title: Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice.
abstract: BACKGROUND
  Inflammation may contribute to the pathogenesis of various forms of pulmonary hypertension (PH). Recent studies in patients with idiopathic PH or PH associated with underlying diseases suggest a role for interleukin-6 (IL-6).
  
  
  METHODS
  To determine whether endogenous IL-6 contributes to mediate hypoxic PH and lung inflammation, we studied IL-6-deficient (IL-6-/-) and wild-type (IL-6+/+) mice exposed to hypoxia for 2 weeks.
  
  
  RESULTS
  Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels were decreased in IL-6-/- mice compared to wild-type controls after 2 weeks' hypoxia, although the pressure response to acute hypoxia was similar in IL-6+/+ and IL-6-/- mice. Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls. Lung IL-6 receptor and gp 130 (the IL-6 signal transducer) mRNA levels increased after 1 and 2 weeks' hypoxia. In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs) and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. IL-6 also markedly stimulated PA-SMC migration without affecting proliferation. Hypoxic IL-6-/- mice showed less inflammatory cell recruitment in the lungs, compared to hypoxic wild-type mice, as assessed by lung protein levels and immunostaining for the specific macrophage marker F4/80, with no difference in lung expression of adhesion molecules or cytokines.
  
  
  CONCLUSIONS
  These data suggest that IL-6 may be actively involved in hypoxia-induced lung inflammation and pulmonary vascular remodeling in mice.
authors.affiliation: INSERM U841, Université Paris XII, F94010 Créteil, France. laurent.savale@hmn.aphp.fr
authors.forename: Laurent
authors.initials: L
authors.lastname: Savale
authors.forename: Ly
authors.initials: L
authors.lastname: Tu
authors.forename: Dominique
authors.initials: D
authors.lastname: Rideau
authors.forename: Mohamed
authors.initials: M
authors.lastname: Izziki
authors.forename: Bernard
authors.initials: B
authors.lastname: Maitre
authors.forename: Serge
authors.initials: S
authors.lastname: Adnot
authors.forename: Saadia
authors.initials: S
authors.lastname: Eddahibi
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000276:immunology; D000860:Hypoxia / Q000150:complications / Q000276:immunology* / Q000503:physiopathology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000473:pathology; D011014:Pneumonia / Q000276:immunology* / Q000503:physiopathology; D011651:Pulmonary Artery / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D013997:Time Factors
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130