations of iNOS, CAT-1, CAT-2 mRNA, iNOS protein, and nitrosylated proteins were measured in lung tissue homogenates. We found that hypothermia abrogated the endotoxin-induced increase in exhaled nitric oxide and lung tissue nitrotyrosine concentrations. Western blot analyses revealed that hypothermia inhibited iNOS, but not endothelial nitric oxide synthase, protein expression in lung tissues. CAT-1, CAT-2, and iNOS mRNA concentrations were lower in the lungs of hypothermic animals. These findings suggest that hypothermia protects against intrapulmonary nitric oxide overproduction and nitric oxide-mediated lung injury by inhibiting transcription of iNOS, CAT-1, and CAT-2.

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