Calcitonin gene-related peptide inhibits local acute inflammation and protects mice against lethal endotoxemia
Calcitonin gene-related peptide inhibits local acute inflammation and protects mice against lethal endotoxemia
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DOI：
10.1097/01.shk.0000183395.29014.7c
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发表时间：
2005-12-01
期刊：
影响因子：
3.1
通讯作者：
Bozza, MT
中科院分区：
文献类型：
--
作者：
Gomes, RN;Castro-Faria-Neto, HC;Bozza, MT
降钙素基因相关肽（CGRP）是一种存在于中枢和外周神经元中的强效血管舒张肽，在炎症部位释放并抑制几种巨噬细胞、树突状细胞和淋巴细胞功能。在本研究中，我们研究了CGRP在局部和全身急性炎症模型中的作用以及对脂多糖（LPS）诱导的巨噬细胞活化的作用。用合成CGRP进行腹膜内预处理在LPS注射后4小时减少血液中和进入腹膜腔的嗜中性粒细胞的数量约50%。CGRP未能抑制由直接趋化血小板活化因子诱导的中性粒细胞募集，而它显着抑制LPS诱导的KC生成，表明CGRP对中性粒细胞募集的影响是间接的，作用于常驻细胞的趋化因子产生。用1 μ g CGRP预处理小鼠可保护小鼠免受致死剂量的LPS。CGRP诱导的保护是受体介导的，因为它完全被CGRP受体拮抗剂CGRP 8-37逆转。CGRP的保护作用与LPS攻击后90分钟小鼠血清中TNF-α的抑制和IL-6和IL-10的诱导相关。最后，CGRP显著抑制LPS诱导的小鼠腹腔巨噬细胞释放TNF-α。这些结果表明，在急性炎症过程中，巨噬细胞上CGRP受体的激活可能是控制急性炎症反应扩展的负反馈机制的一部分。
Calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide present in central and peripheral neurons, is released at inflammatory sites and inhibits several macrophage, dendritic cell, and lymphocyte functions. In the present study, we investigated the role of CGRP in models of local and systemic acute inflammation and on macrophage activation induced by lipopolysaccharide (LPS). Intraperitoneal pretreatment with synthetic CGRP reduces in approximately 50% the number of neutrophils in the blood and into the peritoneal cavity 4 h after LPS injection. CGRP failed to inhibit neutrophil recruitment induced by the direct chemoattractant platelet-activating factor, whereas it significantly inhibited LPS-induced KC generation, suggesting that the effect of CGRP on neutrophil recruitment is indirect, acting on chemokine production by resident cells. Pretreatment of mice with 1 mu g of CGRP protects against a lethal dose of LPS. The CGRP-induced protection is receptor mediated because it is completely reverted by the CGRP receptor antagonist, CGRP 8-37. The protective effect of CGRP correlates with an inhibition of TNF-alpha and an induction of IL-6 and IL-10 in mice sera 90 min after LPS challenge. Finally, CGRP significantly inhibits LPS-induced TNF-alpha released from mouse peritoneal macrophages. These results suggest that activation of the CGRP receptor on macrophages during acute inflammation could be part of the negative feedback mechanism controlling the extension of acute inflammatory responses.