Research ArticleLUNG FIBROSIS

Citrullinated vimentin mediates development and progression of lung fibrosis

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Science Translational Medicine  17 Mar 2021:
Vol. 13, Issue 585, eaba2927
DOI: 10.1126/scitranslmed.aba2927

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Pollutants and lung fibrosis

Environmental factors such as air pollution and cigarette smoke have been shown to be associated with increased risk of developing idiopathic pulmonary fibrosis (IPF). Ultrafine particulate matter from both pollutant and cigarette smoke contains carbon black (CB) and cadmium (Cd). Now, Li et al. show that CB and Cd were increased in lung from patients with IPF and Cd expression correlated with citrullinated vimentin. Cd/CB caused pulmonary fibrosis in mice via citrullination of vimentin that, in turn, promoted fibrosis by triggering fibroblast activation and tissue inflammation, resulting in the expression of fibrotic proteins. The results contribute to elucidate the role of environmental factors in the development of IPF.

Abstract

The mechanisms by which environmental exposures contribute to the pathogenesis of lung fibrosis are unclear. Here, we demonstrate an increase in cadmium (Cd) and carbon black (CB), common components of cigarette smoke (CS) and environmental particulate matter (PM), in lung tissue from subjects with idiopathic pulmonary fibrosis (IPF). Cd concentrations were directly proportional to citrullinated vimentin (Cit-Vim) amounts in lung tissue of subjects with IPF. Cit-Vim amounts were higher in subjects with IPF, especially smokers, which correlated with lung function and were associated with disease manifestations. Cd/CB induced the secretion of Cit-Vim in an Akt1- and peptidylarginine deiminase 2 (PAD2)–dependent manner. Cit-Vim mediated fibroblast invasion in a 3D ex vivo model of human pulmospheres that resulted in higher expression of CD26, collagen, and α-SMA. Cit-Vim activated NF-κB in a TLR4-dependent fashion and induced the production of active TGF-β1, CTGF, and IL-8 along with higher surface expression of TLR4 in lung fibroblasts. To corroborate ex vivo findings, mice treated with Cit-Vim, but not Vim, independently developed a similar pattern of fibrotic tissue remodeling, which was TLR4 dependent. Moreover, wild-type mice, but not PAD2−/− and TLR4 mutant (MUT) mice, exposed to Cd/CB generated high amounts of Cit-Vim, in both plasma and bronchoalveolar lavage fluid, and developed lung fibrosis in a stereotypic manner. Together, these studies support a role for Cit-Vim as a damage-associated molecular pattern molecule (DAMP) that is generated by lung macrophages in response to environmental Cd/CB exposure. Furthermore, PAD2 might represent a promising target to attenuate Cd/CB-induced fibrosis.

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