Experimental Pulmonary Hypertension Is Associated With Neuroinflammation in the Spinal Cord

Abstract

RationalePulmonary hypertension (PH) is a rare but fatal disease characterized by elevated pulmonary pressures and vascular remodeling, leading to right ventricular failure and death. Recently, neuroinflammation has been suggested to be involved in the sympathetic activation in experimental PH. Whether PH is associated with neuroinflammation in the spinal cord has never been investigated.Methods/ResultsPH was well-established in adult male Wistar rats 3-week after pulmonary endothelial toxin Monocrotaline (MCT) injection. Using the thoracic segments of the spinal cord, we found a 5-fold increase for the glial fibrillary acidic protein (GFAP) in PH rats compared to controls (p < 0.05). To further determine the region of the spinal cord where GFAP was expressed, we performed immunofluorescence and found a 3 to 3.5-fold increase of GFAP marker in the gray matter, and a 2 to 3-fold increase in the white matter in the spinal cord of PH rats compared to controls. This increase was due to PH (MCT vs. Control; p < 0.01), and there was no difference between the dorsal versus ventral region. PH rats also had an increase in the pro-inflammatory marker chemokine (C-C motif) ligand 3 (CCL3) protein expression (∼ 3-fold) and (2.8 to 4-fold, p < 0.01) in the white matter. Finally, angiogenesis was increased in PH rat spinal cords assessed by the adhesion molecule CD31 expression (1.5 to 2.3-fold, p < 0.01).ConclusionWe report for the first time evidence for neuroinflammation in the thoracic spinal cord of pulmonary hypertensive rats. The impact of spinal cord inflammation on cardiopulmonary function in PH remains elusive.

Fumagillin Attenuates Spinal Angiogenesis, Neuroinflammation, and Pain in Neuropathic Rats after Chronic Constriction Injury

“…Astrocytes regulate angiogenesis by various mechanisms, including modulation of VEGF and hypoxia-inducible factor α-Wnt/β-catenin signaling [55,56]. Astrocyte activation, neuroinflammation with increased production of inflammatory mediators, and neurovascular endothelial activation with increased CD31 expression occurred in the thoracic spinal cord in a rat model of experimental pulmonary hypertension [57]. CCI induced the activation of spinal astrocytes and increased the production of pro-inflammatory mediators (TNF-α, IL-1β, and IL-6) in the male rat lumbar spinal cord [58][59][60][61].…”

Fumagillin Attenuates Spinal Angiogenesis, Neuroinflammation, and Pain in Neuropathic Rats After Chronic Constriction Injury

“…Similarly, VEGF and signaling [52,53]. Astrocyte activation, neuroin ammation with increased production of in ammatory mediators, and neurovascular endothelial activation with increased CD31 expression occur in the thoracic spinal cord in a rat model of experimental pulmonary hypertension [54]. CCI-induced the activation of spinal astrocytes and increased the production of proin ammatory mediators (TNF-α, IL-1β, and IL-6) in the male rat lumbar spinal cord [55][56][57][58].…”

Thoracic Spinal Cord Neuroinflammation as a Novel Therapeutic Target in Pulmonary Hypertension

“…Neuroinflammation in the brain has recently been implicated in the SNS activation found in MCT-induced PH rats. [19][20][21] Subsequently, our laboratory reported the first evidence for TSC neuroinflammation in MCT-induced PH rats 22 ; however, the precise molecular mechanisms and impact of TSC neuroinflammation and associated SNS activation on cardiopulmonary function in PH and RVF were elusive. In line with the previous reports on left ventricular ischemia, [9][10][11][12][13] we postulated that in severe PH and RVF, afferent signaling from cardiopulmonary neurons via dorsal root ganglia to the dorsal horn of TSC is mediated by TRPV1 that leads to molecular and transcriptomic changes within the TSC.…”