title: Induction of the unfolded protein response by cigarette smoke is primarily an activating transcription factor 4-C/EBP homologous protein mediated process.
abstract: OBJECTIVE
  Cigarette smoke is the major risk factor associated with the development of chronic obstructive pulmonary disease (COPD). Recent studies propose a link between endoplasmic reticulum (ER) stress and emphysema, demonstrated by increased ER stress markers under smoking conditions. Here, we investigate whether cigarette smoke-induced ER stress is cell specific and correlates with acute and chronic cigarette smoke exposure.
  
  
  METHODS
  Gene and protein expression changes in human primary lung cell cultures following cigarette smoke extract (CSE) exposure were monitored by qPCR and Western blot analysis. Mice and guinea pigs were exposed to cigarette smoke and ER stress markers examined in whole lung homogenates. Inflammatory cells from the bronchoalveolar lavage fluid of 10 days smoke exposed mice were also examined.
  
  
  RESULTS
  Cigarette smoke induced a trend increase in the ER stress response through an activating transcription factor 4 (ATF4) mediated induction of C/EBP homologous protein (CHOP) in primary small airway epithelial cells. Bronchial epithelial cells and macrophages responded similarly to CSE. Wild-type mice and guinea pigs exposed to acute levels of cigarette smoke exhibited increased levels of CHOP but not at significant levels. However, after long-term chronic cigarette smoke exposure, CHOP expression was reduced. Interestingly, inflammatory cells from smoke exposed mice had a significant increase in CHOP/ATF4 expression.
  
  
  CONCLUSIONS
  A trend increase in CHOP levels appear in multiple human lung cell types following acute cigarette smoke exposure in vitro. In vivo, inflammatory cells, predominately macrophages, demonstrate significant cigarette smoke-induced ER stress. Early induction of CHOP in cigarette smoke may play a pivotal role in early induction of lung disease, however in vivo long-term cigarette smoke exposure exhibited a reduction in the ER stress response.
authors.affiliation: Department of Medicine, Divisions of Molecular and Pulmonary Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Geraghty
authors.forename: Alison
authors.initials: A
authors.lastname: Wallace
authors.forename: Jeanine M
authors.initials: JM
authors.lastname: D'Armiento
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006168:Guinea Pigs; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018384:Oxidative Stress / Q000187:drug effects; D016133:Polymerase Chain Reaction; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: C497109:ATF4 protein, human; D017931:DNA Primers; D012906:Smoke; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP