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Abstract Rationale Exhaled breath nitric oxide (FeNO) is increased in asthma. NO is produced predominantly by inducible nitric oxide synthase (iNOS). Objectives We evaluated the selective and potent iNOS inhibitor GW274150 in asthma. Methods Twenty-eight steroid-naive patients with asthma participated in a double-blind, randomized, double-dummy, placebo-controlled, three-period cross-over study. Subjects received GW274150 (90 mg), montelukast (10 mg), or placebo once daily for 14 days. FeNO was assessed predose on Days 1, 7, 10, and 14. Adenosine 5′-monophosphate (AMP) challenge was performed on Day 10, allergen challenge on Day 14 followed by methacholine challenge (MCh) 24 hours later, and then bronchoscopy. Measurements and Main Results GW274150 reduced predose FeNO by 73, 75, and 71% on Days 7, 10, and 14, respectively, compared with placebo. Montelukast did not reduce FeNO. GW274150 did not inhibit AMP reactivity whereas for montelukast there was a trend toward inhibition: the mean doubling dose difference versus placebo was 0.64 (95% confidence interval [95% CI], 0 to 1.28). GW274150 did not inhibit early (EAR) and late (LAR) asthmatic responses to allergen, or MCh reactivity, despite reduced FeNO levels. Montelukast inhibited EAR and LAR FEV1; the mean difference versus placebo for minimal FEV1 was 0.37 L (95% CI, 0.19 to 0.55) and 0.18 L (95% CI, 0.04 to 0.32), respectively. MCh reactivity was inhibited by montelukast (mean doubling dose difference vs. placebo, 0.51; 95% CI, 0.02 to 1.01). GW271540 also had no effect on inflammatory cell numbers in bronchoalveolar lavage fluid after allergen challenge. Conclusions Selective iNOS inhibition effectively reduces FeNO but does not affect airway hyperreactivity or airway inflammatory cell numbers after allergen challenge in subjects with asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00273013).

Patients with severe asthma are distinct from patients with milder forms of the disease. Peripheral-blood monocytes from patients with severe asthma were shown to have enhanced expression of markers associated with tumor necrosis factor α (TNF-α). In a pilot, placebo-controlled, crossover study, the TNF-α receptor–binding agent etanercept improved airway responsiveness and asthma-related quality of life. TNF-α may have a role in refractory asthma. In a pilot study, the TNF-α receptor–binding agent etanercept improved airway responsiveness and asthma-related quality of life. TNF-α may have a role in refractory asthma. The rates of death and complications are high among patients with refractory asthma and account for a disproportionate amount of the health resource burden attributed to asthma. 1 Treatment options are limited for these patients. The airway abnormality in refractory asthma differs from that in mild-to-moderate asthma in having a more heterogeneous pattern of inflammatory response, 2 with greater involvement of neutrophils 3 and the distal lung 4 and increased airway remodeling. 5 Tumor necrosis factor α (TNF-α) is a pleiotropic inflammatory cytokine expressed in increased amounts by mast cells 6 and present in increased concentrations in bronchoalveolar fluid from the airways of patients with asthma. . . .

Bronchopulmonary dysplasia and the long-term consequences of prematurity are underrecognized entities, unfamiliar to adult clinicians. Well described by the pediatric community, these young adults are joining the ranks of a growing population of adults with chronic lung disease. To describe the quality of life, pulmonary lung function, bronchial hyperresponsiveness, body composition, and trends in physical activity of adults born prematurely, with or without respiratory complications. Four groups of young adults born in Canada between 1987 and 1993 were enrolled in a cohort study: (1) preterm subjects with no neonatal respiratory complications, (2) preterm subjects with neonatal respiratory distress syndrome, (3) preterm subjects with bronchopulmonary dysplasia, and (4) subjects born at term. The following measurements were compared across the four groups: health-related quality of life, respiratory health, pulmonary function, methacholine challenge test results, and sedentary behavior and physical activity level. Adult subjects who had bronchopulmonary dysplasia in infancy had mild airflow obstruction (FEV1, 80% predicted; FEV1/FCV ratio, 70) and gas trapping compared with others. They also had less total active energy expenditure and more time spent in sedentary behavior compared with subjects born at term. All preterm groups had a high prevalence of bronchial hyperresponsiveness compared with term subjects. In a population-derived, cross-sectional study, we confirmed previous reports that adults 21 or 22 years of age who were born prematurely with neonatal bronchopulmonary dysplasia are more likely to have airflow obstruction, bronchial hyperresponsiveness, and pulmonary gas trapping than subjects born prematurely without bronchopulmonary dysplasia or at term. Clinicians who care for adults need to be better informed of the long-term respiratory consequences of premature birth to assist young patients in maintaining lung function and health.

