Nitric Oxide Potentiates Acute Lung Injury in an Isolated Rabbit Lung Model (original) (raw)
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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.
Partial liquid ventilation and nitric oxide in experimental acute lung injury
Journal of Paediatrics and Child Health, 2002
Objective: To investigate the effects of inhaled nitric oxide (iNO) and partial liquid ventilation (PLV) on oxygenation and pulmonary haemodynamics in acute lung injury (ALI), and to assess their effects on lung function, systemic haemodynamics and lung injury. Methods: Using saline lung lavage, ALI was induced in 18 piglets. A control group was ventilated with conventional mechanical ventilation (CMV) for 2 h. An iNO-first group received iNO for the first hour and then iNO with PLV. A PLVfirst group received PLV for the first hour and then PLV with iNO. Variables were measured at baseline, 5 min postlavage, and at 1 h and 2 h postlavage. Results: During the first hour, both treatment groups showed improvement in oxygenation index (OI). At 2 h, the differences in OI were statistically significant ( P = 0.037), with a mean ± SD of 23.8 ± 20.7 in the control group, 4.4 ± 0.9 in the PLV-first group and 6.5 ± 3.1 in the iNO-first group. The OI was similar in both treatment groups ( P = 0.178). At 2 h, the pulmonary artery pressure (PAP) was significantly different ( P = 0.04) between groups, with a mean ± SD PAP of 36.3 ± 7.2 mmHg in the control group, 27.4 ± 4.0 mmHg in the PLV-first group and 30.0 ± 4.1 mmHg in the iNO-first group. The PAP was similar in both treatment groups ( P = 0.319). Conclusion: In ALI, oxygenation and pulmonary hypertension are improved with PLV and iNO given together, regardless of the order in which they are commenced.
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.
Inhaled Nitric Oxide in Acute Respiratory Distress Syndrome
American Journal of Respiratory and Critical Care Medicine, 1998
The aim of this prospective study was to assess whether the presence of septic shock could influence the dose response to inhaled nitric oxide (NO) in NO-responding patients with adult respiratory distress syndrome (ARDS). Results: Eight patients with ARDS and without septic shock (PaO 2 = 95 ± 16 mmHg, PEEP = 0, FiO 2 = 1.0), and eight patients with ARDS and septic shock (PaO 2 = 88 ± 11 mmHg, PEEP = 0, FiO 2 = 1.0) receiving exclusively norepinephrine were studied. All responded to 15 ppm inhaled NO with an increase in PaO 2 of at least 40 mmHg, at FiO 2 1.0 and PEEP 10 cmH 2 O. Inspiratory intratracheal NO concentrations were recorded continuously using a fast response time chemiluminescence apparatus. Seven inspiratory NO concentrations were randomly administered: 0.15, 0.45, 1.5, 4.5, 15, 45 and 150 ppm. In both groups, NO induced a dose-dependent decrease in mean pulmonary artery pressure (MPAP), pulmonary vascular resistance index (PVRI), and venous admixture (Q VA /Q T ), and a dosedependent increase in PaO 2 /FiO 2 (P ≤ 0.012). Dose-response of MPAP and PVRI were similar in both groups with a plateau effect at 4.5 ppm. Dose-response of PaO 2 /FiO 2 was influenced by the presence of septic shock. No plateau effect was observed in patients with septic shock and PaO 2 /FiO 2 increased by 173 ± 37% at 150 ppm. In patients without septic shock, an 82 ± 26% increase in PaO 2 / FiO 2 was observed with a plateau effect obtained at 15 ppm. In both groups, dose-response curves demonstrated a marked interindividual variability and in five patients pulmonary vascular effect and improvement in arterial oxygenation were dissociated. Conclusion: For similar NOinduced decreases in MPAP and PVRI in both groups, the increase in arterial oxygenation was more marked in patients with septic shock.
Antiinflammatory effect of inhaled nitric oxide on acute lung injury
Despite no reported survival benefit by inhaled nitric oxide (NO) among patients with acute respiratory distress syndrome (ARDS) until now, NO inhalation is still deemed acceptable as a rescue therapy for ARDS patients with refractory hypoxemia to various therapeutic measures. However, it is unclear whether inhaled NO exerts either detrimental or beneficial effects on the pathogenesis of ARDS. Laboratory studies suggest that inhaled NO might reduce some types of acute lung injury (ALI). By contrast, NO and nitrite could interact with neutrophil myeloperoxidase or high oxygen in the alveoli to stimulate oxidative reactions during inflammation. Recent experimental data suggest that inhaled NO might attenuate endotoxin-induced ALI. Considering the diverse role of NO as an important endogenous regulatory molecule on both proinflammatory and antiinflammatory processes, the effects of early and continued therapy with low dose of inhaled NO on ALT should be determined.
Nitric Oxide, 2000
Intratracheal NONOates reduce pulmonary hypertension and improve oxygenation in ALI. We hypothesized that the pharmacologic properties of NO donors would be unaltered after surfactant admixture in vitro and that aerosolized NONOate activity would be enhanced by surfactant pretreatment in vivo. NO donors were added to saline or surfactant and analyzed for nitrite/nitrate production and aortic ring vasodilation. Surfactant did not alter nitrate/ nitrite production or aortic ring vasodilation. A porcine model of ALI with pulmonary hypertension was produced using intravenous oleic acid. Animals were assigned to Surfactant-Saline, Surfactant-NONOate, Saline-Saline, or Saline-NONOate groups. Saline or surfactant was instilled into the trachea, followed by gas exchange, pulmonary function, and hemodynamic measurements. NONOate or saline was then aerosolized, and additional data were collected. Oxygenation was improved in the Surfactant-NONOate group, while pulmonary hypertension was selectively reduced in both NONOate groups. Aerosolized NONOate following surfactant pretreatment improves oxygenation and reduces pulmonary hypertension in ALI.
Critical Care Medicine, 2005
N itric oxide (NO) inhalation has gained great interest in critical care medicine over the past decade (1) because of its "selective" pulmonary vasodilatory properties, its apparent safety, and the easy delivery as a gas by the inhalational route (2). When administered into the airways, NO diffuses into the pulmonary vascular smooth muscle cells, where it increases cyclic guanosine monophosphate (cGMP) concentrations, causing se-lective pulmonary vasodilation (3). Two major indications for NO inhalation are commonly accepted, based on its pulmonary vessel vasodilator properties. The first is rapid improvement of ventilation/ perfusion mismatch and subsequent oxygenation in acute lung injury in adults (4, 5) and, more important, in children . The other indication of pulmonary vessel vasodilation is to improve compromised right ventricular function, especially in the presence of pulmonary hypertension (7). In addition to its direct effect on the pulmonary vasculature, many other effects have been documented suggesting anti-inflammatory (8), anti-platelet aggregation (9, 10), and cytoprotective actions (6).