Fibrinogen mediates cadmium-induced macrophage activation and serves as a predictor of cadmium exposure in chronic obstructive pulmonary disease.

Abstract

The etiologies of chronic obstructive pulmonary disease (COPD) remain unclear. Cadmium (Cd) causes both pulmonary fibrosis and emphysema; however, the predictors for Cd exposure and the mechanisms by which Cd causes COPD remain unknown. We demonstrated that Cd burden was increased in lung tissue from subjects with COPD and this was associated with cigarette smoking. Fibrinogen levels increased markedly in lung tissue of patients with smoked COPD compared with never-smokers and control subjects. Fibrinogen concentration also correlated positively with lung Cd load, but inversely with the predicted % of FEV1 and FEV1/FVC. Cd enhanced the secretion of fibrinogen in a cdc2-dependent manner, whereas fibrinogen further mediated Cd-induced peptidylarginine deiminase 2 (PAD2)-dependent macrophage activation. Using lung fibroblasts from CdCl2-treated Toll-like receptor 4 (TLR4) wild-type and mutant mice, we demonstrated that fibrinogen enhanced Cd-induced TLR4-dependent collagen synthesis and cytokine/chemokine production. We further showed that fibrinogen complexed with connective tissue growth factor (CTGF), which in turn promoted the synthesis of plasminogen activator inhibitor-2 (PAI-2) and fibrinogen and inhibited fibrinolysis in Cd-treated mice. The amounts of fibrinogen were increased in the bronchoalveolar lavage fluid (BALF) of Cd-exposed mice. Positive correlations were observed between fibrinogen with hydroxyproline. Our data suggest that fibrinogen is involved in Cd-induced macrophage activation and increases in fibrinogen in patients with COPD may be used as a marker of Cd exposure and predict disease progression.

• Authors: Fu Jun Li, Ranu Surolia, Pooja Singh, Kevin G Dsouza, Crystal T Stephens, Zheng Wang, Rui-Ming Liu, Sejong Bae, Young-Il Kim, Mohammad Athar, Mark T Dransfield, Veena B Antony
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 322 Issue 4 Pg. L593-L606 (04 01 2022) ISSN: 1522-1504 [Electronic] United States
• PMID: 35200041 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Toll-Like Receptor 4
• Cadmium
• Fibrinogen

Topics

• Animals
• Cadmium (toxicity)
• Fibrinogen (adverse effects)
• Humans
• Lung (metabolism)
• Macrophage Activation
• Mice
• Pulmonary Disease, Chronic Obstructive (metabolism)
• Toll-Like Receptor 4