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

Abstract

AbstractPulmonary Fibrosis is a progressive and incurable condition that complicates many disease states. Adrenergic hyperinnervation and accumulation of fibroblasts expressing ⍺1- adrenoreceptors have been implicated in this process. Previous studies have demonstrated that systemic treatment with an ⍺1-adrenoreceptors antagonist attenuates fibrotic endpoints in lung fibrosis models. In an attempt to develop a lung targeted therapy, we determined whether ⍺1- adrenoreceptors antagonism delivered via inhaled administration of terazosin exerts antifibrotic benefits in experimentally induced lung fibrosis. C57/BL6 mice treated with bleomycin, or a doxycycline inducible line of transgenic mice with lung specific overexpression of the bioactive form of the human TGFβ1 (TGFβ1-Tg+model), received nebulized terazosin at varying doses on a therapeutic schedule following the induction of fibrosis and were sacrificed at 21 days. Airway inflammation, fibrotic endpoints, and lung function were evaluated. ⍺1-adrenoreceptors antagonism delivered via this method did not impact airway inflammation as indicated by bronchoalveolar lavage cell counts, and there was no significant difference observed in soluble collagen content. There was similarly no significant difference in respiratory mechanics with terazosin administration. These data show that inhaled delivery of the ⍺1-adrenoreceptors antagonist terazosin by this method is ineffective at treating fibrosis in these models and suggest that alternative dosing schedules or delivery methods may be more fruitful avenues of investigation. Further exploration of these findings may provide new therapeutic options and illuminate mechanisms through which adrenergic innervation and ⍺1-adrenoreceptors mediate fibrosis in the adult mammalian lung.