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1.
J Pharmacol Exp Ther ; 388(2): 613-623, 2024 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-38050077

RESUMEN

Deployment of the tear gas agent 2-chlorobenzalmalononitrile (CS) for riot control has significantly increased in recent years. The effects of CS have been believed to be transient and benign. However, CS induces severe pain, blepharospasm, lachrymation, airway obstruction, and skin blisters. Frequent injuries and hospitalizations have been reported after exposure. We have identified the sensory neuronal ion channel, transient receptor potential ankyrin 1 (TRPA1), as a key CS target resulting in acute irritation and pain and also as a mediator of neurogenic inflammation. Here, we examined the effects of pharmacologic TRPA1 inhibition on CS-induced cutaneous injury. We modeled CS-induced cutaneous injury by applying 10 µl CS agent [200 mM in dimethyl sulfoxide (DMSO)] to each side of the right ears of 8- to 9-week-old C57BL/6 male mice, whereas left ears were applied with solvent only (DMSO). The TRPA1 inhibitor HC-030031 or A-967079 was administered after CS exposure. CS exposure induced strong tissue swelling, plasma extravasation, and a dramatic increase in inflammatory cytokine levels in the mouse ear skin. We also showed that the effects of CS were not transient but caused persistent skin injuries. These injury parameters were reduced with TRPA1 inhibitor treatment. Further, we tested the pharmacologic activity of advanced TRPA1 antagonists in vitro. Our findings showed that TRPA1 is a crucial mediator of CS-induced nociception and tissue injury and that TRPA1 inhibitors are effective countermeasures that reduce key injury parameters when administered after exposure. Additional therapeutic efficacy studies with advanced TRPA1 antagonists and decontamination strategies are warranted. SIGNIFICANCE STATEMENT: 2-Chlorobenzalmalononitrile (CS) tear gas agent has been deployed as a crowd dispersion chemical agent in recent times. Exposure to CS tear gas agents has been believed to cause transient acute toxic effects that are minimal at most. Here we found that CS tear gas exposure causes both acute and persistent skin injuries and that treatment with transient receptor potential ion channel ankyrin 1 (TRPA1) antagonists ameliorated skin injuries.


Asunto(s)
Clorobencenos , Canales de Potencial de Receptor Transitorio , o-Clorobencilidenomalonitrila , Masculino , Ratones , Animales , Gases Lacrimógenos/farmacología , Ancirinas , Canal Catiónico TRPA1 , Dimetilsulfóxido , Ratones Endogámicos C57BL , Dolor
2.
Tob Control ; 25(Suppl 2): ii50-ii54, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27698211

RESUMEN

BACKGROUND: Nicotine is a major oral irritant in smokeless tobacco products and has an aversive taste. Mentholated smokeless tobacco products are highly popular, suggesting that menthol increases their palatability and may facilitate initiation of product use. While menthol is known to reduce respiratory irritation by tobacco smoke irritants, it is not known whether this activity extends to oral nicotine and its aversive effects. STUDY DESIGN: The two-bottle choice drinking assay was used to characterise aversion and preference in C57BL/6 mice to a range of menthol concentrations (10-200 µg/mL). Then, effects of menthol on oral nicotine aversion were determined. Responses were compared with those in mice deficient in the cold/menthol receptor, TRPM8, expressed in trigeminal sensory neurons innervating the oral cavity. RESULTS: Mice showed aversion to menthol concentrations of 100 µg/mL and above. When presented with a highly aversive concentration of nicotine (200 µg/mL), mice preferred solutions with 50 or 100 µg/mL menthol added over nicotine alone. In contrast to wild-type mice, Trpm8-/- showed a strong aversion to mentholated (100 µg/mL) nicotine (200 µg/mL) and preferred nicotine alone. Trpm8-/- mice show aversion to lower concentrations of menthol than wild-type mice. CONCLUSIONS: Oral menthol can reduce the aversive effects of oral nicotine and, at higher concentrations, acts as an irritant by itself. Menthol's effects in relation to nicotine require TRPM8, the cool temperature sensing ion channel that activates analgesic and counterirritant mechanisms. These mechanisms may underlie preference for menthol-containing smokeless tobacco products and may facilitate initiation of product use.


Asunto(s)
Mentol/farmacología , Nicotina/toxicidad , Agonistas Nicotínicos/toxicidad , Canales Catiónicos TRPM/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Masculino , Mentol/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Canales Catiónicos TRPM/genética , Tabaco sin Humo/toxicidad
3.
Am J Physiol Lung Cell Mol Physiol ; 307(2): L158-72, 2014 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-24838754

