A Fungal Protease Allergen Provokes Airway Hyperresponsiveness in Asthma

Kirk M. Druey, MD, Nariman Balenga, PhD, Zhihui Xie, PhD, Michel Laviolette, MD, Michael Klichinsky, Reynold A. Panettieri Jr., MD, Eunice C. Chan, PhD, Joseph Jude, Ming Zhao, PhD

Abstract: 

Rationale

Asthma, a common disorder that affects more than 250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine, bradykinin and histamine, also termed airway hyper-responsiveness (AHR). Although chronic inflammation leads to desquamation of the respiratory epithelium, increased bronchial smooth muscle mass, and mucous gland hypertrophy in asthma, the mechanisms by which such airway “remodeling” bring about enhanced contraction of airway smooth muscle (ASM) cells to pro-contractile ligands are poorly understood. Nearly 10% of people with asthma have severe, treatment-resistant disease, which is frequently associated with IgE sensitization to ubiquitous fungi, typicallyAspergillus fumigatus (Af).

 

Methods

Here we show that a major Af allergen, Asp f13, which is a serine protease, alkaline protease 1 (Alp 1), mediates AHR directly by disrupting ASM cell-extracellular matrix (ECM) interactions to induce pathophysiological excitation-contraction signaling.

 

Results

Alp 1-induced ECM degradation and ablation of integrin-mediated focal adhesions led to RhoA activation and increased RhoA-activated kinase (ROCK) activity. Consequently, cells produced more phosphatidylinositol 4,5-bisphosphate (PIP2), the principal substrate for phospholipase Cbeta (PLCb), which mediates G-protein-coupled receptor (GPCR)-evoked release of cytosolic Ca2+ and contraction. Alp 1 was present in bronchial smooth muscle bundles of human subjects with asthma and allergen-challenged mice but not in control subjects or naïve mice.

 

Conclusions

These findings support a previously unknown pathogenic mechanism in asthma and other lung diseases associated with epithelial barrier impairment whereby airway smooth muscle cells respond directly to inhaled environmental allergens to generate AHR.

abstract No: 

L25
    • AAAAI 2015 (71st)