Abstract 3481: A Novel Mechanism Contributing to End Organ Damage in Endotoxic Shock: Role of TRPV1
We previously showed that transient receptor potential vanilloid type 1 (TRPV1) channels play a vital role in the survival of animals during endotoxic shock. To examine effects of TRPV1 on systemic hemodynamics, inflammatory responses, and renal and liver function/damage during endotoxic shock, lipopolysaccharide (LPS, 10 mg/kg) was injected i.p. into wild type (WT) and TRPV1-null mutant (TRPV1−/−) mice. Mean arterial pressure (MAP, mmHg) measured with radiotelemetry in conscious mice were severely decreased 11 hours after LPS injection in WT and TRPV1−/− mice, with no difference between the two strains (76±6 vs. 71±4, p>0.05). The serum levels of alanine aminotransferase (ALT, indicator of liver dysfunction, IU/L) or creatinine (indicator of renal dysfunction, mg/dL) were increased 6 and 24 h after LPS injection in WT and TRPV1−/− mice, with a greater magnitude in the latter strain (ALT, 79±11 vs. 105±16; creatinine, 0.7±0.09 vs. 1.2±0.08, p<0.05). Serum cytokine (pg/ml) and chemokine (ng/ml) levels were higher 6 h after LPS injection in TRPV1−/− compared to WT mice (TNF-α, 718±43 vs. 428±44; IL-1β, 736±39 vs. 420±46; KC, 100±8 vs. 60±7; MIP-2, 2.2±0.4 vs. 1.3±0.3, p<0.05). LPS-induced neutrophil infiltration (cells/mm2) was greater in the kidney and liver in TRPV1−/− than in WT mice (kidney, 93±6 vs. 38±4; liver, 247±13 vs. 156±12, p<0.05). VCAM-1 or ICAM-1 expression was increased 6 and 24 h after LPS injection in the kidney and liver in WT and TRPV1−/− mice, with a greater magnitude in the latter strain (p<0.05). Renal glomerular hypercellularity and hepatocellular injury were apparent 24 h after LPS injection in WT and TRPV1−/− mice, with greater cellular density or injury in the latter strain. These data demonstrate that deletion of TRPV1 had no effect on LPS-induced fall in MAP, but accelerated organ damage during endotoxic shock. Exaggerated organ damage was accompanied by increased inflammatory responses as evident by enhanced neutrophil infiltration, proinflammatory cytokine production, and adhesion molecule expression. These data indicate that activation of TRPV1 attenuates organ damage possibly via its anti-inflammatory action without affecting systemic hemodynamics during endotoxic shock.