Exaggerated airway constriction triggered by repeated exposure to allergen, also called hyperreactivity, is a hallmark of asthma. Whereas vagal sensory neurons are known to function in allergen-induced hyperreactivity 1 – 3 , the identity of downstream nodes remains poorly understood. Here we mapped a full allergen circuit from the lung to the brainstem and back to the lung. Repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract (nTS) neurons in a mast cell-, interleukin-4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA sequencing, followed by RNAscope assay at baseline and allergen challenges, showed that a Dbh + nTS population is preferentially activated. Ablation or chemogenetic inactivation of Dbh + nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it. Viral tracing indicated that Dbh + nTS neurons project to the nucleus ambiguus (NA) and that NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction. Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the transmitter between Dbh + nTS and NA. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. This knowledge informs how neural modulation could be used to control allergen-induced airway hyperreactivity. Mapping a full allergen circuit from the lung to the brainstem and back, repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract neurons in a mast cell-, interleukin-4- and vagal nerve-dependent manner.

Abstract Airway hyperreactivity in asthma is mediated by airway nerves, including sensory nerves in airway epithelium and parasympathetic nerves innervating airway smooth muscle. Isolating the function of these two nerve populations in vivo, to distinguish how each is affected by inflammatory processes and contributes to hyperreactivity in asthma, has been challenging. In this study, we used optogenetic activation of airway nerves in vivo to study parasympathetic contributions to airway hyperreactivity in two mouse models of asthma: 1) acute challenge with house dust mite antigen; and 2) chronic airway hypereosinophilia due to genetic IL-5 overexpression in airways. Overall airway hyperreactivity, as measured by bronchoconstriction to an inhaled agonist, was increased in both models. In contrast, optogenetic stimulation of isolated efferent parasympathetic nerves induced bronchoconstriction only in the acute house dust mite antigen challenge group. Using whole-mount tissue immunofluorescence and modeling software, we then measured, in three dimensions, the interactions between eosinophils and parasympathetic nerves in both models and found that eosinophils were more numerous and more proximal to airway parasympathetic nerves in antigen-challenged and IL-5–transgenic mice than in their respective controls but were not significantly different between the two asthma models. Thus, even though eosinophils were increased around nerves in both models, parasympathetic nerves only mediated airway hyperreactivity in the antigen-challenged mice. This study demonstrates divergent effects of acute versus chronic eosinophilia on parasympathetic airway nerve activity and points to eosinophil–nerve interactions as a key regulator of airway hyperreactivity in antigen challenged mice.

This proof-of-principle trial showed that imatinib treatment reduced mast-cell activation and improved airway responsiveness in patients with severe refractory asthma. Many patients with severe asthma do not have adequate disease control despite the use of high-dose inhaled or systemic glucocorticoids. 1 Severe asthma is associated with airway hyperresponsiveness — that is, an exaggerated response to a bronchoconstrictor stimulus — and airway inflammation, both of which persist despite high-dose glucocorticoid therapy. 2 , 3 Increased airway hyperresponsiveness is associated with a progressive loss of lung function, 4 and, among patients with moderate-to-severe asthma, those with airway hyperresponsiveness have a poorer quality of life than those without this trait. 5 In addition, studies have shown that treatment targeting airway hyperresponsiveness leads to more effective control of asthma . . .