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Background: S-nitrosoglutathione (GSNO) serves as a reservoir for nitric oxide (NO) and thus is a key homeostatic regulator of airway smooth muscle tone and inflammation. Decreased levels of GSNO in the lungs of asthmatics have been attributed to increased GSNO catabolism via GSNO reductase (GSNOR) leading to loss of GSNO- and NO- mediated bronchodilatory and anti-inflammatory actions. GSNOR inhibition with the novel small molecule, N6022, was explored as a therapeutic approach in an experimental model of asthma., Methods: Female BALB/c mice were sensitized and subsequently challenged with ovalbumin (OVA). Efficacy was determined by measuring both airway hyper-responsiveness (AHR) upon methacholine (MCh) challenge using whole body plethysmography and pulmonary eosinophilia by quantifying the numbers of these cells in the bronchoalveolar lavage fluid (BALF). Several other potential biomarkers of GSNOR inhibition were measured including levels of nitrite, cyclic guanosine monophosphate (cGMP), and inflammatory cytokines, as well as DNA binding activity of nuclear factor kappa B (NFκB). The dose response, onset of action, and duration of action of a single intravenous dose of N6022 given from 30 min to 48 h prior to MCh challenge were determined and compared to effects in mice not sensitized to OVA. The direct effect of N6022 on airway smooth muscle tone also was assessed in isolated rat tracheal rings., Results: N6022 attenuated AHR (ED50 of 0.015 ± 0.002 mg/kg; Mean ± SEM) and eosinophilia. Effects were observed from 30 min to 48 h after treatment and were comparable to those achieved with three inhaled doses of ipratropium plus albuterol used as the positive control. N6022 increased BALF nitrite and plasma cGMP, while restoring BALF and plasma inflammatory markers toward baseline values. N6022 treatment also attenuated the OVA-induced increase in NFκB activation. In rat tracheal rings, N6022 decreased contractile responses to MCh., Conclusions: The significant bronchodilatory and anti-inflammatory actions of N6022 in the airways are consistent with restoration of GSNO levels through GSNOR inhibition. GSNOR inhibition may offer a therapeutic approach for the treatment of asthma and other inflammatory lung diseases. N6022 is currently being evaluated in clinical trials for the treatment of inflammatory lung disease.

Exercise-induced bronchospasm is a common condition of patients who have asthma. Its mechanism appears to be related to cooling of the airways. Clinically, it can be managed by pretreatment with beta-adrenergic medications or cromolyn. Measures to protect the airway from excessive loss of heat, such as the use of scarves or participating in indoor activity, are also effective strategies in its management.

A retrospective analysis of 811 patients admitted to the hospital for status asthmaticus over a nine-year period was performed. Eight patients died, and 19 required mechanical ventilation. All persons who died of status asthmaticus were in the group that required mechanical ventilation. In 12 of the patients who received ventilation, no definite cause for the acute exacerbation could be identified, although initial arterial blood gas analyses showed profound hypoxemia, hypercapnia, and acute respiratory acidosis. Seventy-eight major complications occurred during mechanical ventilation. Pneumothorax, endotracheal tube malfunction, alveolar hypoventilation on the ventilator, and pneumonia were associated with decreased survival. Mucous plugging of the airways was found in all autopsied patients. Mechanical ventilation in status asthmaticus is a life-support system associated with substantial morbidity and should be instituted only when it becomes evident that maximal medical therapy will not be efficacious.

Three instances of intense laryngospasm and bronchospasm occurred as a result of fiberoptic bronchoscopic examination in three patients with quiescent bronchial asthma. The indications for the procedure were hemoptysis in one patient and lobar collapse in two. It is likely that vagally mediated reflex laryngospasm and bronchoconstriction occur when irritant receptors are mechanically stimulated by the bronchoscope. Therefore, in the asthmatic population with its increased airway reactivity, indications for fiberoptic bronchoscopy should be absolute, and the procedure should be performed under optimal conditions. A rationale for minimizing the risk of this procedure in patients with bronchial asthma is discussed.