Mitochondria are involved in bronchial smooth muscle remodeling in severe preschool wheezers.

ABSTRACT Background Bronchial remodeling is a key feature of asthma already present in preschool wheezers. Moreover, bronchial smooth muscle (BSM) remodeling at preschool age is predictive of asthma at school age. However, the mechanism responsible for BSM remodeling in preschool wheezers remains totally unknown. By contrast, in adult asthma, BSM remodeling has been associated to an increase in BSM cell proliferation related to increased mitochondrial mass and biogenesis triggered by an altered calcium homeostasis. Indeed, BSM cell proliferation was decreased in vitro by the calcium channel blocker gallopamil. Objective To investigate the mechanisms involved in BSM cell proliferation in severe preschool wheezers, with special attention to the role of mitochondria and calcium signaling. Methods Bronchial tissue obtained from 12 non-wheezing preschool controls and 10 severe preschool wheezers, was used to measure BSM mass and establish primary BSM cell cultures. BSM cell proliferation was assessed by manual counting and flow cytometry, ATP content by bioluminescence, mitochondrial respiration either by Seahorse and Oroboros, mitochondrial mass and biogenesis by immunoblotting, and calcium response to carbachol by confocal microscopy. The effect of gallopamil was also evaluated. Results BSM mass, cell proliferation, ATP content, mitochondrial respiration, mass and biogenesis, and calcium response were all increased in severe preschool wheezers compared to those of controls. Gallopamil significantly decreased BSM mitochondrial biogenesis and mass, and cell proliferation. Conclusion Mitochondria are a key player in BSM cell proliferation in severe preschool wheezers and could represent a potential target to treat BSM remodeling at an early stage of the disease.