Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

Autor: Gérald Simonneau, Nicolas Raymond, Marc Humbert, Frédéric Perros, Marie-Camille Chaumais, Maria Giannakouli, Olaf Mercier, Peter Dorfmüller, Frédéric Charlotte, David Montani, Elie Fadel, Ingrid Durand-Gasselin
Přispěvatelé: School of Medicine, Université Paris-Sud - Paris 11 (UP11), Centre national de référence de l'hypertension pulmonaire sévère, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologiques, Hôpital Marie Lannelongue, Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), BMC, Ed., Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Marie-Lannelongue
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Male
Pulmonary and Respiratory Medicine
Pathology
medicine.medical_specialty
Endothelium
Hypertension
Pulmonary
Inflammation
Pulmonary Artery
030204 cardiovascular system & hematology
medicine.disease_cause
[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Proinflammatory cytokine
Rats
Sprague-Dawley
Random Allocation
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
medicine.artery
medicine
Animals
030304 developmental biology
lcsh:RC705-779
0303 health sciences
business.industry
CD68
Research
Nitrotyrosine
lcsh:Diseases of the respiratory system
medicine.disease
Pulmonary hypertension
Rats
3. Good health
Disease Models
Animal
Oxidative Stress
medicine.anatomical_structure
chemistry
Pulmonary artery
Airway Remodeling
[SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Endothelium
Vascular
medicine.symptom
business
Blood Flow Velocity
Oxidative stress
Zdroj: Respiratory Research
Respiratory Research, BioMed Central, 2011, 12 (1), pp.119. ⟨10.1186/1465-9921-12-119⟩
Respiratory Research, Vol 12, Iss 1, p 119 (2011)
ISSN: 1465-9921
Popis: 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. Conclusion 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.
Databáze: OpenAIRE
Externí odkaz: