α1 adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with IPF

Idiopathic Pulmonary Fibrosis is increasingly associated with nerve-driven processes and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. The study report that noradrenaline (NA) derived from the lung's adrenergic nerve supply drives αSMA-expressing fibroblast accumulation via mechanisms involving α1 adrenoreceptors and mtDNA. Using the bleomycin model, the authors compared the ablation of the lung's adrenergic nerve supply to surgical adrenal resection. They found that NA derived from local but not adrenal sources drives experimentally induced lung fibrosis and the emergence of an αSMA+ fibroblast population expressing adrenoreceptor alpha-1D (ADRA1D). Cultured normal human lung fibroblasts displayed α1 adrenoreceptors and, in response to co-stimulation with TGFβ1 and NA, adopted ACTA2 expression and extracellular mtDNA release. These findings were opposed by terazosin. IPF patients prescribed α1 adrenoreceptor antagonists for non-pulmonary indications demonstrated improved survival and reduced plasma mtDNA. The study observations link nerve-derived NA, α1 adrenoreceptors, extracellular mtDNA, and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuroinnate connection may yield new avenues for investigation in the clinical and basic science realms.