Air pollution induces enhanced mitochondrial oxidative stress in cystic fibrosis airway epithelium

Abstract

We studied the effects of airborne particulate matters (PM) on cystic fibrosis (CF) epithelium. We noted that PM enhanced human CF bronchial epithelial apoptosis, activated caspase-9 and PARP-1; and reduced mitochondrial membrane potential. Mitochondrial inhibitors (4,4-diisothiocyanatostilbene-2,2 0 disulfonic acid, rotenone and thenoyltrifluoroacetone) blocked PM-induced generation of reactive oxygen species and apoptosis. PM upregulated pro-apoptotic Bad, Bax, p53 and p21; and enhanced mitochondrial localization of Bax. The antiapoptotic Bcl-2, Bcl-xl, Mcl-1 and Xiap remained unchanged; however, overexpression of Bcl-xl blocked PM-induced apoptosis. Accordingly, we provide the evidence that PM enhances oxidative stress and mitochondrial signaling mediated apoptosis via the modulation of Bcl family proteins in CF.

Inhibition of acinar apoptosis occurs during acute pancreatitis in the human homologue ΔF508 cystic fibrosis mouse

“…Furthermore, observations from multiple nonpancreatic studies indicate that resistance to apoptosis occurs in CF (2,6,27,31,37,38,50,83). This concept remains controversial (33,35,65,75), possibly because the predominant mode of cell death is tissue dependent (74) and because the CFTR-dependent effect on cell death may differ based on cell type, injury model, trigger, and the end points measured. For example, Rottner et al (65) observed that actinomycin D increased apoptosis in a mutant CFTR pancreatic ductal cell line and also in WT and mutant ductal cell lines pretreated with the CFTR inhibitor CFTR inh -172.…”

“…It remains controversial whether CFTR mutations impair (2,6,15,27,31,37,38,50,83) or increase (33,35,65,75) cellular apoptosis in response to cell injury. That apoptosis execution machinery is impaired in models of CF is supported by in vivo studies (6,15), including ours in UNC-CF mice (15) and those performed by Cannon et al (6) in respiratory epithelial cells from ⌬F508-CF mice.…”

Mitochondrial Function in Allergic Disease

“…A study assessing the effect of cadmium on MRC 5 foetal lung fibroblasts found that cadmium-induced oxidative stress led to peroxidation of lipids, DNA damage and protein oxidation. Further, in mouse and rat liver cells, subcutaneous administration of cadmium led to cadmium intoxication for 4-8 h and caused sustained lipid peroxidation [59]. Lipid peroxidation is known to cross-link and polymerise membrane components resulting in modification of membrane lipids and altered membrane activity such as release of mitochondrial calcium.…”

Particulates and Oxidative Stress

“…Using authentic air pollution particles, the ultrafi ne fraction induces structural mitochondrial damage, whereas the mitochondrial architecture remained intact by exposure to coarse particles (Li et al, 2003 ). Particulates collected from ambient street air, wood burning, and diesel exhaust also increases mitochondrial depolarization in cells (Kamdar et al, 2008 ;Karlsson et al, 2008a ). The mitochondrial dysfunction could arise as a consequence of direct interference of particles with mitochondrial enzymes, or it might be caused by cytosolic ROS generation.…”