Abstract

Background: Pulmonary hypertension (PH) is a devastating disease characterized by increase in pulmonary pressure that eventually leads to right heart failure and death. PH is associated with heightened circulatory cytokines and infiltration of inflammatory cells within the diseased lungs. However, involvement of inflammation within the central nervous system (CNS) in PH pathophysiology has never been investigated. Emerging evidence suggest that activated microglial cells and neuro-inflammation within the CNS play an important role in the pathology of several CNS disorders, including resistant hypertension. Objective: These observations led us to propose the hypothesis that microglial activation and neuro-inflammation in the autonomic brain regions play regulatory role in PH. Minocycline (Mino), an anti-inflammatory antibiotic, which has been reported to inhibit microglial activation in the autonomic brain regions, was used to test this hypothesis. Methods: PH was induced in adult male rats by a single injection of monocrotaline (MCT; 50mg/kg sc). A subset of MCT-injected animals was infused intracerebroventricularly (ICV) with Mino (20mg/ml). After 4 weeks of treatment, animals were sacrificed for the measurement of physiological and pathological parameters. Results: ICV infusion of Mino significantly attenuated right ventricular systolic pressure (RVSP; Con: 30.1±5, MCT: 76.1±14, MCT+Mino: 50.1±11 mmHg) and right ventricular hypertrophy (RVH; Con: 0.26±0.02, MCT: 0.49±0.12, MCT+Mino: 0.38+0.1) induced by MCT. MCT administration resulted in ~2 fold increase in microglial cells, predominantly in the hypothalamic paraventricular nucleus (PVN), an effect significantly attenuated by ICV Mino (Con: 4.0±1.0, MCT: 8.6±1.1, MCT+Mino: 5.0±1.0). MCT injection increased pro-inflammatory cytokines [IL-1β (155%), TNF-α (165%) and IL-6 (113%)] and decreased IL-10 (46%) levels in the PVN. However, ICV Mino treatment restored these cytokines to control levels. Conclusion: Our observations demonstrate that microglial activation in the PVN is involved in PH pathophysiology. They, for the first time, suggest the involvement of neuro-inflammation and autonomic dysregulation in the development and establishment of PH.

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