Blocking Cyclic Adenosine Diphosphate Ribose-mediated Calcium Overload Attenuates Sepsis-induced Acute Lung Injury in Rats.
Blocking Cyclic Adenosine Diphosphate Ribose-mediated Calcium Overload Attenuates Sepsis-induced Acute Lung Injury in Rats.
复制标题
阻断环二磷酸腺苷核糖介导的钙超载可减轻脓毒症引起的大鼠急性肺损伤。
DOI：
10.4103/0366-6999.185854
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发表时间：
2016-07-20
影响因子：
6.1
通讯作者：
Ai YH
中科院分区：
文献类型：
--
作者：
Peng QY;Zou Y;Zhang LN;Ai ML;Liu W;Ai YH
背景：急性肺损伤（ALI）是脓毒症的常见并发症，与高死亡率相关。细胞内Ca2+超载在脓毒症引起的ALI的病理生理学中起着重要作用，而环二磷酸腺苷核糖（cADPR）是细胞内Ca2+动员的重要调节因子。分化簇 38 (CD38)/cADPR 通路已被发现在多种炎症过程中发挥作用，但其在脓毒症诱导的 ALI 中的作用仍不清楚。本研究旨在探讨 CD38/cADPR 信号通路在脓毒症诱导的 ALI 中是否被激活，以及阻断 cADPR 介导的钙超载是否可以减轻 ALI。方法：采用盲肠结扎穿刺法（CLP）建立脓毒症大鼠模型。将大鼠分为假手术组、CLP组和CLP+8-溴环二磷酸腺苷核糖(8-Br-cADPR)组。在 CLP 手术后 6、12、24 和 48 小时测量肺组织中烟酰胺腺嘌呤二核苷酸 (NAD+)、cADPR、CD38 和细胞内 Ca2+ 水平。测量肺组织学损伤、肿瘤坏死因子（TNF）-α、丙二醛（MDA）水平和超氧化物歧化酶（SOD）活性。结果：CLP术后24 h脓毒症大鼠肺内NAD+、cADPR、CD38和细胞内Ca2+水平显着升高。使用 cADPR 特异性抑制剂 8-Br-cADPR 治疗，显着降低细胞内 Ca2+ 水平 (P = 0.007)，减轻肺组织学损伤 (P = 0.023)，减少 TNF-α 水平。脓毒症大鼠肺部的 SOD 和 MDA 水平（分别为 P < 0.001 和 P = 0.002）以及恢复的 SOD 活性（P = 0.031）。结论：CD38/cADPR 通路在脓毒症大鼠的肺部被激活，用 8-Br-cADPR 阻断 cADPR 介导的钙超载可预防脓毒症引起的 ALI。
Background:Acute lung injury (ALI) is a common complication of sepsis that is associated with high mortality. Intracellular Ca2+ overload plays an important role in the pathophysiology of sepsis-induced ALI, and cyclic adenosine diphosphate ribose (cADPR) is an important regulator of intracellular Ca2+ mobilization. The cluster of differentiation 38 (CD38)/cADPR pathway has been found to play roles in multiple inflammatory processes but its role in sepsis-induced ALI is still unknown. This study aimed to investigate whether the CD38/cADPR signaling pathway is activated in sepsis-induced ALI and whether blocking cADPR-mediated calcium overload attenuates ALI. Methods:Septic rat models were established by cecal ligation and puncture (CLP). Rats were divided into the sham group, the CLP group, and the CLP+ 8-bromo-cyclic adenosine diphosphate ribose (8-Br-cADPR) group. Nicotinamide adenine dinucleotide (NAD+), cADPR, CD38, and intracellular Ca2+ levels in the lung tissues were measured at 6, 12, 24, and 48 h after CLP surgery. Lung histologic injury, tumor necrosis factor (TNF)-&agr;, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activities were measured. Results:NAD+, cADPR, CD38, and intracellular Ca2+ levels in the lungs of septic rats increased significantly at 24 h after CLP surgery. Treatment with 8-Br-cADPR, a specific inhibitor of cADPR, significantly reduced intracellular Ca2+ levels (P = 0.007), attenuated lung histological injury (P = 0.023), reduced TNF-&agr; and MDA levels (P < 0.001 and P = 0.002, respectively) and recovered SOD activity (P = 0.031) in the lungs of septic rats. Conclusions:The CD38/cADPR pathway is activated in the lungs of septic rats, and blocking cADPR-mediated calcium overload with 8-Br-cADPR protects against sepsis-induced ALI.