Involvement of Neuroinflammation in the Pathogenesis of Monocrotaline-Induced Pulmonary Hypertension

Abstract

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.

Targeted neurotransmitter metabolomics profiling of oleanolic acid in the treatment of spontaneously hypertensive rats

“…It is associated with a variety of pathological disorders including neurotransmitter changes, disordered angiotensin levels, impaired endothelial functions, and overexcited sympathetic nerves as well as other processes such as inammatory factors and oxidative stress. [31][32][33] OA has a signicant antihypertensive effect on hypertensive animals, and its antihypertensive mechanism mainly involves the inhibition of vascular smooth muscle cell proliferation and inammation of the blood vessel wall, thus reducing blood vessel stenosis caused by balloon catheter injury and other causes. [34][35][36] Despite extensive studies, its mechanism associated with neuropathology remains completely unclear.…”

A neuro-inflammatory model can explain the onset, symptoms and flare-ups of myalgic encephalomyelitis/chronic fatigue syndrome

“…19,20 The literature also indicated that a dysfunctional hypothalamic paraventricular nucleus was not only integral to some other physiological diseases, but was also likely caused by localised neuro-inflammation from overactive glial cells. [20][21][22] Might this circuitry be jolted into dysfunction by the triggers of the disease, thereby initiating a neuro-inflammatory response within the brains of ME/CFS patients? Then, neuroinflammation (and ME/CFS itself) could then be Figure 1).…”

The protective of baicalin on pulmonary hypertension vascular remodeling through regulation of TNF-α signaling pathway

“…More than 70% of heritable and 20% of idiopathic PH cases have the BMPR2 gene mutations. Recent studies have found that in ammation is thought to be strong trigger factors and promotes the development of PH in Bmpr2 +/mice, in ammatory play an important role in PAH [7][8][9], in ammatory factors was signi cantly increased in clinical PH patient. In ammatory mediator tumor necrosis factor-α (TNF-α) could further promote the development of PH by reducing BMPR2 expression in PASMCs.…”

“…Scutellaria baicalensis Georgi (huang qin) is a widely used herb in traditional Chinese medicinal herbs. The study found that baicalin has several biological effects including antioxidant, anti-in ammatory, antiviral, neuroprotective, anxiolytic, and anti-cancer activities [9][10][11][12][13]. Our previous study showed that baicalin could inhibit in ammatory, improve PH vascular remodeling and right ventricular impairment in monocrotaline (MCT)-induced experimental [14,15].…”