Crucial role of fatty acid oxidation in asthmatic bronchial smooth muscle remodeling

Abstract

Bronchial smooth muscle (BSM) remodeling has an important prognostic value in asthma, since it is associated with lower lung function and increased exacerbation rate. BSM cell hyperplasia has been related to an increased proliferation of asthmatic BSM cells. We previously demonstrated that the increased BSM cell proliferation was related to an increased number of mitochondria in the BSM of severe asthmatic patients. The impact of this increased mitochondrial mass on asthmatic BSM cell metabolism remains to be elucidated. We enrolled 21 asthmatic patients from the COBRA cohort, and 31 non-asthmatic subjects. Energetic metabolism has been studied through many different approaches such as cellular oxygen consumption, glucose consumption, lactate, ATP production, proteomic and TCA cycle intermediates metabolites expression. Energetic metabolism was modified in asthmatic BSM cells, since oxygen consumption was increased and less lactate was produced than in control BSM cells with no difference in glucose consumption. TCA cycle intermediates analysis and large-scale proteomic have highlighted a shift of asthmatic BSM cells metabolism from glycolysis toward oxidative phosphorylation. Moreover, we showed a significant increased fatty acid internalization in asthmatic BSM cells, demonstrating the importance of fatty acid consumption in asthmatic BSM. Levels of CPT2 and LDL-receptor were both increased in asthmatic BSM cells. Blocking CPT2 or LDL-receptor drastically and specifically reduced asthmatic BSM cell proliferation. Taken together asthmatic BSM cells shifted to mitochondrial β-oxidation. We identified fatty acid metabolism as a new key target to reduce BSM remodeling in asthma.