Modified proteins affect the development of lung fibrosis after exposure to cadmium / carbon black

The causes and causes of severe acute lung disease – idiopathic lung fibrosis, or IPF – are not yet clear.

Now research published in Science Translational Medicine shows how cadmium and carbon black can stimulate lung macrophages to produce altered protein, citrullinated vimentin, or cit vim, which leads to lung fibrosis. Researchers from the University of Alabama in Birmingham and three other American universities will also describe a series of mechanistic steps in lung macrophages and lung fibroblasts leading to lung rupture.

One of the enzymes involved in these steps – peptidylarginine deiminase 2, or PAD2 – may be a promising target for reducing carbon – induced cadosis / fibrosis, they say. The researchers are also reporting on a possible disease model for lung fibrosis and IPF – the use of cadmium chloride to induce interstitial fibrosis in mice.

The study, led by Veena Antony, MD, included patients with IPF, stress tests and mouse models. Antony is Professor of Environmental Safety in the UAB Department of Medicine, and leads the UAB Superfund Research Program.

Overall, these studies support a role for cit-vim as a damage-related molecular pattern molecule, or DAMP, generated by lung macrophages in response to environmental cadmium / carbon black exposure. “

Veena Antony, MD, Endowed Professor of Environmental Medicine, UAB Department of Medicine

Cadmium is a heavy toxic metal that has been identified as a cause of lung fibrosis. Cadmium can advertise carbon black granules. In the lung, these grains are ingested by macrophages, the sentinel host immune cells of the mammalian lung. Up to two-thirds of IPF patients have a history of smoking, and cigarette smoke contains cadmium and carbon black. Air pollution from biomass fuels and coal furnaces is also a source of both pollutants.

Data from human subjects

The researchers evaluated the accumulation of cadmium and cit-vim in print, using lung biopsies from 25 subjects with IPF – eight non-smokers and 17 smokers – and 14 controls – eight non-smokers and six smokers.

The researchers found that both cadmium and carbon black were highly concentrated in lung tissue from IPF subjects. Moreover, the cadmium concentrations in IPF lung cigarettes were directly related to cit-vim amounts, and the cit-vim amounts were higher in smoked IPF strains compared to non-smoked IPF strains. Also, subjects with IPF had higher levels of cit-vim in plasma, and these amounts were significantly associated with lung function. Lung macrophages from subjects with IPF significantly increased in vimentin and cit-vim expression compared with macrophages from controls. Vimentin is a structural protein in animal cells.

Data from human weaves

Using lung macrophages from subjects with IPF, researchers found that vimentin-induced cadmium / carbon black citrullination, and secretion of cit-vim from lung macrophages depended on the activation of two enzymes, Akt1 and PAD2. Citrullination is the binding of the amino acid citrulline to a protein.

Cit-vim isolated and cleared from lung macrophages was able to attack pulmospheres with primary lung fibroblasts from normal subjects. Cit-vim supplemented collagen expression with the fibroblasts, and the expression of collagen with lung fibroblasts from IPF subjects was even greater. The pulmospheres – 3-dimensional spheroids – were derived from normal lung material. Fibroblast proliferation and excessive collagen deposition are part of lung scarring in IPF.

DAMPs are molecules from damaged or dying cells that stimulate an immune response of tissue to clear the damage. Researchers showed that cit-vim acted as a DAMP to activate fibroblasts through 4 receptor-like signaling signals. The activated fibroblasts secreted profibrotic cytokines, contributing to the pathogenesis of IPF.

Thus, the data highlight a crucial role for lung macrophages in the development of lung fibrosis.

Data from mice

In animals, researchers found that mice treated with cit-vim, but not normal vimentin, developed lung fibrosis independently, with architectural destruction and increased collagen deposition, in a 4-dependent fashion. receptor like taxes. Wild-type mice exposed to cadmium / carbon black – but not mouse mutants with a lack of PAD2 or receptor-like receptor 4 – produced large amounts of cit-vim in plasma and in bronchoalveolar lava flow, and the mice developed lung fibrosis.

“This finding is important,” Antony said, “because cit-vim is sufficient to stimulate in vitro fibroblast activity and in vivo-dependent TLR4-dependent cytokine / chemokine and lung fibrosis production.

“Our data show that cadmium / carbon black is a risk factor, not only in subjects with smoked IPF, but also in nonsmokers. Higher concentrations of cadmium in non-smoking patients caused by exposure to cadmium through food and / or occupation or environment. “