Veena Antony, M.D.; A. Brent Carter, M.D.; Mohammad Athar, Ph.D.
University of Alabama, Birmingham
P42ES027723, R01ES029981, R01ES015981, U54ES030246
A new NIEHS-funded study revealed a series of molecular steps that lead to severe scarring in the lungs, called idiopathic pulmonary fibrosis (IPF), in response to environmental exposures. The key step involves a modified version of vimentin, a structural protein that usually maintains cellular integrity.
The researchers combined studies in mice and humans with lung fibrosis to uncover the mechanism by which exposure to cadmium and carbon black in particulates damages the lungs. They also leveraged a three-dimensional model, called a pulmosphere, which uses lung tissue from humans to create a realistic representation of the cell types and relationships present in the human lung.
Lung tissue of IPF patients had higher levels of carbon black and cadmium compared to healthy controls. Cadmium concentrations were directly proportional with levels of the modified version of vimentin, called citrullinated vimentin (Cit-Vim). Exposure to cadmium and carbon black stimulated production of Cit-Vim in lung macrophages from IPF patients and in mice.
In pulmospheres, Cit-Vim activated invasive connective tissue cells called fibroblasts and increased the expression of collagen, both key components of lung scarring in fibrosis. Mice treated with Cit-Vim developed a similar pattern of fibrosis, but those lacking a key enzyme called PAD2 had lower amounts of Cit-Vim and lower incidence of lung fibrosis compared to mice with the enzyme.
According to the authors, lung macrophages generate Cit-Vim in response to environmental exposure, which in turn triggers cellular events leading to fibrosis. However, PAD2 may offer a promising target for treatment.
Citation: Li FJ, Surolia R, Li H, Wang Z, Liu G, Kulkarni T, Massicano AVF, Mobley JA, Mondal S, de Andrade JA, Coonrod SA, Thompson PR, Wille K, Lapi SE, Athar M, Thannickal VJ, Carter AB, Antony VB. 2021. Citrullinated vimentin mediates development and progression of lung fibrosis. Sci Transl Med 13(585):eaba2927.