α1 Adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with idiopathic pulmonary fibrosis

Abstract

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. Here we 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, we compared ablation of the lung's adrenergic nerve supply to surgical adrenal resection and 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). Therapeutic delivery of the α1 adrenoreceptor antagonist terazosin reversed these changes and suppressed extracellular mtDNA accumulation. 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. Our 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.

Aerosolized ⍺1adrenoreceptor antagonism does not affect experimentally induced lung fibrosis in animal models

“…Our data indicate that the administration of terazosin in nebulized form did not impact lung inflammation, airway compliance or resistance, collagen accumulation, or histologic measures of lung remodeling in the bleomycin and TGFβ1-Tg + models of murine pulmonary fibrosis. These results are in contrast to prior work in which intraperitoneal administration of terazosin modulates fibrotic changes in bleomycin challenged mice [17] and numerous studies demonstrating that ⍺ 1 -AR blockade improves fibrotic endpoints in cross-organ models of tissue fibrosis including the lung, liver, heart, and kidney [41][42][43][44]. Notably, because the present study assessed localized tissue delivery as opposed to systemic ⍺ 1 -AR antagonism, our data indicate that alternate approaches will be required to support the repositioning of this drug for the treatment of lung fibrosis.…”

“…Adrenergic hyperinnervation and the accumulation of ⍺ 1 -adrenoreceptor (⍺ 1 -AR) expressing cells are associated with fibrosis in animal models, where interruption of adrenergic signaling via chemical denervation and ⍺ 1 -AR antagonism mitigates fibrotic endpoints [17,19]. It has further been shown that in some settings the blood [20] and lungs [19] of IPF patients are enriched for noradrenaline, and that IPF patients prescribed ⍺ 1 -AR antagonists for non-pulmonary indications experience improved survival [19].…”

“…Pulmonary expression of ⍺ 1 -ARs is the best characterized in smooth muscle cells of the airways and vasculature, where they are reported to mediate noradrenaline-induced contractile responses [23,24]. Interestingly, this receptor class is also expressed in parenchymal endothelium and fibroblasts [25], which may, in part, account for the capillary leak-associated fibroblast activation and extracellular matrix expansion caused by intravenous infusion of the ⍺ 1 -AR agonist phenylephrine [26,27] and the therapeutic benefit of systemically administered ⍺ 1 -AR antagonism delivered via the oral or intraperitoneal routes [17][18][19]. However, ⍺ 1 -ARs are also expressed by populations of lung epithelia and airway inflammatory cells which may contribute to noradrenaline's well described role in remodeling responses of apoptosis [28], inflammatory cell trafficking [29], and cytokine production [30].…”

Α2-Adrenoreceptor ANTAGONIST AMELIORATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY SUPPRESSING NOREPINEPHRINE-MEDIATED FIBROBLAST DIFFERENTIATION VIA INHIBITING PKC ACTIVATION

“…Rassler et al (8) reported that during NE stimulation, α-adrenergic mechanisms mainly contribute to pulmonary remodeling. A recent study showed that the α 1 -AR antagonist terazosin mitigates lung fibrosis caused by NE elevation due to bleomycin stimulation (27). However, the premise of this conclusion is that bleomycin leads to significantly increased expression of three α 1 -AR subtypes, especially α 1D -AR, in pulmonary tissue.…”

The Effect of Adrenalectomy on Bleomycin-Induced Pulmonary Fibrosis in Mice

“…The adrenal glands are important regulators of systemic homeostasis and respond to various stimuli via their production of catecholamines and aldosterone (ALD). Emerging studies suggest that fibrosis is associated with catecholamines such as adrenaline (AD) and noradrenaline (NA) [6][7][8][9][10]. Additionally, work from our lab has shown that NA derived from lungspecific adrenergic nerves contributes to pulmonary fibrosis [6,8,11] which was ameliorated with alpha-adrenergic receptor 1D (ADRA1D) antagonism [8].…”