Clark Natalie, Keeble Julie, Fernandes Elizabeth S, Starr Anna, Liang Lihuan, Sugden David, de Winter Patricia, Brain Susan D
Cardiovascular Division, King's College London, Waterloo Campus, 150 Stamford St., London SE1 9NH, UK.
FASEB J. 2007 Nov;21(13):3747-55. doi: 10.1096/fj.06-7460com. Epub 2007 Jun 29.
Transient potential vanilloid 1 (TRPV1) receptor is an ion channel receptor primarily localized on sensory nerves and activated by specific stimuli to initiate and amplify pain and inflammation, as typified by murine models of scald and arthritis. Little is known of the role of TRPV1 in sepsis, an infective disease associated with inflammation. Through use of a sublethal murine model of lipopolysaccharide-induced peritoneal sepsis, we provide novel evidence that genetic deletion of TRPV1 leads to an enhanced onset of various pathological components of systemic endotoxemia. Paired studies of TRPV1 knockout (KO) and wild-type mice demonstrate significantly enhanced hypotension (56+/-2% vs. 38+/-6% decrease in blood pressure, n=12), hypothermia (13+/-3% vs. 7+/-1% decrease in core temperature, n=6), and peritoneal exudate mediator levels (TNF-alpha, 0.78+/-0.2 vs. 0.38+/-0.1 ng/ml; nitrite, for NO, 35+/-10 vs. 15+/-3 microM; n=8) in TRPV1 KO mice, indicating loss of protective effect. Findings correlated with liver edema and raised plasma levels of aspartate aminotransferase in TRPV1 KO mice. These data suggest that TRPV1 may play an important regulatory role in sepsis independent of the major sensory neuropeptide substance P. The findings are relevant to developing strategies that increase the beneficial, and reduce the harmful, components of sepsis to prevent and treat this often fatal condition.
瞬时受体电位香草酸亚型1（TRPV1）受体是一种离子通道受体，主要位于感觉神经上，可被特定刺激激活，从而引发并放大疼痛和炎症，烫伤和关节炎的小鼠模型就是典型例子。关于TRPV1在脓毒症（一种与炎症相关的感染性疾病）中的作用，人们所知甚少。通过使用脂多糖诱导的亚致死性小鼠腹膜脓毒症模型，我们提供了新的证据，即TRPV1基因缺失会导致全身内毒素血症各种病理成分的发病过程加快。对TRPV1基因敲除（KO）小鼠和野生型小鼠的配对研究表明，TRPV1基因敲除小鼠的低血压（血压下降56±2% 对比38±6%，n = 12）、体温过低（核心体温下降13±3% 对比7±1%，n = 6）以及腹膜渗出液介质水平（肿瘤坏死因子-α，0.78±0.2对比0.38±0.1 ng/ml；亚硝酸盐，代表一氧化氮，35±10对比15±3 μM；n = 8）显著增强，表明保护作用丧失。这些发现与TRPV1基因敲除小鼠的肝水肿和血浆天冬氨酸转氨酶水平升高相关。这些数据表明，TRPV1可能在脓毒症中发挥重要的调节作用，且独立于主要的感觉神经肽P物质。这些发现对于制定增加脓毒症有益成分、减少有害成分以预防和治疗这种常致命疾病的策略具有重要意义。
