Endogenous antimicrobial peptide LL-37 induces human vasodilatation
Endogenous antimicrobial peptide LL-37 induces human vasodilatation
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DOI：
10.1093/bja/aen074
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发表时间：
2008-06-01
影响因子：
9.8
通讯作者：
Bodelsson, M.
中科院分区：
文献类型：
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作者：
Berkestedt, I.;Nelson, A.;Bodelsson, M.
背景资料。感染性休克包括血管扩张和天然免疫的激活，这反过来又会导致抗菌肽的释放，如LL-37。已有研究表明，IL-37可通过脂氧素A(4)受体(ALX，FPRL1)吸引白细胞。ALX也存在于血管内皮细胞中。为了探索感染性休克的药物干预的可能途径，我们调查了LL-37是否会影响血管张力。在腹部手术中获取人的大网膜动脉和静脉，并在器官浴中研究环状平滑肌的活动。逆转录-聚合酶链式反应检测基因表达。在微摩尔浓度下，IL-37在静脉中诱导浓度和内皮依赖性的松弛，但在由内皮素-1预收缩的动脉节段上则不诱导。用氯化钾(30 MM)抑制内皮源性超极化因子后，这种松弛作用明显减弱，而一氧化氮合酶抑制剂L-N-硝基-精氨酸甲酯对这种松弛作用影响较小，而消炎痛则完全不影响这种松弛。ALX激动剂WKYMVm也引起松弛，而ALX拮抗剂WRWWWW可抑制IL-37和WKYMVm引起的松弛。ALX在静脉内皮细胞中有表达。我们首次证明，人类抗菌肽，LL-37，通过对内皮细胞ALX的影响，在人的大网膜静脉中诱导内皮依赖的松弛。这种松弛包括一氧化氮和EDHF的释放，但不包括前列腺素。脓毒症时白细胞释放的IL-37可能参与了血管扩张，ALX拮抗剂治疗可能是成功的。
Background. Septic shock includes blood vessel dilatation and activation of innate immunity, which in turn causes release of antimicrobial peptides such as LL-37. It has been shown that LL-37 can attract leucocytes via the lipoxin A(4) receptor (ALX, FPRL1). ALX is also present in vascular endothelial cells. To explore possible ways of pharmacological intervention in septic shock, we investigated if LL-37 can affect vascular tone.Mehods. Human omental arteries and veins were obtained during abdominal surgery, and circular smooth muscle activity was studied in organ baths. Gene expression was studied using reverse transcriptase-polymerase chain reaction.Results. LL-37, at micromolar concentrations, induced a concentration- and endothelium-dependent relaxation in vein but not in artery segments precontracted by endothelin-1. The relaxation was profoundly reduced by potassium chloride (30 mM) to inhibit endothelium-derived hyperpolarizing factor (EDHF), whereas it was less affected by the NOS inhibitor, L-N-G-nitroarginine methyl ester, and not at all by indomethacin. The ALX agonist, WKYMVm, also induced a relaxation and both the relaxations induced by LL-37 and WKYMVm were inhibited by the ALX antagonist, WRWWWW. ALX was expressed in the vein endothelium.Conclusions. We demonstrate, for the first time, that the human antimicrobial peptide, LL-37, induces endothelium-dependent relaxation in human omental veins mediated via an effect on endothelial ALX. The relaxation involves the release of nitric oxide and EDHF but not prostanoids. LL-37 released from white blood cells could contribute to blood vessel dilatation during sepsis and treatment with ALX antagonists might be successful.