We investigated the role of peroxynitrite, which is formed by a rapid reaction between nitric oxide (NO) and superoxide anion (O(2)(-)), in the airway microvascular hyperpermeability during the late allergic response (LAR) in sensitized guinea pigs in vivo. The occurrence of LAR was assessed as a 100% increase in the transpulmonary pressure, which was monitored by the esophageal catheter technique. Airway microvascular permeability was assessed by Monastral blue dye trapping between the endothelium using an image analyzer. In the LAR phase (4 to 6 h after antigen inhalation), microvascular hyperpermeability and eosinophil infiltration within the airway wall were observed. NO production and xanthine oxidase (XO)/xanthine dehydrogenase activity, which are responsible for O(2)(-) production, were enhanced during the LAR. Peroxynitrite formation assessed by nitrotyrosine immunostaining was also exaggerated at that time. The microvascular hyperpermeability during the LAR was largely reduced by NO synthase inhibitor (L-NAME, 72.7% inhibition; p < 0.05), XO inhibitor (AHPP, 60.8% inhibition; p < 0. 05) and peroxynitrite scavenger (ebselen, 81.0% inhibition; p < 0. 05). L-NAME had a small but significant inhibitory effect on airway eosinophil accumulation, but AHPP and ebselen had no effect. These results suggest that excessive production of O(2)(-) and NO occurs in the LAR. These two molecules appear to cause airway microvascular hyperpermeability via peroxynitrite formation.
Nitric oxide (NO), a neurotransmitter of inhibitory nonadrenergic noncholinergic (iNANC) nerves in airways, is a radical with a short half-life, and its function may be modified by airway inflammation. To test this hypothesis, we examined whether airway allergic inflammation affects iNANC responses mediated by NO in guinea pigs in vitro. Animals sensitized with ovalbumin (OA) were challenged with 0.03% OA (OA group) or saline (saline group) by inhalation on 3 consecutive days. On the day after the final challenge, iNANC responses elicited by electrical field stimulation (2 to 16 Hz) or relaxation responses to 3-morpholinosydnonimine (SIN-1), 10(-8) to 10(-4) M, were obtained in the tracheal strips precontracted by histamine (3 x 10(-6) M) in the presence of atropine and propranolol (both 10(-6) M). The INANC responses of the OA group were significantly attenuated compared with those of the saline group (p < 0.05), and the inhibitory effect of a NO synthase (NOS) inhibitor, Nm-nitro-L-arginine methyl ester, on the INANC responses was abolished in the OA group. SIN-1-induced tracheal smooth muscle relaxation was also significantly affected by antigen exposure (p < 0.05), the effect of which disappeared in the presence of a NO scavenger, carboxy PTIO (3 x 10(-6) M). The impairment of the INANC responses after antigen exposure was significantly restored by superoxide dismutase (1,000 U/ml), especially at lower frequencies. Histochemical demonstration of NADPH-diaphorase-positive nerves representing neural NOS density was not different between the two groups. These results suggest that allergic airway inflammation impairs neural NO-induced relaxation, presumably by inhibiting the access of neural NO to the airway smooth muscle.
Airway hyperresponsiveness (AHR), in which airway inflammation has been reported to be a key factor, is an important component of asthma. However the precise role of inflammation in AHR is still unclear.In this report, airway inflammatory changes were assessed using hypertonic salineinduced sputum examination and exhaled nitric oxide analysis, and the relation between AHR to methacholine, airway calibre forced expiratory volume in one second (FEV1) and airway inflammatory indices examined. Furthermore, the changes in these variables were also examined by means of 8 weeks' open uncontrolled inhaled steroid administration (800 mg . beclomethasone . day -1 ).Asthmatic subjects had higher eosinophil counts and bradykinin concentration in induced sputum and higher exhaled NO levels, and showed AHR to methacholine. Baseline AHR significantly correlated with FEV1 but not with indices of inflammation in sputum or exhaled air. Steroid inhalation therapy was associated with a reduction in eosinophil and bradykinin concentration in sputum and NO levels in exhaled air and an improvement in FEV1 and AHR. The changes in FEV1 and AHR were significantly related to changes in markers in sputum and exhaled air (p<0.01 for each).These results suggest that baseline airway hyperresponsiveness can be predicted from the airway calibre but not from inflammatory parameters in sputum or exhaled air. In contrast, the reversible component of airway hyperresponsiveness appeared to be associated with the reduction in airway inflammation. Eur Respir J 2000; 15: 248±253.
Role of endogenous nitric oxide in airway microvascular leakage induced by inflammatory mediators. N. Kageyama, M. Miura, M. Ichinose, M. Tomaki, J. Ishikawa, Y. Ohuchi, N. Endoh, K. Shirato. ERS Journals Ltd 1997. ABSTRACT: This study examines the role of endogenous nitric oxide (NO) in airway microvascular leakage induced by inflammatory mediators, which play an important role in asthmatic airways.Guinea-pigs were anaesthetized and mechanically-ventilated with monitoring of arterial blood pressure, and airway microvascular leakage induced by intravenous injection of substance P (SP), leukotriene D 4 (LTD 4 ) and histamine was evaluated using Evans blue dye and Monastral blue dye in the presence and absence of the NO synthase inhibitors, L-N G -nitroarginine methyl ester (L-NAME) and L-N Gmonomethyl arginine (L-NMMA). The effect of a soluble guanylate cyclase inhibitor, LY83583, on SP-induced dye leakage was also examined.Intravenous injection of SP (1 µg·kg -1 ), LTD 4 (1 µg·kg -1 ) and histamine (100 µg·kg -1 ) significantly increased dye extravasation at all airway levels. Pretreatment with L-NAME (10 mg·kg -1 i.v.) and L-NMMA (100 mg·kg -1 i.v.) significantly inhibited SP-induced extravasation, and L-arginine (100 mg·kg -1 i.v.) reversed L-NAMEinduced inhibition. L-NAME (10 mg·kg -1 i.v.) also significantly inhibited LTD 4 -induced dye extravasation only in central airways, and this inhibitory effect was abolished by a neurokinin-1 (NK 1 ) antagonist, FK888 (10 mg·kg -1 i.v.) pretreatment. Histamineinduced dye extravasation was not affected by L-NAME. LY83583 (2.5 and 7.5 mg·kg -1 i.v.) partially but significantly reduced SP-induced dye leakage.These results suggest that endogenous nitric oxide plays a role in neurokinin-1 receptor-mediated airway microvascular leakage, and presumably involves the guanylate cyclase pathway. Eur Respir J., 1997; 10: 13-19
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