Contributions of nitric oxide synthase isoforms to pulmonary oxygen toxicity, local vs. mediated effects (original) (raw)
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American Journal of Physiology-Lung Cellular and Molecular Physiology, 2007
Pulmonary manifestations of oxygen toxicity were studied and quantified in rats breathing >98% O2at 1, 1.5, 2, 2.5, and 3 ATA to test our hypothesis that different patterns of pulmonary injury would emerge, reflecting a role for central nervous system (CNS) excitation by hyperbaric oxygen. At 1.5 atmosphere absolute (ATA) and below, the well-recognized pattern of diffuse pulmonary damage developed slowly with an extensive inflammatory response and destruction of the alveolar-capillary barrier leading to edema, impaired gas exchange, respiratory failure, and death; the severity of these effects increased with time over the 56-h period of observation. At higher inspired O2pressures, 2–3 ATA, pulmonary injury was greatly accelerated but less inflammatory in character, and events in the brain were a prelude to a distinct lung pathology. The CNS-mediated component of this lung injury could be attenuated by selective inhibition of neuronal nitric oxide synthase (nNOS) or by unilateral ...
Two faces of nitric oxide: implications for cellular mechanisms of oxygen toxicity
Journal of Applied Physiology, 2008
Recent investigations have elucidated some of the diverse roles played by reactive oxygen and nitrogen species in events that lead to oxygen toxicity and defend against it. The focus of this review is on toxic and protective mechanisms in hyperoxia that have been investigated in our laboratories, with an emphasis on interactions of nitric oxide (NO) with other endogenous chemical species and with different physiological systems. It is now emerging from these studies that the anatomical localization of NO release, which depends, in part, on whether the oxygen exposure is normobaric or hyperbaric, strongly influences whether toxicity emerges and what form it takes, for example, acute lung injury, central nervous system excitation, or both. Spatial effects also contribute to differences in the susceptibility of different cells in organs at risk from hyperoxia, especially in the brain and lungs. As additional nodes are identified in this interactive network of toxic and protective respo...
American Journal of Respiratory and Critical Care Medicine, 1997
Nitric oxide (NO) may either protect against or contribute to oxidant-induced lung injury. In this study, we sought to determine whether either inhaled NO in concentration of 10 and 100 parts per million (ppm) or inhibition of endogenous NO formation with L-NG nitroarginine methyl ester (L-NAME) or aminoguanidine alters the extent of lung injury in rats breathing 100% 0 2. Lung thiobarbituric acid reactive substances (TBARS), wet to dry lung weight ratio (Q W/QD), vascular and epithelial permeability (assessed by simultaneous intravenous administration of 131 1-labeled albumin and intraalveolar instillation of 125 1-labeled albumin), alveolar liquid clearance (evaluated based on the increase in alveolar protein concentration), and lung liquid clearance (gravimetric method) were determined after 40 h exposure to either 100% or 21% 0 2 . Exposure to hyperoxia caused increases in lung TBARS from 10.5 ± 0.7 to 13.7 ± 1.5 µmol/mg protein (p < 0.05); in blood hemoglobin concentration (Hb) from 14 ± 1 g/dI to 17 ± 1 g/d1 (p < 0.05); in the QW/QD ratio from 4.02 ± 0.3 to 5.31 ± 0.5 (p < 0.05); and in alveolar-arterial oxygen tension difference from 124 ± 14 mm Hg to 241 ± 61 mm Hg (p < 0.05); as well as a decrease in blood pressure, from 131 ± 15 mm Hg to 72 ± 26 mm Hg (p < 0.05). Hyperoxia also increased vascular albumin leakage and moderately altered epithelial barrier permeability to protein. Inhalation of 10 ppm NO prevented the increases in TBARS and QW/QD, had no effect on the alveolar barrier impermeability to protein, and improved alveolar liquid clearance. Inhalation of 100 ppm NO did not alter the increases in TBARS and QW/QD but increased vascular permeability to protein. Survival of rats exposed to hyperoxia was not improved by inhaled NO. Treatment with L-NAME or aminoguanidine reduced survival. L-NAME, but not aminoguanidine, increased lung TBARs. These results suggest that, depending on its concentration, inhaled NO can either reduce or increase the early consequences of hyperoxic lung injury. Treatment with L-NAME, and to a lesser extent aminoguanidine, worsened hyperoxic lung injury, indicating a protective effect of endogenous NO. Garat C, Jayr C, Eddahibi S, Laffon M, Meignan M, Adnot S. Effects of Inhaled nitric oxide or Inhibition of endogenous nitric oxide formation on hyperoxic lung Injury.
Respiratory Medicine, 2007
Study objectives: High-concentration oxygen therapy is used to treat tissue hypoxia, but hyperoxia causes lung injury. Overproduction of nitric oxide by nitric oxide synthase (NOS) is thought to promote hyperoxic lung injury. The present study was conducted to examine the role of inducible nitric oxide synthase (iNOS) in hyperoxic lung injury in mice. Measurements and results: Mice were exposed to 498% oxygen for 72 h, and ONO-1714 (0.05 mg/kg) (ONO) was subcutaneously administered to block iNOS. Hyperoxia significantly increased total cell count, protein concentration, and nitrites/nitrates in the bronchoalveolar lavage fluid and proinflammatory cytokines in the lung tissue. ONO significantly prevented the increases in all of these variables. ONO suppressed histologic evidence of lung injury. ONO markedly inhibited iNOS protein expression and nitrotyrosine production in lung homogenates. After exposure to hyperoxia, alveolar epithelial cells stained positively for 8-hydroxy-2 0-deoxyguanosine, a proper marker of oxidative DNA damage by reactive oxygen species. ONO attenuated this finding. Conclusions: NOS play important roles in the pathogenesis of hyperoxic lung injury. Selective iNOS inhibitors may be useful for the treatment of hyperoxic lung injury.
