Abstract:
:Pleural organization may occur after empyema or complicated parapneumonic effusion and can result in restrictive lung disease with pleural fibrosis (PF). Pleural mesothelial cells; PMCs, may contribute to PF through acquisition of a profibrotic phenotype; meso-mesenchymal transition (MesoMT), which is characterized by increased expression of α-smooth muscle actin (α-SMA) and other myofibroblast markers. While MesoMT has been implicated in the pathogenesis of PF, the role of the reactive oxygen species and the NADPH oxidase family in pleural remodeling remains unclear. Here we show that NOX1 expression is enhanced in nonspecific human pleuritis. and is induced in PMCs by thrombin. 4-Hydroxynonenal (HNE), an indicator of reactive oxygen species damage, was likewise increased in our mouse model of pleural injury. NOX1 downregulation blocked thrombin- and Xa-mediated MesoMT as did pharmacological inhibition of NOX1 with ML-171. NOX1 inhibition also reduced phosphorylation of Akt, p65, and Tyrosine 216-GSK-3β, signaling molecules previously shown to be implicated in MesoMT. Conversely, ML-171 did not reverse established MesoMT. NOX4 down-regulation attenuated TGF-β- and thrombin-mediated MesoMT. However, NOX1 downregulation did not affect NOX4 expression. NOX1 and NOX4 deficient mice were also protected in our mouse model of S. pneumoniae-mediated pleural fibrosis. These data show that NOX1 and NOX4 are critical determinants of MesoMT.
journal_name
Am J Respir Cell Mol Biolauthors
Qin W,Jeffers A,Owens S,Chauhan P,Komatsu S,Qian G,Guo X,Ikebe M,Idell S,Tucker TAdoi
10.1165/rcmb.2020-0077OCsubject
Has Abstractpub_date
2021-01-29 00:00:00eissn
1044-1549issn
1535-4989pub_type
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