title: N-acetylcysteine protects murine alveolar type II cells from cigarette smoke injury in a nuclear erythroid 2-related factor-2-independent manner.
abstract: Emphysema is caused by the cigarette smoke (CS)-induced destruction of alveolar wall septa, and CS is the main risk factor for chronic obstructive pulmonary disease (COPD). To study the mechanisms of response to this insult, we focused on oxidant-induced lung injury and the potential role of nuclear erythroid 2-related factor-2 (Nrf2), which is a key regulator of the antioxidant defense system. We studied the protective role of N-acetylcysteine (NAC) against the injury of alveolar type II (ATII) cells induced by CS in vivo and in vitro. ATII cells were isolated and purified using magnetic MicroBeads (Miltenyi Biotec, Auburn, CA) from Nrf2(-/-) mice and wild-type mice. We analyzed pulmonary injury, inflammation, glutathione (GSH) concentrations, the expression of glutathione cysteine ligase catalytic subunit mRNA, glutathione cysteine ligase modifier subunit mRNA, and glutathione reductase mRNA, and Nrf2, heme oxygenase-1, and nicotinamide adenine dinucleotide phosphate-reduced:quinone oxireductase levels by Western blotting, TUNEL assay, and immunocytofluorescence for 4-hydroxynonenal as a marker of oxidative stress. We found that CS induced greater injury in ATII cells obtained from Nrf2(-/-) mice than from wild-type mice. Furthermore, NAC attenuated the injuries by CS in ATII cells obtained from wild-type mice both in vivo and in vitro. Moreover, NAC decreased the injury of ATII cells obtained from Nrf2(-/-) mice. Our results suggest that Nrf2-GSH signaling is important for the protective activity of NAC. In addition, in ATII cells deficient in Nrf2, this compound can provide partial protection through its reactive oxygen species-scavenging activities. Targeting the antioxidant system regulated by Nrf2 may provide an effective strategy against lung injury in COPD.
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO 80206, USA. KosmiderB@NJHealth.org
authors.forename: Elise M
authors.initials: EM
authors.lastname: Messier
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
authors.forename: Karim
authors.initials: K
authors.lastname: Bahmed
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.forename: Russell P
authors.initials: RP
authors.lastname: Bowler
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mason
authors.forename: Beata
authors.initials: B
authors.lastname: Kosmider
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D056809:Alveolar Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D004646:Emphysema / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D012906:Smoke; D012907:Smoking / Q000009:adverse effects*; D014026:Nicotiana / Q000737:chemistry
chemical_list: D016166:Free Radical Scavengers; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012906:Smoke; D000111:Acetylcysteine