Aging reverses the role of the transient receptor potential vanilloid-1 channel in systemic inflammation from anti-inflammatory to proinflammatory.
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.
Systemic Inflammation Laboratory (FeverLab), Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
Samuel P
SP
Wanner
Andras
A
Garami
Eszter
E
Pakai
Daniela L
DL
Oliveira
Narender R
NR
Gavva
Cândido C
CC
Coimbra
Andrej A
AA
Romanovsky
D000367:Age Factors; D000375:Aging; D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D055786:Gene Knockout Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016016:Proportional Hazards Models; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D018805:Sepsis / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D052160:Benzothiazoles; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D011743:Pyrimidines; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014409:Tumor Necrosis Factor-alpha