title: Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension.
abstract: BACKGROUND
  Involvement of inflammation in pulmonary hypertension (PH) has previously been demonstrated and recently, immune-modulating dendritic cells (DCs) infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH) and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS), as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation.
  
  
  METHODS
  We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT), monocrotaline-exposure/pneumonectomy (MCT/PE).
  
  
  RESULTS
  Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine) in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature. Immunolabeling for OX62, CD68 and actin revealed adventitial and medial DC- and monocyte-infiltration; in MCT/PE, medial smooth muscle cells were admixed with CD68+/vimentin+ cells.
  
  
  CONCLUSIONS
  Our experimental findings support a new concept of immunologic responses to increased OS in MCT/PE-induced PAH, possibly linking recruitment of dendritic cells and OS-producing mast-cells to characteristic vasculopathy.
authors: Université Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, F-94276, France. peter.dorfmuller@u-psud.fr
authors: Peter
authors: P
authors: Dorfmüller
authors: Marie-Camille
authors: MC
authors: Chaumais
authors: Maria
authors: M
authors: Giannakouli
authors: Ingrid
authors: I
authors: Durand-Gasselin
authors: Nicolas
authors: N
authors: Raymond
authors: Elie
authors: E
authors: Fadel
authors: Olaf
authors: O
authors: Mercier
authors: Frédéric
authors: F
authors: Charlotte
authors: David
authors: D
authors: Montani
authors: Gérald
authors: G
authors: Simonneau
authors: Marc
authors: M
authors: Humbert
authors: Frédéric
authors: F
authors: Perros
mesh_terms: D056151:Airway Remodeling / Q000502:physiology; D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress / Q000502:physiology*; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley