TRPV1 Deletion Enhances Local Inflammation and Accelerates the Onset of Systemic Inflammatory Response Syndrome

Fernandes, Elizabeth S.; Liang, Lijun; Smillie, Sarah-Jane; Kaiser, Frank J.; Purcell, Robert H.; Rivett, Damian W.; Alam, Saydul; Howat, Sarah; Collins, Helen; Thompson, Stephen; Keeble, Julie; Riffo‐Vasquez, Yanira; Bruce, Kenneth D.; Brain, Susan D.

doi:10.4049/jimmunol.1102147

Cited by 119 publications

(134 citation statements)

References 53 publications

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“…These results indicate that TRPV1 protects against LPS-induced organ damage via inhibition of the production of proinflammatory cytokines and chemokines and are consistent with the reports showing that TRPV1 plays a counterregulatory role against acute lung inflammatory injury induced by intratracheal administration of LPS (27). This notion is supported by most recent studies showing that TRPV1 protects against the transition from a local to a systemic inflammatory state in a cecal ligation and puncture (CLP) model of sepsis (28). In addition, it has been shown that the proinflammatory cytokines stimulate expression of adhesion molecules that lead to neutrophil-dependent organ damage (29).…”

Section: Discussionsupporting

confidence: 91%

TRPV1 Ablation Aggravates Inflammatory Responses and Organ Damage during Endotoxic Shock

Wang

2013

Clin. Vaccine Immunol.

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bTo test the hypothesis that ablation of transient receptor potential vanilloid type 1 (TRPV1) channels leads to exacerbated inflammatory responses and organ damage during endotoxic shock, lipopolysaccharide (LPS; 5 million endotoxin units/kg of body weight) was injected intraperitoneally (i.p.) into wild-type (WT) and TRPV1-null mutant (TRPV1 ؊/؊ ) mice. Mean arterial pressure and heart rate, determined by radiotelemetry, were severely depressed after LPS injection into WT and TRPV1 ؊/؊ mice, with no distinction between the two strains. At 24 h after LPS injection, renal glomerular hypercellularity and hepatocellular injury were observed in both strains, accompanying further elevated serum levels of creatinine and alanine aminotransferase in T he transient receptor potential vanilloid type 1 (TRPV1) channel, also known as vanilloid receptor type 1, is a ligand-gated nonselective ion channel (1). It functions as a molecular transducer to integrate multiple physical and chemical stimuli, including noxious heat, low pH, exogenous and endogenous vanilloid compounds, and lipid metabolites (2, 3). Immunohistochemical labeling studies have shown that, in addition to the central nervous system, TRPV1 resides predominantly in unmyelinated C fibers and thinly myelinated A␦-afferent nerve fibers innervating the cardiovascular tissues, including the heart, blood vessel, and kidney (2). In addition to a function as afferent nerves sending information to the central nervous system, sensory nerves possess an efferent function by releasing a number of sensory neurotransmitters, commonly substance P and calcitonin gene-related peptide (CGRP) (2).Endotoxic shock is caused mainly by an exaggerated systemic response to endotoxemia induced by Gram-negative bacteria and their characteristic cell wall component, lipopolysaccharide (LPS) (4). It is characterized by refractory hypotension, multiple organ failure, and high mortality (5). In addition to hypotension, abnormalities in renal, hepatic, pulmonary, and hematologic systems are common in the course of endotoxic shock. The development of multiple organ failure contributes to mortality associated with endotoxic shock (6). Beyond refractory hypotension, excessive inflammatory responses are believed to result in tissue and cellular injury during endotoxic shock. Inflammation-induced tissue damage may be attributed as a main cause of multiple organ failure and mortality in the course of endotoxic shock.Increased production of an endocannabinoid, anandamide, by macrophages has been reported to contribute to endotoxin-induced hypotension (7,8). Recently, evidence has shown that TRPV1 can be activated by anandamide, suggesting that TRPV1 may be involved in the pathogenesis of endotoxic shock (3, 9).Activation of TRPV1 expressed in sensory nerves may cause release of a number of sensory neuropeptides, including CGRP and substance P, which are potent vasodilators in various vascular beds (2). These studies suggest that activation of TRPV1 during endotoxic shock may contribute to decreased...

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Section: Discussionsupporting

confidence: 91%

TRPV1 Ablation Aggravates Inflammatory Responses and Organ Damage during Endotoxic Shock

Wang

2013

Clin. Vaccine Immunol.

