Abstract
Guidance cues such as semaphorins are attractive novel therapeutic targets for allergic disorders. We have previously described an inhibitory effect of semaphorin 3E (Sema3E) on human airway smooth muscle cell function. We have further addressed a canonical role for Sema3E in acute model of allergic asthma in vivo. Considering the chronic nature of the disease, the potential implication of Sema3E to alleviate long-lasting deficits should be investigated. Expression of Sema3E in a chronic model of allergic asthma was assessed after exposure to house dust mite (HDM) as a clinically relevant allergen. Chronic features of allergic asthma including airway hyper-responsiveness (AHR), inflammation, and remodeling were studied in Sema3E-deficient mice. Additionally, the effect of exogenous Sema3E treatment was evaluated in prophylactic and therapeutic experimental models. We have demonstrated that expression of Sema3E is robustly suppressed in the airways upon chronic HDM exposure. Chronic allergic airway disease was significantly augmented in Sema3E-deficient mouse model which was associated with an increased AHR, remodeling, and Th2/Th17 inflammation. Intranasal Sema3E administration restored chronic deficits of allergic asthma in mice. Data from this study unveil a key regulatory role of Sema3E in chronic course of asthma via orchestration of impaired inflammatory and remodeling responses.
Highlights
Asthma is one of the most common chronic diseases which affects approximately 300 million people worldwide
Chronic allergic asthma is characterized by persistent airway inflammation, hyperresponsiveness (AHR) and structural changes in the lungs collectively known as airway remodeling [4, 5]
We demonstrated that chronic exposure to house dust mite (HDM) markedly reduces semaphorin 3E (Sema3E) immunoreactivity in mouse airways suggestive of a potential protective role for this mediator against chronic deficits of allergic asthma
Summary
Asthma is one of the most common chronic diseases which affects approximately 300 million people worldwide. Despite remarkable advances in asthma treatment, optimal control of the disease remains unachieved among those of inhaled corticosteroid users suffering chronic symptoms [1]. Chronic allergic asthma is characterized by persistent airway inflammation, hyperresponsiveness (AHR) and structural changes in the lungs collectively known as airway remodeling [4, 5]. AHR is an exaggerated airway narrowing caused by nonspecific irritants or agonists associated with increased lung infiltration by inflammatory cells [6]. The persistent AHR in patients refractory to steroid therapy is associated www.impactjournals.com/oncotarget with airflow limitation or remodeled airway leading to a change in mechanical properties [7]. The precise mechanisms underlying pathological features of chronic asthma are far from resolved
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