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Theses

Rôles clinico-biologiques du monoxyde d'azote produit par les voies aériennes

Abstract : In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (NOS-1), inducible NOS (NOS-2), and endothelial NOS (NOS-3). NO derived from the constitutive isoforms of NOS (NOS-1 and NOS-3) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone. On the other hand, NO derived from NOS-2 seems to be a proinflammatory mediator with immunomodulatory effects. This thesis explores the physiological and pathophysiological role of endogenous nitric oxide in the airways, and the clinical aspects of monitoring nitric oxide in exhaled air of patients with respiratory disease.First Study: competition between nitric oxide synthases (NOSs) and arginases for their common substrate l-arginine could be involved in the regulation of cholinergic airway reactivity and subsequent airway remodeling. The aims of this study were to evaluate the relationships between the expression of this enzymatic balance and the effects of NOS and arginase inhibition on bronchoconstrictive response to acetylcholine of patients without and with early chronic obstructive pulmonary disease (COPD). Twenty-two human bronchi were investigated for immunohistochemistry and modulation of acetylcholine-induced airway constriction. Significantly increased expression of NOS2 in immunoblots of bronchial tissue and staining in smooth muscle cells was evidenced in patients with COPD compared with control subjects. Forced expiratory volume in 1 s (FEV1) and NOS2 expression were negatively correlated. Pharmacological experiments demonstrated that resting tension was elevated in COPD compared with control subjects and was positively correlated with the expression of NOS2. The sole effect of the specific arginase inhibitor Nomega-hydroxy-nor-L-arginine was to decrease sensitivity in COPD patients, whereas NG-nitro-L-arginine methyl ester unexpectedly decreased resting tension because of a non-cGMP-dependent effect. In conclusion, an upregulation of NOS2 expression in COPD patients is involved in airway tone regulation and functional airflow limitation, whereas increased arginase activity is involved in airway sensitivity.Second Study: the change in exhaled NO after cardio-pulmonary bypass remains controversial. The aims were to determine whether exhaled NO sources (alveolar or bronchial) are modified after bypass, and whether mechanical ventilation (MV) settings during bypass modify exhaled NO changes. Thirty-two patients were divided into three groups: without MV during bypass and positive end-expiratory pressure (PEEP) (n=12), dead space MV without PEEP (n=10) and dead space MV with PEEP (n=10). Alveolar NO concentration and bronchial NO flux were calculated before and 1h after surgery using a two-compartment model of NO exchange developed in spontaneous breathing patients. Whereas a significant decrease in bronchial NO was found after bypass in the two groups without PEEP during bypass, this decrease was not observed in patients with dead space ventilation with PEEP. Alveolar NO was not significantly modified whatever the ventilation settings. In conclusion, the impairment of bronchial NO seemed related to airway closure since dead space mechanical ventilation with PEEP prevented its decrease.Third Study: the development of biomarkers able to predict the occurrence of nosocomial infection could help manage preventive strategies, especially in medical patients whose degree of acquired immunosuppression may be variable. We hypothesized that the NO fraction present in the airways (upper and lower) of critically ill patients under mechanical ventilation could constitute such a biomarker. We conducted an observational study in a medical intensive care unit. Forty-five patients (26 men; 72 [25th-75th percentiles] years [56-82]; Simplified Acute Physiology Score II, 63 [50-81], 14 infected) under mechanical ventilation (>3 days) underwent on day 1 and day 3 of their stay: nasal and exhaled (partitioned in bronchial and alveolar sources) bedside NO measurements, determination of urine NO end products and plasma cytokine (IL-6, IL-10) concentrations, and Sequential Organ Failure Assessment score calculation. Nosocomial infection incidence was recorded during the 15 subsequent days. Fifteen patients (33%) acquired a nosocomial infection. Nasal NO was the only marker significantly different between patients with and without subsequent infection (day 1, 52 ppb [20-142] vs. 134 [84-203], P = 0.038; day 3, 98 ppb [22-140] vs. 225 [89-288], P = 0.006, respectively). Nasal NO fraction 148 ppb or less at day 3 had an 80% sensitivity, a 70% specificity, and an odds ratio of 2.7 (95% confidence interval, 1.9-3.8) to predict acquisition of nosocomial infection. Nasal NO seems to be a relatively sensitive and specific biomarker of subsequent nosocomial infection acquisition.
Keywords : Immunity Copd
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Jean Marc Tadie. Rôles clinico-biologiques du monoxyde d'azote produit par les voies aériennes. Médecine humaine et pathologie. Université Paris-Est, 2010. Français. ⟨NNT : 2010PEST0053⟩. ⟨tel-00667281⟩

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