The Inflammatory Preatherosclerotic Remodeling Induced by Intermittent Hypoxia Is Attenuated by RANTES/CCL5 Inhibition
The Inflammatory Preatherosclerotic Remodeling Induced by Intermittent Hypoxia Is Attenuated by RANTES/CCL5 Inhibition
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DOI：
10.1164/rccm.201012-2033oc
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发表时间：
2011-09-15
影响因子：
24.7
通讯作者：
Dematteis, Maurice
中科院分区：
文献类型：
--
作者：
Arnaud, Claire;Beguin, Pauline C.;Dematteis, Maurice
基本原理：阻塞性睡眠呼吸暂停综合征（OSA）以间歇性缺氧（IH）为主要症状，是心血管疾病死亡的危险因素。对阻塞性睡眠呼吸暂停的病理生理学认识不足，限制了特异性治疗方法的发展，而金标准的持续气道正压通气治疗可能不能完全逆转阻塞性睡眠呼吸暂停的慢性后果，并且在某些患者中接受程度有限。目的：探讨IH诱导的炎症对阻塞性睡眠呼吸暂停心血管并发症的影响。我们研究了暴露于IH（21- 5%FI（O2），60秒周期）或常氧8小时，每天长达14天的C57 BL 6小鼠的全身和血管炎症变化。在整个IH暴露期间，在用活化后调节的正常T细胞表达和分泌（RANTES）/CC趋化因子配体5（CCL 5）信号传导途径的阻断抗体处理的小鼠中或用IgG同种型对照处理的小鼠中重新评估血管改变。IH诱导的全身性炎症结合脾淋巴细胞增殖和趋化因子表达增加，伴有早期和主要的RANTES/CCL 5改变，增强脾细胞向RANTES/CCL 5的迁移。IH还诱导结构和炎性血管改变。白细胞-内皮细胞粘附相互作用增加，证实白细胞滚动和细胞间粘附分子-1在肠系膜血管的表达。主动脉内膜中层厚度增加，伴有弹性纤维改变、粘液沉积、核因子-κ B-p50和细胞间粘附分子-1过表达、过表达RANTES/CCL 5的平滑肌细胞肥大和外膜-外膜周T淋巴细胞浸润。RANTES/CCL 5中和防止内膜中层增厚和炎症改变，独立的IH相关的proatherogenic dyslipidemia.Conclusions：炎症是一个决定性的机制，IH诱导的动脉粥样硬化前重塑涉及RANTES/CCL 5，动脉粥样硬化形成中的一个关键趋化因子。炎症反应的表征可以识别有并发症风险的患者，其药理学操作可能代表睡眠呼吸暂停后果的潜在补充治疗。
Rationale: The highly prevalent obstructive sleep apnea syndrome (OSA) with its main component intermittent hypoxia (IH) is a risk factor for cardiovascular mortality. The poor knowledge of its pathophysiology has limited the development of specific treatments, whereas the gold standard treatment, continuous positive airway pressure, may not fully reverse the chronic consequences of OSA and has limited acceptance in some patients.Objectives: To examine the contribution of IH-induced inflammation to the cardiovascular complications of OSA.Methods: We investigated systemic and vascular inflammatory changes in C57BL6 mice exposed to IH (21-5% FI(O2), 60-s cycle) or normoxia 8 hours per day up to 14 days. Vascular alterations were reassessed in mice treated with a blocking antibody of regulated upon activation, normal T-cell expressed and secreted (RANTES)/CC chemokine ligand 5 (CCL5) signaling pathway, or with the IgG isotype control throughout the IH exposure.Measurements and Main Results: IH induced systemic inflammation combining increased splenic lymphocyte proliferation and chemokine expression, with early and predominant RANTES/CCL5 alterations, and enhanced splenocyte migration toward RANTES/CCL5. IH also induced structural and inflammatory vascular alterations. Leukocyte-endothelium adhesive interactions were increased, attested by leukocyte rolling and intercellular adhesion molecule-1 expressionin mesenteric vessels. Aortas had increased intima-media thickness with elastic fiber alterations, mucoid depositions, nuclear factor-kappa B-p50 and intercellular adhesion molecule-1 overexpression, hypertrophy of smooth-muscle cells overexpressing RANTES/CCL5, and adventitial-periadventitial T-lymphocyte infiltration. RANTES/CCL5 neutralization prevented both intima-media thickening and inflammatory alterations, independently of the IH-associated proatherogenic dyslipidemia.Conclusions: Inflammation is a determinant mechanism for IH-induced preatherosclerotic remodeling involving RANTES/CCL5, a key chemokine in atherogenesis. Characterization of the inflammatory response could allow identifying at-risk patients for complications, and its pharmacologic manipulation may represent a potential complementary treatment of sleep apnea consequences.