title: Adverse Outcomes Associated with Cigarette Smoke Radicals Related to Damage to Protein-disulfide Isomerase.
abstract: Identification of factors contributing to the development of chronic obstructive pulmonary disease (COPD) is crucial for developing new treatments. An increase in the levels of protein-disulfide isomerase (PDI), a multifaceted endoplasmic reticulum resident chaperone, has been demonstrated in human smokers, presumably as a protective adaptation to cigarette smoke (CS) exposure. We found a similar increase in the levels of PDI in the murine model of COPD. We also found abnormally high levels (4-6 times) of oxidized and sulfenilated forms of PDI in the lungs of murine smokers compared with non-smokers. PDI oxidation progressively increases with age. We begin to delineate the possible role of an increased ratio of oxidized PDI in the age-related onset of COPD by investigating the impact of exposure to CS radicals, such as acrolein (AC), hydroxyquinones (HQ), peroxynitrites (PN), and hydrogen peroxide, on their ability to induce unfolded protein response (UPR) and their effects on the structure and function of PDIs. Exposure to AC, HQ, PN, and CS resulted in cysteine and tyrosine nitrosylation leading to an altered three-dimensional structure of the PDI due to a decrease in helical content and formation of a more random coil structure, resulting in protein unfolding, inhibition of PDI reductase and isomerase activity in vitro and in vivo, and subsequent induction of endoplasmic reticulum stress response. Addition of glutathione prevented the induction of UPR, and AC and HQ induced structural changes in PDI. Exposure to PN and glutathione resulted in conjugation of PDI possibly at active site tyrosine residues. The findings presented here propose a new role of PDI in the pathogenesis of COPD and its age-dependent onset.
authors.affiliation: From the Anderson Cancer Institute, Memorial Health University Medical Center, Savannah, Georgia 31404.
authors.forename: Harshavardhan
authors.initials: H
authors.lastname: Kenche
authors.affiliation: the College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Ye
authors.affiliation: From the Anderson Cancer Institute, Memorial Health University Medical Center, Savannah, Georgia 31404.
authors.forename: Kokilavani
authors.initials: K
authors.lastname: Vedagiri
authors.affiliation: From the Anderson Cancer Institute, Memorial Health University Medical Center, Savannah, Georgia 31404.
authors.forename: Dylan M
authors.initials: DM
authors.lastname: Richards
authors.affiliation: Genetics, Case Western Reserve University, Cleveland, Ohio 44106, and.
authors.forename: Xing-Huang
authors.initials: XH
authors.lastname: Gao
authors.affiliation: the College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Tew
authors.affiliation: the College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Danyelle M
authors.initials: DM
authors.lastname: Townsend
authors.affiliation: From the Anderson Cancer Institute, Memorial Health University Medical Center, Savannah, Georgia 31404, the Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia 31404, the Departments of Surgery and axb811@case.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Blumental-Perry
mesh_terms: D000171:Acrolein / Q000633:toxicity; D000818:Animals; D001273:Atmosphere Exposure Chambers; D002460:Cell Line; D002470:Cell Survival; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005609:Free Radicals / Q000633:toxicity*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D006900:Hydroxylation; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000633:toxicity; D011487:Protein Conformation; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D011809:Quinones / Q000633:toxicity; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D012907:Smoking / Q000009:adverse effects*; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D005609:Free Radicals; D011809:Quinones; D030421:Peroxynitrous Acid; D000171:Acrolein; D006861:Hydrogen Peroxide; D019704:Protein Disulfide-Isomerases
keywords: endoplasmic reticulum stress (ER stress); post-translational modification (PTM); protein-disulfide isomerase; reactive nitrogen species; unfolded protein response (UPR)