Pharmacological Gq targeting prevents asthmatic airway remodeling

Airway remodeling is a critical hallmark of chronic asthma that is very difficult to treat. We have investigated this pathological process and found that local application of the pharmacological Gq inhibitor FR900359 (FR) attenuates the main features of airway remodeling, namely collagen deposition and goblet cell metaplasia in the chronic ovalbumin-induced asthma model in mice. We have explored the molecular mechanisms underlying the FR action and demonstrate that FR mitigates the growth of human lung fibroblasts in response to pathological stimuli in vitro. Likewise, FR inhibits mucus production and secretion in air-liquid interface cultures of human bronchial epithelial cells and in a human lung mucoepidermoid cell line. Notably, FR blocks mucus secretion in human lung slices from asthmatic patients. Thus, Gq proteins play a critical role in airway remodeling, hence pharmacological inhibition of Gq signaling represents a promising strategy for the treatment of chronic asthma.