Nitric oxide-mediated central sympathetic excitation promotes CNS and pulmonary O2 toxicity
Journal of Applied Physiology, 2012
In hyperbaric oxygen (HBO2) at or above 3 atmospheres absolute (ATA), autonomic pathways link central nervous system (CNS) oxygen toxicity to pulmonary damage, possibly through a paradoxical and poorly characterized relationship between central nitric oxide production and sympathetic outflow. To investigate this possibility, we assessed sympathetic discharges, catecholamine release, cardiopulmonary hemodynamics, and lung damage in rats exposed to oxygen at 5 or 6 ATA. Before HBO2 exposure, either a selective inhibitor of neuronal nitric oxide synthase (NOS) or a nonselective NOS inhibitor was injected directly into the cerebral ventricles to minimize effects on the lung, heart, and peripheral circulation. Experiments were performed on both anesthetized and conscious rats to differentiate responses to HBO2 from the effects of anesthesia. EEG spikes, markers of CNS toxicity in anesthetized animals, were approximately four times as likely to develop in control rats than in animals with...
Respiratory Care, 2012
To analyze the early effects of low INO dose on oxygenation, oxidative stress, inflammatory, and histopathological lung injury in a rabbit model of acute lung injury (ALI). METHODS: This was a prospective, controlled, in vivo animal laboratory study. Forty rabbits were instrumented and ventilated at F IO 2 1.0. ALI was induced by tracheal infusion of warm saline (30 mL/kg, 38°C) and lung oxidative stress was assessed by total antioxidant performance (TAP) assay. Animals were assigned to groups: control group (no. ؍ 10, low tidal volume [V T ] ؍ 6 mL/kg, PEEP ؍ 5 cm H 2 O), ALI without INO (no-INO group, no. ؍ 10, low V T ؍ 6 mL/kg, PEEP ؍ 10 cm H 2 O), ALI plus INO (INO group, no. ؍ 10, low V T ؍ 6 mL/kg, PEEP ؍ 10 cm H 2 O, INO ؍ 5 ppm). Plateau pressure was limited to 30 cm H 2 O in all groups. Ten non-instrumented animals (healthy group) were studied for TAP assay. Ventilatory and hemodynamic parameters were recorded every 30 min for 4 hours. RESULTS: After lung injury, the instrumented groups were worse than the control group for P aO 2 (control group 438 ؎ 87 mm Hg, no-INO group 80 ؎ 13 mm Hg, INO group 81 ؎ 24 mm Hg, P < .001). The INO group showed decreased lung inflammation by leukocyte count in lung lavage fluid (no-INO group 4.8 ؎ 1.64, control group 0.16 ؎ 0.15, INO group 0.96 ؎ 0.35 polymorphonuclear cells ؋ 10 6 /bronchoalveolar lavage fluid/lung, P < .001), decreased histopathological injury score (no-INO group 5 [range 1-16], INO group 2 [range 0 -5], control group 0 [range 0 -3], P < .001), and better lung protection against oxidative injury than the no-INO group (healthy group 68 ؎ 8.7, control group 66.4 ؎ 6.8, INO group 56.3 ؎ 5.1, no-INO group 45.9 ؎ 3.4 percent protection/g protein, P < .001). CONCLUSIONS: INO attenuates oxidative stress and histopathological and inflammatory lung injury in a saline-lavaged rabbit ALI model. Key words: ARDS; mechanical ventilation; oxidative injury; acute lung injury; rabbits; inhaled nitric oxide. [Respir Care 2012;57(2): 273-281.
The Chinese journal of physiology, 2006
Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia on the protein expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), nitric oxide (NO) production, and hypoxic pulmonary vasoconstriction (HPV) in rat lung. Twenty-four male rats were divided into hyperoxic and normoxic groups. Hyperoxic rats were placed in > 90% F1O2 for 60 h prior to experiments. After baseline in vitro analysis, the rats underwent isolated, perfused lung experiments. Two consecutive hypoxic challenges (10 min each) were administered with the administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), in between. We measured intravascular NO production, pulmonary arterial pressure, and protein expression of eNOS and iNOS by immunohistochemistry. We found that hyperoxia rats exhibited increased baseline NO production (P < 0.001) and blunted HPV response (P < 0.001) during hypoxic challeng...
Nitric Oxide Potentiates Acute Lung Injury in an Isolated Rabbit Lung Model
The Annals of Thoracic Surgery, 1998
Background. The effect of inhaled nitric oxide (NO) treatment on pulmonary function in the setting of adult respiratory distress syndrome is controversial. We examined the effect of inhaled NO on pulmonary function in an isolated rabbit lung model of oleic acid (OA)-induced acute lung injury. We hypothesized that NO would decrease pulmonary artery pressure and improve oxygenation.
Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species
Proceedings of the National Academy of Sciences, 1993
Nitric oxide, NO, which is generated by various components of the immune system, has been presumed to be cytotoxic. However, NO has been proposed to be protective against cellular damage resulting during ischemia reperfusion. Along with NO there is often concomitant formation of superoxide/hydrogen peroxide, and hence a synergistic relationship between the cytotoxic effects of nitric oxide and these active oxygen species is frequently assumed. To study more carefully the potential synergy between NO and active oxygen species in mammalian cell cytotoxicity, we utilized either hypoxanthine/xanthine cell cytotoxicity, we utilized either hypoxanthine/xanthine oxidase (a system that generates superoxide/hydrogen peroxide) or hydrogen peroxide itself. NO generation was accomplished by the use of a class of compounds known as "NONOates," which release NO at ambient temperatures without the requirement of enzyme activation or biotransformation. When Chinese hamster lung fibroblast...