title: Wood smoke extract promotes both apoptosis and proliferation in rat alveolar epithelial type II cells: the role of oxidative stress and heme oxygenase-1.
abstract: OBJECTIVE
  Inhalation of toxic smoke causes oxidant lung injury. Alveolar epithelial type II cells are important in the re-epithelialization of alveolar walls after lung injury. We investigated the responses of alveolar epithelial type II cells to insult by wood smoke extract, and we identified the role of reactive oxygen species and heme oxygenase-1 (an oxidative stress protein) in these responses.
  
  
  METHODS
  A randomized, controlled study.
  
  
  METHODS
  A research laboratory.
  
  
  METHODS
  Cultured rat L2 and primary alveolar epithelial type II cells.
  
  
  RESULTS
  Exposure of L2 alveolar epithelial type II cells to smoke extract (60 microg/mL) caused increases in reactive oxygen species, mitogen-activated protein kinases phosphorylation, heme oxygenase-1 expression, apoptosis, proliferation and cell population, all of which were largely reduced by N-acetylcysteine (an antioxidant). Additionally, the smoke extract-induced heme oxygenase-1 induction was significantly attenuated by mitogen-activated protein kinases inhibitors, by small interfering RNA targeting mitogen-activated protein kinases or by N-acetylcysteine. Furthermore, knockdown of heme oxygenase-1 by small interfering RNA prevented heme oxygenase-1 induction whereas increasing smoke extract-induced apoptosis and suppressing smoke extract-induced proliferation. Conversely, cobalt protoporphyrin IX (a heme oxygenase-1 inducer) amplified heme oxygenase-1 induction while suppressing smoke extract-induced apoptosis and augmenting smoke extract-induced proliferation. Consequently, the smoke extract-induced increase in cell population was changed into a decrease by heme oxygenase-1 small interfering RNA, but was further elevated by cobalt protoporphyrin IX. Smoke extract also caused increases in heme oxygenase-1 expression, apoptosis, proliferation and cell population in primary alveolar epithelial type II cells, and heme oxygenase-1 small interfering RNA similarly augmented smoke extract-induced apoptosis and suppressed smoke extract-induced proliferation in these primary cells.
  
  
  CONCLUSIONS
  Smoke extract increases intracellular reactive oxygen species, which up-regulates heme oxygenase-1 via the mitogen-activated protein kinase pathways and also promotes both apoptosis and proliferation in rat alveolar epithelial type II cells. Additionally, smoke extract-induced heme oxygenase-1 induction counteracts smoke extract-induced apoptosis, but mediates smoke extract-induced proliferation, resulting in a net increase in cell population. Thus, in response to oxidant smoke insult, alveolar epithelial type II cells have evolved an adaptive mechanism involving heme oxygenase-1 that increases their cell population, presumably to help them perform their function of re-epithelialization following lung injury.
authors.affiliation: Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
authors.forename: Yu-Ju
authors.initials: YJ
authors.lastname: Liu
authors.forename: Gau-Jun
authors.initials: GJ
authors.lastname: Tang
authors.forename: Huey-Wen
authors.initials: HW
authors.lastname: Yien
authors.forename: Yuh-Lin
authors.initials: YL
authors.lastname: Wu
authors.forename: Yu Ru
authors.initials: YR
authors.lastname: Kou
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System; D008297:Male; D018384:Oxidative Stress; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D014934:Wood
chemical_list: D000975:Antioxidants; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012906:Smoke; D051547:Heme Oxygenase-1; D000111:Acetylcysteine