title: Pulmonary hypertension and vascular oxidative damage in cigarette smoke exposed eNOS(-/-) mice and human smokers.
abstract: BACKGROUND
  Cigarette smoke is known to be associated with pulmonary hypertension in humans and in animal models. Although the etiology of pulmonary hypertension in smokers is not understood, recent work has suggested a role for inducible nitric oxide synthase (iNOS) in inducing oxidative stress.
  
  
  OBJECTIVE
  To further evaluate this question, we assessed eNOS-/- mice exposed to air or cigarette smoke for the presence of pulmonary hypertension and examined vascular remodeling and expression of nitrotyrosine, a marker of reactive nitrogen species-induced oxidative damage, using immunohistochemistry. To ascertain whether oxidants may play a role in humans, we also examined lung tissue from nonsmokers, and patients with chronic obstructive pulmonary disease (COPD) with and without pulmonary hypertension.
  
  
  RESULTS
  We found that eNOS(-/-) mice developed increased pulmonary arterial pressure after six months cigarette smoke exposure, and this was associated with vascular remodeling and increased vascular nitrotyrosine staining. iNOS gene expression was decreased in the pulmonary arteries of the smoke exposed animals, and no protein was detectable by immunohistochemistry. In humans, vascular nitrotyrosine staining intensity was increased in smokers with COPD compared to nonsmokers, and further increased in smokers with combined COPD and pulmonary hypertension.
  
  
  CONCLUSIONS
  We conclude that cigarette smoke-induced pulmonary hypertension is associated with evidence of oxidative vascular damage by reactive nitrogen species, but that iNOS does not appear to be the major contributor to such damage. Most likely the source of reactive nitrogen species is the cigarette smoke itself.
authors.affiliation: Department of Pathology, University of British Columbia, Vancouver, B.C. Canada. jlwright@interchange.ubc.ca
authors.forename: J L
authors.initials: JL
authors.lastname: Wright
authors.forename: S
authors.initials: S
authors.lastname: Zhou
authors.forename: A
authors.initials: A
authors.lastname: Churg
mesh_terms: D000818:Animals; D015415:Biomarkers; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced*; D008168:Lung / Q000098:blood supply; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D012907:Smoking / Q000009:adverse effects*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D015415:Biomarkers; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III