Role of Transient Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury
Role of Transient Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury
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瞬时受体电位 Vanilloid 4 在中性粒细胞激活和急性肺损伤中的作用
DOI：
10.1165/rcmb.2014-0225oc
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发表时间：
2016
影响因子：
6.4
通讯作者：
Flem
中科院分区：
文献类型：
--
作者：
Yin Jun;Michalick Laura;Tang Christine;Tabuchi Arata;Goldenberg Neil;Dan Qinghong;Awwad Khader;Wang Liming;Erfin;a Lasti;Nouailles Geraldine;Witzenrath Martin;Vogelzang Alexis;Lv Lu;Lee Warren L.;Zhang Haibo;Rotstein Ori;Kapus Andras;Szaszi Katalin;Flem
阳离子通道瞬时受体电位香草酸（TRPV）4在内皮细胞和免疫细胞中表达;然而，其在急性肺损伤（ALI）中的作用尚不清楚。TRPV 4的功能相关性在体内、分离的鼠肺和分离的中性粒细胞中进行评估。TRPV 4的遗传缺陷减弱了酸诱导的ALI的功能、组织学和炎症标志。TRPV 4抑制剂GSK 2193874的预防性给药获得了类似的保护作用;然而，在ALI诱导后TRPV 4抑制剂HC-067047的治疗性给药没有有益作用。在离体肺中，血小板活化因子（PAF）增加了trpv 4 +/+比trpv 4 −/−血液灌注肺的血管通透性，与肺基因型无关，这表明血细胞上的TRPV 4对肺血管屏障衰竭的贡献。在中性粒细胞中，TRPV 4抑制或缺乏减弱PAF诱导的细胞内钙增加。PAF诱导中性粒细胞形成epoxyeicosatrienoic acids，这反过来又刺激TRPV 4依赖的Ca 2+信号，而epoxyeicosatrienoic acids形成的抑制抑制Ca 2+对PAF的反应。TRPV 4缺乏阻止了中性粒细胞对促炎刺激的反应，包括活性氧的形成、中性粒细胞粘附和趋化性，由于Rac的活化减少而导致脓毒症。然而，在嵌合体小鼠中，酸诱导的ALI中的大多数保护作用归因于实质组织中TRPV 4的遗传缺陷，而循环血细胞中TRPV 4的缺陷主要降低肺髓过氧化物酶活性。我们的研究结果确定TRPV 4作为中性粒细胞活化的新调节因子，并表明实质和嗜中性粒细胞TRPV 4在ALI的病理生理学中的贡献。
The cation channel transient receptor potential vanilloid (TRPV) 4 is expressed in endothelial and immune cells; however, its role in acute lung injury (ALI) is unclear. The functional relevance of TRPV4 was assessedin vivo, in isolated murine lungs, and in isolated neutrophils. Genetic deficiency of TRPV4 attenuated the functional, histological, and inflammatory hallmarks of acid-induced ALI. Similar protection was obtained with prophylactic administration of the TRPV4 inhibitor, GSK2193874; however, therapeutic administration of the TRPV4 inhibitor, HC-067047, after ALI induction had no beneficial effect. In isolated lungs, platelet-activating factor (PAF) increased vascular permeability in lungs perfused withtrpv4+/+more than withtrpv4−/−blood, independent of lung genotype, suggesting a contribution of TRPV4 on blood cells to lung vascular barrier failure. In neutrophils, TRPV4 inhibition or deficiency attenuated the PAF-induced increase in intracellular calcium. PAF induced formation of epoxyeicosatrienoic acids by neutrophils, which, in turn, stimulated TRPV4-dependent Ca2+signaling, whereas inhibition of epoxyeicosatrienoic acid formation inhibited the Ca2+response to PAF. TRPV4 deficiency prevented neutrophil responses to proinflammatory stimuli, including the formation of reactive oxygen species, neutrophil adhesion, and chemotaxis, putatively due to reduced activation of Rac. In chimeric mice, however, the majority of protective effects in acid-induced ALI were attributable to genetic deficiency of TRPV4 in parenchymal tissue, whereas TRPV4 deficiency in circulating blood cells primarily reduced lung myeloperoxidase activity. Our findings identify TRPV4 as novel regulator of neutrophil activation and suggest contributions of both parenchymal and neutrophilic TRPV4 in the pathophysiology of ALI.