Involvement of Neuroinflammation in the Pathogenesis of Monocrotaline-Induced Pulmonary Hypertension
| Autor: | Joseph J. Lebowitz, Ravindra K. Sharma, Gilberto O Lobaton, Aline C. Oliveira, Anandharajan Rathinasabapathy, Katya Rigatto, Mohan K. Raizada, Ashok Kumar, Vinayak Shenoy, Elaine M. Richards, Habibeh Khoshbouei, Jasenka Zubcevic, Victor Aquino, Michael J. Katovich, Seungbum Kim |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Hypertension Pulmonary 030204 cardiovascular system & hematology Pharmacology Article Proinflammatory cytokine Rats Sprague-Dawley Pathogenesis 03 medical and health sciences 0302 clinical medicine Internal Medicine Animals Medicine Pulmonary Wedge Pressure Neuroinflammation Monocrotaline Lung business.industry Interleukin medicine.disease Pulmonary hypertension Rats Disease Models Animal 030104 developmental biology medicine.anatomical_structure Paraventricular nucleus of hypothalamus Cytokines Tumor necrosis factor alpha Microglia business Paraventricular Hypothalamic Nucleus |
| Zdroj: | Hypertension. 71:1156-1163 |
| ISSN: | 1524-4563 0194-911X |
| DOI: | 10.1161/hypertensionaha.118.10934 |
| Popis: | Pulmonary hypertension (PH) is a devastating disease and its successful treatment remains to be accomplished despite recent advances in pharmacotherapy. It has been proposed that PH be considered as a systemic disease, rather than primarily a disease of the pulmonary vasculature. Consequently, an investigation of the intricate interplay between multiple organs such as brain, vasculature, and lung in PH could lead to the identification of new targets for its therapy. However, little is known about this interplay. This study was undertaken to examine the concept that altered autonomic–pulmonary communication is important in PH pathophysiology. Therefore, we hypothesize that activation of microglial cells in the paraventricular nucleus of hypothalamus and neuroinflammation is associated with increased sympathetic drive and pulmonary pathophysiology contributing to PH. We utilized the monocrotaline rat model for PH and intracerebroventricular administration of minocycline for inhibition of microglial cells activation to investigate this hypothesis. Hemodynamic, echocardiographic, histological, immunohistochemical, and confocal microscopic techniques assessed cardiac and pulmonary function and microglial cells. Monocrotaline treatment caused cardiac and pulmonary pathophysiology associated with PH. There were also increased activated microglial cells and mRNA for proinflammatory cytokines (IL [interleukin]-1β, IL-6, and TNF [tumor necrosis factor]-α) in the paraventricular nucleus. Furthermore, increased sympathetic drive and plasma norepinephrine were observed in rats with PH. Intracerebroventricular infusion of minocycline inhibited all these parameters and significantly attenuated PH. These observations implicate a dysfunctional autonomic–lung communication in the development and progression of PH providing new therapeutic targets, such as neuroinflammation, for PH therapy. |
| Databáze: | OpenAIRE |
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