胸部脊髓神经炎症作为肺动脉高压的一个新的治疗靶点。
Thoracic Spinal Cord Neuroinflammation as a Novel Therapeutic Target in Pulmonary Hypertension.
机构信息
Department of Anesthesiology and Perioperative Medicine Division of Molecular Medicine (A.R., S.B., S.U.), David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA.
Department of Medicine, Division of Pulmonary and Critical Care Medicine (J.H.), David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA.
出版信息
Hypertension. 2023 Jun;80(6):1297-1310. doi: 10.1161/HYPERTENSIONAHA.122.20782. Epub 2023 Apr 24.
BACKGROUND
Pulmonary hypertension (PH) is associated with aberrant sympathoexcitation leading to right ventricular failure (RVF), arrhythmias, and death. Microglial activation and neuroinflammation have been implicated in sympathoexcitation in experimental PH. We recently reported the first evidence of thoracic spinal cord (TSC) neuroinflammation in PH rats. Here, we hypothesize that PH is associated with increased cardiopulmonary afferent signaling leading to TSC-specific neuroinflammation and sympathoexcitation. Furthermore, inhibition of TSC neuroinflammation rescues experimental PH and RVF.
METHODS
We performed transcriptomic analysis and its validation on the TSC of monocrotaline (n=8) and Sugen hypoxia (n=8) rat models of severe PH-RVF. A group of monocrotaline rats received either daily intrathecal microglial activation inhibitor minocycline (200 μg/kg per day, n=5) or PBS (n=5) from day 14 through 28. Echocardiography and right ventricle-catheterization were performed terminally. Real-time quantitative reverse transcription PCR, immunolocalization, microglia+astrocyte quantification, and terminal deoxynucleotidyl transferase dUTP nick end labeling were assessed. Plasma catecholamines were measured by ELISA. Human spinal cord autopsy samples (Control n=3; pulmonary arterial hypertension n=3) were assessed to validate preclinical findings.
RESULTS
Increased cardiopulmonary afferent signaling was demonstrated in preclinical and clinical PH. Our findings delineated common dysregulated genes and pathways highlighting neuroinflammation and apoptosis in the remodeled TSC and highlighted increased sympathoexcitation in both rat models. Moreover, we validated significantly increased microglial and astrocytic activation and CX3CL1 expression in TSC of human pulmonary arterial hypertension. Finally, amelioration of TSC neuroinflammation by minocycline in monocrotaline rats inhibited microglial activation, decreased proinflammatory cytokines, sympathetic nervous system activation and significantly attenuated PH and RVF.
CONCLUSIONS
Targeting neuroinflammation and associated molecular pathways and genes in the TSC may yield novel therapeutic strategies for PH and RVF.
背景
肺动脉高压（PH）与异常的交感兴奋有关，导致右心室衰竭（RVF）、心律失常和死亡。小胶质细胞激活和神经炎症与实验性 PH 中的交感兴奋有关。我们最近报道了 PH 大鼠胸段脊髓（TSC）神经炎症的首个证据。在这里，我们假设 PH 与增加心肺传入信号有关，导致 TSC 特异性神经炎症和交感兴奋。此外，抑制 TSC 神经炎症可挽救实验性 PH 和 RVF。
方法
我们对两种严重 PH-RVF 大鼠模型（野百合碱组和 Sugen 低氧组）的 TSC 进行了转录组分析及其验证（每组 8 只）。一组野百合碱大鼠从第 14 天至第 28 天每天接受鞘内小胶质细胞激活抑制剂米诺环素（200μg/kg/天，n=5）或 PBS（n=5）治疗。终末期进行超声心动图和右心导管检查。实时定量逆转录 PCR、免疫定位、小胶质细胞+星形胶质细胞计数和末端脱氧核苷酸转移酶 dUTP 缺口末端标记法进行评估。通过 ELISA 测量血浆儿茶酚胺。评估了人类脊髓尸检样本（对照组 n=3；肺动脉高压 n=3）以验证临床前研究结果。
结果
在临床前和临床 PH 中均证实了心肺传入信号的增加。我们的研究结果描绘了共同失调的基因和途径，突出了重塑的 TSC 中的神经炎症和细胞凋亡，并强调了两种大鼠模型中交感兴奋的增加。此外，我们验证了人类肺动脉高压 TSC 中显著增加的小胶质细胞和星形胶质细胞激活以及 CX3CL1 表达。最后，米诺环素治疗可改善野百合碱大鼠的 TSC 神经炎症，抑制小胶质细胞激活，减少促炎细胞因子，交感神经系统激活，并显著减轻 PH 和 RVF。
结论
靶向 TSC 中的神经炎症和相关分子途径和基因可能为 PH 和 RVF 提供新的治疗策略。
Zotero 插件