Impaired PPARγ activation by cadmium exacerbates infection-induced lung injury

Abstract

Emerging data indicates an association between environmental heavy metal exposure and lung disease, including lower respiratory tract infections (LRTIs). Here, we show by single cell RNAsequencing an increase in Pparg gene expression in lung macrophages from mice exposed to cadmium and/or infected with S. pneumoniae. However, the heavy metal cadmium or infection mediated an inhibitory post-translational modification of peroxisome proliferator-activated receptor ɣ (PPARɣ) to exacerbate LRTIs. Cadmium and infection increased ERK activation to regulate PPARɣ degradation in monocyte-derived macrophages. Mice harboring a conditional deletion of Pparg in monocyte-derived macrophages had more severe S. pneumoniae infection after cadmium exposure, showed greater lung injury, and had increased mortality. Inhibition of ERK activation with BVD-523 protected mice from lung injury after cadmium exposure or infection. Moreover, subjects residing in areas of high air cadmium levels had increased cadmium concentration in their BAL fluid and showed PPARɣ inhibition that was mediated, at least in part, by ERK activation in isolated BAL cells. These observations suggest that impaired activation of PPARɣ in monocyte-derived macrophages exacerbates lung injury and the severity of LRTIs.

The Correlation between Metal Mixed Exposure and Lung Function in Different Ages of the Population

“…Furthermore, another study showed that Cd-metalloprotein is associated with lung adenocarcinoma [ 66 ]. The correlation between Cd levels in male blood and lung functions was confirmed by epidemiological and in vivo, respectively [ 67 , 68 ]. Cd can cause an anti–apoptotic survival response via many signaling pathways, contributing to cell death [ 69 ], repair and survival, or malignant transformation.…”

Involvement of ERK and Oxidative Stress in Airway Exposure to Cadmium Chloride Aggravates Airway Inflammation in Ovalbumin-Induced Asthmatic Mice

“…Evidence indicates that ERK and oxidative stress are involved in CdCl 2 -induced inflammation in the lungs of humans and mice [ 4 , 17 , 19 ]. This suggests that these two factors may intensify the exacerbation of asthma induced by CdCl 2 .…”

“…The ERK pathway plays a pivotal role in the inflammation induced by CdCl 2 in mouse lung tissue. Exposure to CdCl 2 initiates ERK activation in mouse lung tissue, which subsequently orchestrates the degradation of peroxisome proliferator-activated receptor γ (PPARγ) in macrophages, thereby exacerbating pulmonary infection in mice [ 17 ]. Moreover, CdCl 2 activation of the ERK pathway leads to apoptosis in human bronchial epithelial cells (BEAS-2B) in vitro [ 18 ].…”

“…Recent studies suggest that ERK signaling may play a significant role in the impact of Cd on pulmonary inflammation. For instance, Larson-Casey et al observed that Cd exacerbates lower respiratory tract infections in mice by triggering ERK activation [ 17 ]. Additionally, Cao et al revealed that Cd induces ERK pathway activation, leading to the apoptosis of human bronchial epithelial cells (BEAS-2B) [ 18 ].…”

Urinary cadmium concentration is associated with the severity and clinical outcomes of COVID-19: a bicenter observational cohort study

“…Cadmium, a heavy metal toxicant, environmental pollutant and carcinogen, is harmful to immune function and multiple organ systems including cardiovascular, pulmonary, hepatic, renal, skeletal, and reproductive systems [ 6 ]. Cumulative cadmium exposure is a risk factor for the severity of infectious disease including respiratory viral infectious diseases (influenza virus and respiratory syncytial virus), non-airborne viral diseases, bacterial pneumonia, Helicobacter pylori, Toxoplasma gondii, and hepatitis B virus infections [ 7 – 10 ]. The primary source of cadmium exposure in the general population is through diet and cigarette smoking, with other routes including airborne pollution and occupational exposure [ 11 ].…”