RESUMEN

The treatment of acute lung injury caused by exposure to reactive chemicals remains challenging because of the lack of mechanism-based therapeutic approaches. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), an ion channel expressed in pulmonary tissues, is a crucial mediator of pressure-induced damage associated with ventilator-induced lung injury, heart failure, and infarction. Here, we examined the effects of two novel TRPV4 inhibitors in mice exposed to hydrochloric acid, mimicking acid exposure and acid aspiration injury, and to chlorine gas, a severe chemical threat with frequent exposures in domestic and occupational environments and in transportation accidents. Postexposure treatment with a TRPV4 inhibitor suppressed acid-induced pulmonary inflammation by diminishing neutrophils, macrophages, and associated chemokines and cytokines, while improving tissue pathology. These effects were recapitulated in TRPV4-deficient mice. TRPV4 inhibitors had similar anti-inflammatory effects in chlorine-exposed mice and inhibited vascular leakage, airway hyperreactivity, and increase in elastance, while improving blood oxygen saturation. In both models of lung injury we detected increased concentrations of N-acylamides, a class of endogenous TRP channel agonists. Taken together, we demonstrate that TRPV4 inhibitors are potent and efficacious countermeasures against severe chemical exposures, acting against exaggerated inflammatory responses, and protecting tissue barriers and cardiovascular function.


Asunto(s)
Lesión Pulmonar Aguda/inducido químicamente , Canales Catiónicos TRPV/antagonistas & inhibidores , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Líquido del Lavado Bronquioalveolar/química , Cloro/toxicidad , Células HEK293 , Humanos , Ácido Clorhídrico/toxicidad , Masculino , Ratones , Neumonía/tratamiento farmacológico , Ratas , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/deficiencia
4.
FASEB J ; 27(9): 3549-63, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23722916

RESUMEN

Allergic contact dermatitis is a common skin disease associated with inflammation and persistent pruritus. Transient receptor potential (TRP) ion channels in skin-innervating sensory neurons mediate acute inflammatory and pruritic responses following exogenous stimulation and may contribute to allergic responses. Genetic ablation or pharmacological inhibition of TRPA1, but not TRPV1, inhibited skin edema, keratinocyte hyperplasia, nerve growth, leukocyte infiltration, and antihistamine-resistant scratching behavior in mice exposed to the haptens, oxazolone and urushiol, the contact allergen of poison ivy. Hapten-challenged skin of TRPA1-deficient mice contained diminished levels of inflammatory cytokines, nerve growth factor, and endogenous pruritogens, such as substance P (SP) and serotonin. TRPA1-deficient sensory neurons were defective in SP signaling, and SP-induced scratching behavior was abolished in Trpa1(-/-) mice. SP receptor antagonists, such as aprepitant inhibited both hapten-induced cutaneous inflammation and scratching behavior. These findings support a central role for TRPA1 and SP in the integration of immune and neuronal mechanisms leading to chronic inflammatory responses and pruritus associated with contact dermatitis.


Asunto(s)
Dermatitis Alérgica por Contacto/inmunología , Dermatitis Alérgica por Contacto/metabolismo , Inflamación/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Animales , Dermatitis Alérgica por Contacto/tratamiento farmacológico , Femenino , Inflamación/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oxazolona/toxicidad , Canal Catiónico TRPA1 , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Canales de Potencial de Receptor Transitorio/genética
5.
Part Fibre Toxicol ; 8: 11, 2011 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-21388553

RESUMEN

BACKGROUND: Increased asthma risk/exacerbation in children and infants is associated with exposure to elevated levels of ultrafine particulate matter (PM). The presence of a newly realized class of pollutants, environmentally persistent free radicals (EPFRs), in PM from combustion sources suggests a potentially unrecognized risk factor for the development and/or exacerbation of asthma. METHODS: Neonatal rats (7-days of age) were exposed to EPFR-containing combustion generated ultrafine particles (CGUFP), non-EPFR containing CGUFP, or air for 20 minutes per day for one week. Pulmonary function was assessed in exposed rats and age matched controls. Lavage fluid was isolated and assayed for cellularity and cytokines and in vivo indicators of oxidative stress. Pulmonary histopathology and characterization of differential protein expression in lung homogenates was also performed. RESULTS: Neonates exposed to EPFR-containing CGUFP developed significant pulmonary inflammation, and airway hyperreactivity. This correlated with increased levels of oxidative stress in the lungs. Using differential two-dimensional electrophoresis, we identified 16 differentially expressed proteins between control and CGUFP exposed groups. In the rats exposed to EPFR-containing CGUFP; peroxiredoxin-6, cofilin1, and annexin A8 were upregulated. CONCLUSIONS: Exposure of neonates to EPFR-containing CGUFP induced pulmonary oxidative stress and lung dysfunction. This correlated with alterations in the expression of various proteins associated with the response to oxidative stress and the regulation of glucocorticoid receptor translocation in T lymphocytes.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Hiperreactividad Bronquial/inducido químicamente , Radicales Libres/toxicidad , Material Particulado/toxicidad , Animales , Animales Recién Nacidos , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Niño , Citocinas/inmunología , Femenino , Humanos , Lactante , Pulmón/citología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Tamaño de la Partícula , Neumonía/inducido químicamente , Proteoma/análisis , Ratas
6.
J Immunol ; 181(5): 3486-94, 2008 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-18714021