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“…Although the mechanism of TRPV1 channel activation after irradiation is still unknown, possible mediators include radiation-induced reactive oxygen species and secondary generation of nitric oxide in irradiated cells, 33) or radiation-induced extracellular release of ATP from cells, we have reported. [34][35][36][37] On the other hand, it is well known that TRPV1 channel is involved in inflammation and pain sensation, [38][39][40][41] and TRPV1 channel inhibitors are candidates as analgesic drugs to relieve cancer pain. 42,43) Therefore, TRPV1 inhibitors might offer dual benefits in cancer therapy, having both anti-inflammatory and radiosensitizing actions.…”

Section: Resultsmentioning

confidence: 99%

Radiosensitizing Effect of TRPV1 Channel Inhibitors in Cancer Cells

Nishino

Tanamachi

Nakanishi

et al. 2016

Biological & Pharmaceutical Bulletin

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Radiosensitizers are used in cancer therapy to increase the γ-irradiation susceptibility of cancer cells, including radioresistant hypoxic cancer cells within solid tumors, so that radiotherapy can be applied at doses sufficiently low to minimize damage to adjacent normal tissues. Radiation-induced DNA damage is repaired by multiple repair systems, and therefore these systems are potential targets for radiosensitizers. We recently reported that the transient receptor potential vanilloid type 1 (TRPV1) channel is involved in early responses to DNA damage after γ-irradiation of human lung adenocarcinoma A549 cells. Therefore, we hypothesized that TRPV1 channel inhibitors would have a radiosensitizing effect by blocking repair of radiation-induced cell damage. Here, we show that pretreatment of A549 cells with the TRPV1 channel inhibitors capsazepine, AMG9810, SB366791 and BCTC suppressed the γ-ray-induced activation of early DNA damage responses, i.e., activation of the protein kinase ataxia-telangiectasia mutated (ATM) and accumulation of p53-binding protein 1 (53BP1). Further, the decrease of survival fraction at one week after γ-irradiation (2.0 Gy) was enhanced by pretreatment of cells with these inhibitors. On the other hand, inhibitor pretreatment did not affect cell viability, the number of apoptotic or necrotic cells, or DNA synthesis at 24 h after irradiation. These results suggest that inhibition of DNA repair by TRPV1 channel inhibitors in irradiated A549 cells caused gradual loss of proliferative ability, rather than acute facilitation of apoptosis or necrosis. TRPV1 channel inhibitors could be novel candidates for radiosensitizers to improve the efficacy of radiation therapy, either alone or in combination with other types of radiosensitizers. Key words γ-ray; radiosensitizer; transient receptor potential vanilloid type 1 channelRadiation therapy plays an important role in treatment of numerous cancers, 1) because ionizing radiation induces potentially lethal DNA damage, such as DNA double-strand breaks (DSBs). Although DSBs cause cell death or genomic instability, 2,3) they can be repaired by mechanisms such as non-homologous end joining (NHEJ) or homologous recombination (HR). NHEJ rejoins the DNA ends without requiring sequence homologies, and is mediated by a DNA-dependent protein kinase holoenzyme. On the other hand, HR processes use undamaged homologous DNA sequences (sister chromatid or the homologous chromosome) to ensure the fidelity of the repair process. [4][5][6] The DNA damage response pathways protect genomic integrity and act as a barrier against cancer, 7) and are important for recovery of irradiated normal cells. However, overexpression of DNA repair proteins is involved in radioresistance of cancer cells, [8][9][10] and therefore these mechanisms also decrease the efficiency of radiation therapy.Since ionizing radiation does not discriminate between cancer cells and normal cells, damage to normal tissues is usually a dose-limiting factor in radiation therapy. In addition, many solid ...

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“…5G and 10, C, D, and F) (125,126). In these published studies, the loss of TRPV1 exacerbates the inflammatory response to infection.…”

Section: Discussionmentioning

confidence: 99%

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells

Wilhelmsen

Khakpour

Tran

et al. 2014

Journal of Biological Chemistry

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Background:The endothelium is centrally involved in acute inflammatory disorders. Results: WIN55,212-2 and the endocannabinoid N-arachidonoyl dopamine (NADA), but not anandamide nor 2-arachidonoylglycerol, reduce endothelial activation by bacterial Toll-like receptor agonists and TNF␣. Conclusion: NADA is a newly identified endogenous regulator of endothelial inflammation. Significance: The endothelial endocannabinoid system represents a novel immune regulatory system that could be exploited therapeutically.

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TRPV1 Deletion Enhances Local Inflammation and Accelerates the Onset of Systemic Inflammatory Response Syndrome

Cited by 119 publications

References 53 publications

TRPV1 Ablation Aggravates Inflammatory Responses and Organ Damage during Endotoxic Shock

TRPV1 Ablation Aggravates Inflammatory Responses and Organ Damage during Endotoxic Shock

Radiosensitizing Effect of TRPV1 Channel Inhibitors in Cancer Cells

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells

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