Systemic Inflammation Laboratory (FeverLab), Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
Cell Cycle. 2012 Jan 15;11(2):343-9. doi: 10.4161/cc.11.2.18772.
Studies in young rodents have shown that the transient receptor potential vanilloid-1 (TRPV1) channel plays a suppressive role in the systemic inflammatory response syndrome (SIRS) by inhibiting production of tumor necrosis factor (TNF)α and possibly by other mechanisms. We asked whether the anti-inflammatory role of TRPV1 changes with age. First, we studied the effect of AMG517, a selective and potent TRPV1 antagonist, on aseptic, lipopolysaccharide (LPS)-induced SIRS in young (12 wk) mice. In agreement with previous studies, AMG517 increased LPS-induced mortality in the young. We then studied the effects of TRPV1 antagonism (AMG517 or genetic deletion of TRPV1) on SIRS in middle-aged (43-44 wk) mice. Both types of TRPV1 antagonism delayed and decreased LPS-induced mortality, indicating a reversal of the anti-inflammatory role of TRPV1 with aging. In addition, deletion of TRPV1 decreased the serum TNFα response to LPS, suggesting that the suppressive control of TRPV1 on TNFα production is also reversed with aging. In contrast to aseptic SIRS, polymicrobial sepsis (induced by cecal ligation and puncture) caused accelerated mortality in aged TRPV1-deficient mice as compared with wild-type littermates. The recovery of TRPV1-deficient mice from hypothermia associated with the cecal ligation and puncture procedure was delayed. Hence, the reversal of the anti-inflammatory role of TRPV1 found in the aged and their decreased systemic inflammatory response are coupled with suppressed defense against microbial infection. These results caution that TRPV1 antagonists, widely viewed as new-generation painkillers, may decrease the resistance of older patients to infection and sepsis.
在年轻啮齿动物中的研究表明，瞬时受体电位香草酸 1 型（TRPV1）通道通过抑制肿瘤坏死因子（TNF）α的产生和可能通过其他机制在全身炎症反应综合征（SIRS）中发挥抑制作用。我们询问 TRPV1 的抗炎作用是否随年龄而变化。首先，我们研究了选择性和有效的 TRPV1 拮抗剂 AMG517 对年轻（12 周龄）小鼠无菌性、脂多糖（LPS）诱导的 SIRS 的影响。与先前的研究一致，AMG517 增加了年轻小鼠 LPS 诱导的死亡率。然后，我们研究了 TRPV1 拮抗作用（AMG517 或 TRPV1 基因缺失）对中年（43-44 周龄）小鼠 SIRS 的影响。两种类型的 TRPV1 拮抗作用均延迟并降低 LPS 诱导的死亡率，表明 TRPV1 的抗炎作用随着年龄的增长而逆转。此外，TRPV1 缺失减少了 LPS 诱导的血清 TNFα反应，表明 TRPV1 对 TNFα产生的抑制控制也随着年龄的增长而逆转。与无菌性 SIRS 相反，多微生物败血症（由盲肠结扎和穿刺引起）导致年老的 TRPV1 缺陷型小鼠的死亡率比野生型同窝仔鼠加速，与盲肠结扎和穿刺程序相关的 TRPV1 缺陷型小鼠的体温恢复延迟。因此，在年老的小鼠中发现的 TRPV1 抗炎作用的逆转及其全身炎症反应的降低与对微生物感染的防御抑制有关。这些结果提醒人们，广泛认为是新一代止痛药的 TRPV1 拮抗剂可能会降低老年患者对感染和败血症的抵抗力。
