Alpha-1 adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with IPF

Idiopathic Pulmonary Fibrosis is increasingly associated with adrenergic innervation and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here we report that noradrenaline (NA) derived from the lungs adrenergic nerve supply drives the accumulation of SMA-expressing fibroblasts via a mechanism involving 1 adrenoreceptors and mtDNA. Using the bleomycin model of lung fibrosis we compared the effect of lung specific adrenergic denervation achieved via the inhalational administration of the sympathetic neurotoxin 6-hydroxydopamine to surgically mediated adrenal ablation and found that NA derived from local but not adrenal sources drives lung fibrosis. Bleomycin induced the appearance of a SMA+ fibroblast population co-expressing the adrenoreceptor alpha-1D (ADRA1D). Therapeutic delivery of the 1 adrenoreceptor antagonist terazosin reversed these changes and suppressed the accumulation of extracellular mtDNA. TGF{beta}1-stimulated normal human lung fibroblasts treated with TGF{beta}1 and Noradrenaline expressed ADRA1D and developed reduced SMA expression and extracellular mtDNA concentrations when treated with terazosin. IPF patients prescribed 1 adrenoreceptor antagonists for non-pulmonary indications showed improved survival and reduced concentrations of plasma mtDNA. These findings link nerve-derived NA and 1 adrenoreceptor antagonism with mtDNA accumulation and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuro-innate connection may yield new avenues for investigation in the clinical and basic science realms.