Cigarette smoke (CS) is well known to induce chronic obstructive pulmonary disease (COPD) and cancer in humans. Cadmium is the most abundant toxic heavy metal that is present in CS. Cadmium is also present in contaminated air, food and water. Cadmium inhalation has been reported to be associated with development of COPD and lung cancer. Importantly, cadmium accumulates in the host with a half-life of 20 to 30 years. CS was shown to reduce the expression of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). CFTR is a chloride channel that is mostly expressed in epithelial cells and is key in maintaining the surface hydration of the lung. Absence of functional CFTR causes Cystic Fibrosis, a disease characterized by impaired mucocilliary clearance, and chronic infection and inflammation in the lung. Therefore, the potential importance of CS-induced CFTR abnormalities in the pathophysiology of smoking-related diseases should be further evaluated. It also gives us an opportunity to define a novel mechanism of action for the development and/or worsening of COPD. Indeed, over 80% of COPD patients have a smoking history. This proposal stems from our recent evidence that cadmium decreases CFTR expression in lung epithelial cells resulting in reduction of chloride transport, and increased secretion of the pro-inflammatory cytokine IL-8. Our hypothesis is that the toxic heavy metal cadmium inhibits the expression of the CFTR chloride channel, therefore leading to lung dysfunction and COPD. Here we propose (1) to determine the expression of the ion channels CFTR and ENaC (the epithelial sodium channel that is co-regulated by CFTR), and the pro- inflammatory cytokine IL-8 using quantitative RT-PCR, and (2) to measure the level of heavy metals using inductively coupled plasma mass spectroscopy (ICP-MS) in lungs samples from cigarette smokers that developed COPD and from control patients that are non-smokers. This study will set the stage to understanding the contribution of heavy metals and the ion channel CFTR in the development of COPD.
Cigarette smoke (CS) contains toxic heavy metals like cadmium, and both CS and cadmium can induce COPD. We found that cadmium can suppress the Cystic Fibrosis Transmembrane conductance Regulator, a chloride channel that when dysfunctional leads to cystic fibrosis.
|Hassan, Fatemat; Xu, Xiaohua; Nuovo, Gerard et al. (2014) Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels. Respir Res 15:69|
|Hassan, Fatemat; Nuovo, Gerard J; Crawford, Melissa et al. (2012) MiR-101 and miR-144 regulate the expression of the CFTR chloride channel in the lung. PLoS One 7:e50837|
|Rennolds, Jessica; Malireddy, Smitha; Hassan, Fatemat et al. (2012) Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium. Biochem Biophys Res Commun 417:256-61|
|Cormet-Boyaka, Estelle; Jolivette, Kalyn; Bonnegarde-Bernard, Astrid et al. (2012) An NF-?B-independent and Erk1/2-dependent mechanism controls CXCL8/IL-8 responses of airway epithelial cells to cadmium. Toxicol Sci 125:418-29|
|Rennolds, Jessica; Butler, Susie; Maloney, Kevin et al. (2010) Cadmium regulates the expression of the CFTR chloride channel in human airway epithelial cells. Toxicol Sci 116:349-58|