title: Pulmonary microvascular lesions regress in reperfused chronic thromboembolic pulmonary hypertension.
abstract: BACKGROUND
  Pulmonary microvascular disease (PMD) develops in both occluded and non-occluded territories in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and may cause persistent pulmonary hypertension after pulmonary endarterectomy. Endothelin-1 (ET-1) and interleukin-6 (IL-6) are potential PMD severity biomarkers, but it remains unknown whether they are related to occluded or non-occluded territories. We assessed PMD and ET-1/IL-6 gene expression profiles in occluded and non-occluded territories with and without chronic lung reperfusion in an animal CTEPH model.
  
  
  METHODS
  Chronic PH was induced in 10 piglets by left pulmonary artery (PA) ligation followed by weekly embolization of right lower lobe arteries with enbucrilate tissue adhesive for 5 weeks. At Week 6, 5 of 10 animals underwent left PA reperfusion. At Week 12, animals with and without reperfusion were compared with sham animals (n = 5). Hemodynamics, lung morphometry and ET-1/IL-6 gene expression profiles were assessed in the left lung (LL, occluded territories) and right upper lobe (RUL, non-occluded territories).
  
  
  RESULTS
  At Week 12, mean PA pressure remained elevated without reperfusion (29.0 ± 2.8 vs 27.0 ± 1.1 mm Hg, p = 0.502), but decreased after reperfusion (30.0 ± 1.5 vs 20.5 ± 1.7 mm Hg, p = 0.013). Distal media thickness in the LL and RUL PAs and systemic vasculature to the LL were significantly lower in the reperfused and sham groups compared with the non-reperfused group. PMD progression was related to ET-1 and IL-6 gene expression in the RUL and to the ET-A/ET-B gene expression ratio in the LL.
  
  
  CONCLUSIONS
  PMD regressed in occluded and non-occluded territories after lung reperfusion. Changes in ET-1 and IL-6 gene expression were associated with PMD in non-occluded territories.
authors.affiliation: Laboratoire de Recherche Chirurgicale, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson.
authors.forename: David
authors.initials: D
authors.lastname: Boulate
authors.affiliation: INSERM U999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Perros
authors.affiliation: Laboratoire de Recherche Chirurgicale, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; INSERM U999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; Service d'Anatomopathologie, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmuller
authors.affiliation: Laboratoire de Recherche Chirurgicale, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; INSERM U999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Arthur-Ataam
authors.affiliation: Laboratoire de Recherche Chirurgicale, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson.
authors.forename: Julien
authors.initials: J
authors.lastname: Guihaire
authors.affiliation: Service de Chirurgie Thoracique, Vasculaire et de Transplantation Cardiopulmonaire, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson.
authors.forename: Lilia
authors.initials: L
authors.lastname: Lamrani
authors.affiliation: Laboratoire de Recherche Chirurgicale, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson.
authors.forename: Benoit
authors.initials: B
authors.lastname: Decante
authors.affiliation: INSERM U999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France; Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: INSERM U999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson.
authors.forename: Saadia
authors.initials: S
authors.lastname: Eddahibi
authors.affiliation: Laboratoire de Recherche Chirurgicale, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; INSERM U999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France; Service de Chirurgie Thoracique, Vasculaire et de Transplantation Cardiopulmonaire, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dartevelle
authors.affiliation: Laboratoire de Recherche Chirurgicale, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; INSERM U999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France; Service de Chirurgie Thoracique, Vasculaire et de Transplantation Cardiopulmonaire, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson.
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.affiliation: Laboratoire de Recherche Chirurgicale, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; INSERM U999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson; Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France; Service de Chirurgie Thoracique, Vasculaire et de Transplantation Cardiopulmonaire, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson. Electronic address: o.mercier@ccml.fr.
authors.forename: Olaf
authors.initials: O
authors.lastname: Mercier
mesh_terms: D000818:Animals; D001706:Biopsy; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000473:pathology*; D008297:Male; D008833:Microcirculation; D011651:Pulmonary Artery / Q000473:pathology* / Q000503:physiopathology; D011652:Pulmonary Circulation; D011655:Pulmonary Embolism / Q000150:complications* / Q000175:diagnosis / Q000503:physiopathology; D015427:Reperfusion Injury; D012720:Severity of Illness Index; D013552:Swine; D014655:Vascular Resistance
chemical_list: D016207:Cytokines
keywords: chronic thromboembolic pulmonary hypertension; endothelin-1; interleukin-6; microvascular disease; pulmonary endarterectomy; pulmonary hypertension