Abstract
We review three recent findings that have fundamentally altered our understanding of causative mechanisms underlying fungal-related asthma. These mechanisms may be partially independent of host inflammatory processes but are strongly dependent upon the actions of Alp1 on lung structural cells. They entail (i) bronchial epithelial sensing of Alp1; (ii) Alp1-induced airway smooth muscle (ASM) contraction; (iii) Alp1-induced airflow obstruction. Collectively, these mechanisms point to Alp1 as a new target for intervention in fungal asthma.
Highlights
Asthma is a widely prevalent and incurable respiratory disease that affects nearly 300 million people worldwide [1]
These results suggest that both Alp1 protease activity and allergic airway inflammation may be necessary for the accumulation of fungal protease in airway smooth muscle (ASM)-containing areas of the lung
One appealing possibility is that these moieties can be identified through high-throughput screening (HTS) (Figure 3)
Summary
Asthma is a widely prevalent and incurable respiratory disease that affects nearly 300 million people worldwide [1]. The clinical heterogeneity of asthma was recognized decades ago, only recently have we appreciated the existence of unique molecular pathways leading to AHR—termed “endotypes”—that underlie disease in distinct subpopulations [2]. One such endotype, comprising nearly 15–30 million patients, is termed “severe asthma with fungal sensitization” (SAFS) or fungal asthma [3,4,5,6]. Additional treatment is largely focused on alleviating endobronchial fungal infection or airway inflammation Whether this is attempted using anti-fungal agents or neutralizing antibodies against specific cytokines or mediators (e.g., anti-IgE, anti-IL-4/5/13) [7], clinical success has been inconsistent [8,9]. We review recent studies supporting the hypothesis that fungal allergens exert direct effects on lung structural cells independent of the inflammatory response and discuss the possibility that specific targeting of allergen protease activity represents a viable strategy for the treatment of AHR in fungal asthma
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