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 smoked COPD patients, compared to 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 suggests 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.

How and why tobacco use affects reconstructive surgical practice: a contemporary narrative review

“…These include microvascular damage, increased oxidative stress, genomic damage, and impairment of the local immune response, which is a critical aspect of an epithelial surface that encounters outside pathogens on a regular basis (53)(54)(55). Combined, these insults result in tobacco users developing chronic inflammation which leads to destruction of necessary tissue architecture by overactivation of local macrophages and ultimately peribronchiolar fibrosis (55,56).…”

“…Key changes are also seen in the T-Cell immune response, in large part due to their increased prevalence in the affected mucosa, which causes structural damage through their induction of matrix metalloproteinase 12 (MMP12) in the nearby over-populated macrophages. Specific toxins found in tobacco smoke, such as cadmium, have also been found to induce fibrinogen production from the macrophages, further damaging the mucosa ( 56 ). Ultimately, all of this activity causes an impaired immune response through downregulation of important cytokines such as interleukin 1, interleukin 6, and Tumor Necrosis Factor-α ( 55 ).…”

Biological Effects of Human Exposure to Environmental Cadmium

“…Lungs are also a target organ for Cd toxicity. In chronic Cd exposure, progressive pulmonary fibrosis and impaired lung function with obstructive lung disease may occur [66,67]. Cd also induces neurological dysfunction and brain toxicity, with a complex mechanism [68,69].…”

Impaired PPARγ activation by cadmium exacerbates infection-induced lung injury

“…Widely distributed in the environment, natural air emission sources of cadmium can come from volcanoes, airborne soil particles, forest fires, coal fired plants, coke factories, and quarries (11). Cadmium adversely affects lung function and contributes to pulmonary fibrosis, cancer, asthma, and chronic obstructive pulmonary disease (12)(13)(14). Although environmental cadmium was recently identified to be associated with a higher risk of mortality from influenza or pneumonia (15), the mechanism(s) regulating cadmium-mediated respiratory infections is not known.…”