title: Preconditioning by inhaled nitric oxide prevents hyperoxic and ischemia/reperfusion injury in rat lungs.
abstract: Since the generation of nitric oxide (NO) is an essential step in the trigger phase of ischemic preconditioning, short-term inhalation of NO before ischemia should ameliorate ischemia/reperfusion (I/R) injury of the lung. We tested this hypothesis in high oxygen (>99%) ventilated rats in order to additionally evaluate compatibility of NO and exposure to hyperoxia. Male adult Sprague-Dawley rats inhaled NO (15 ppm, 10 min) before the left lung hilum was clamped for 1 h, and the reperfusion phase was observed for 4 h (NO group). Animals in the I/R group underwent the same treatment, but without NO inhalation. A third group without I/R served as time-matched controls. Animals in the I/R group showed severe I/R injury in terms of arterial pO2 (apO2), which was reduced to 22% of surgical controls (SCs) at time point 30 min reperfusion, and increased endothelial permeability (Evans blue procedure). The pretreatment with NO attenuated these effects. The pO2 after 4 h reperfusion was still 3.0-fold higher in the NO group compared to I/R. In contrast, the I/R- and hyperoxia-induced invasion of leukocytes, as determined by measuring myeloperoxidase (MPO) activity, was not affected by NO. These data were correlated with the activity of major cellular signaling pathways by measuring the phosphorylation at activating and inhibitory sites of extracellular-signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, protein kinase B (AKT), and glycogen synthase kinase 3beta (GSK-3beta), and by determination of cGMP in plasma and lung tissue. Inhalation of NO partly prevented the loss of activation by I/R and hyperoxic ventilation of ERK, JNK, and AKT, and it reduced the I/R-induced activation of GSK-3beta. The level of cGMP in plasma and lung tissue was increased in the NO group after 4 h reperfusion. In conclusion, application of inhaled NO in the preconditioning mode prevented I/R injury in the rat lung without interfering effects of hyperoxic ventilation. The effects of NO on cellular signaling pathways resemble mechanisms of ischemic preconditioning, but further studies have to evaluate the physiological relevance of these results.
authors.affiliation: Clinic for Cardiac Surgery, University Hospital Dresden, Fetscherstr. 76, 01307 Dresden, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Waldow
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Witt
authors.forename: André
authors.initials: A
authors.lastname: Ulmer
authors.forename: Andreas
authors.initials: A
authors.lastname: Janke
authors.forename: Konstantin
authors.initials: K
authors.lastname: Alexiou
authors.forename: Klaus
authors.initials: K
authors.lastname: Matschke
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002199:Capillary Permeability; D006152:Cyclic GMP / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D038341:Glycogen Synthase Kinases / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D019194:Ischemic Preconditioning; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011659:Pulmonary Gas Exchange; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction
chemical_list: D009569:Nitric Oxide; D038341:Glycogen Synthase Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D006152:Cyclic GMP