Peng, X. Y. | bioRxiv Science

bioRxiv2026

Loss of Sun2 ablates nuclear mechanosensing-driven extracellular matrix production and mitigates lung fibrosis

Fibrosis and pathological stiffening of tissue are driven by mechanical and biochemical signaling pathways. Here, we find that Sun2, an integral inner nuclear membrane component of Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes, is up-regulated in the lung of patients suffering from fibrotic conditions and in fibroblasts during an injury-induced mouse model of lung fibrosis. Sun2 protein levels also increase in primary lung fibroblasts in a substrate stiffness-dependent manner. Sun2-/- primary lung fibroblasts respond to TGF{beta}, become contractile, and express a key marker of extracellular matrix-producing fibroblasts, Cthrc1. Consistent with this, Sun2 is dispensable for myofibroblast formation and repairing the alveolar barrier after bleomycin injury. Remarkably, however, fibrosis does not develop in bleomycin-treated Sun2-/- mouse lungs. This is explained by the requirement for Sun2 to up-regulate genes encoding extracellular matrix proteins. We therefore suggest that Sun2-containing LINC complexes contribute to a mechanical coincidence detection mechanism that acts in concert with canonical TGF{beta} signaling necessary for pathologic extracellular matrix protein production, representing a nuclear mechanosensing node for intervention in fibrotic diseases of the lung.

cell biology↗

bioRxiv2023

Aerosolized α1 adrenoreceptor antagonism does not affect experimentally induced lung fibrosis in animal models

Pulmonary 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 TGF{beta}1 (TGF{beta}1-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.

pathology↗