RESUMEN

Influenza infection remains a significant cause of pulmonary morbidity and mortality worldwide, with the highest hospitalization and mortality rates occurring in infants and elder adults. The mechanisms inducing this considerable morbidity and mortality are largely unknown. To address this question, we established a neonatal mouse model of influenza infection to test the hypothesis that the immaturity of the neonatal immune system is responsible for the severe pulmonary disease observed in infants. Seven-day-old mice were infected with influenza A virus (H1N1) and allowed to mature. As adults, these mice showed enhanced airway hyperreactivity, chronic pulmonary inflammation, and diffuse emphysematous-type lesions in the lungs. The adaptive immune responses of the neonates were much weaker than those of adults. This insufficiency appeared to be in both magnitude and functionality and was most apparent in the CD8(+) T cell population. To determine the role of neonatal CD8(+) T cells in disease outcome, adult, naive CD8(+) T cells were adoptively transferred into neonates before infection. Neonatal mice receiving the adult CD8(+) T cells had significantly lower pulmonary viral titers and greatly improved pulmonary function as adults (airway resistance similar to SHAM). Additional adoptive transfer studies using adult CD8(+) T cells from IFN-gamma-deficient mice demonstrated the importance of IFN-gamma from CD8(+) T cells in controlling the infection and in determining disease outcome. Our data indicate that neonates are more vulnerable to severe infections due to immaturity of their immune system and emphasize the importance of vaccination in infants.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Subtipo H1N1 del Virus de la Influenza A , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/terapia , Traslado Adoptivo , Factores de Edad , Animales , Animales Recién Nacidos , Linfocitos T CD8-positivos/trasplante , Modelos Animales de Enfermedad , Humanos , Interferón gamma , Enfermedades Pulmonares/patología , Enfermedades Pulmonares/virología , Ratones , Ratones Noqueados , Neumonía , Enfisema Pulmonar , Hipersensibilidad Respiratoria , Resultado del Tratamiento
7.
Part Fibre Toxicol ; 6: 11, 2009 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-19374750

RESUMEN

BACKGROUND: Combustion generated particulate matter is deposited in the respiratory tract and pose a hazard to the lungs through their potential to cause oxidative stress and inflammation. We have previously shown that combustion of fuels and chlorinated hydrocarbons produce semiquinone-type radicals that are stabilized on particle surfaces (i.e. environmentally persistent free radicals; EPFRs). Because the composition and properties of actual combustion-generated particles are complex, heterogeneous in origin, and vary from day-to-day, we have chosen to use surrogate particle systems. In particular, we have chosen to use the radical of 2-monochlorophenol (MCP230) as the EPFR because we have previously shown that it forms a EPFR on Cu(II)O surfaces and catalyzes formation of PCDD/F. To understand the physicochemical properties responsible for the adverse pulmonary effects of combustion by-products, we have exposed human bronchial epithelial cells (BEAS-2B) to MCP230 or the CuO/silica substrate. Our general hypothesis was that the EPFR-containing particle would have greater toxicity than the substrate species. RESULTS: Exposure of BEAS-2B cells to our combustion generated particle systems significantly increased reactive oxygen species (ROS) generation and decreased cellular antioxidants resulting in cell death. Resveratrol treatment reversed the decline in cellular glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) levels for both types of combustion-generated particle systems. CONCLUSION: The enhanced cytotoxicity upon exposure to MCP230 correlated with its ability to generate more cellular oxidative stress and concurrently reduce the antioxidant defenses of the epithelial cells (i.e. reduced GSH, SOD activity, and GPx). The EPFRs in MCP230 also seem to be of greater biological concern due to their ability to induce lipid peroxidation. These results are consistent with the oxidizing nature of the CuO/silica ultrafine particles and the reducing nature and prolonged environmental and biological lifetimes of the EPFRs in MCP230.

8.
Lab Anim (NY) ; 52(1): 4, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36600010
9.
Toxicol Lett ; 293: 140-148, 2018 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-29535050

RESUMEN

The skin is highly sensitive to the chemical warfare agent in mustard gas, sulfur mustard (SM) that initiates a delayed injury response characterized by erythema, inflammation and severe vesication (blistering). Although SM poses a continuing threat, used as recently as in the Syrian conflict, no mechanism-based antidotes against SM are available. Recent studies demonstrated that Transient Receptor Potential Ankyrin 1 (TRPA1), a chemosensory cation channel in sensory nerves innervating the skin, is activated by SM and 2-chloroethyl ethyl sulfide (CEES), an SM analog, in vitro, suggesting it may promote vesicant injury. Here, we investigated the effects of TRPA1 inhibitors, and an inhibitor of Calcitonin Gene Related Peptide (CGRP), a neurogenic inflammatory peptide released upon TRPA1 activation, in a CEES-induced mouse ear vesicant model (CEES-MEVM). TRPA1 inhibitors (HC-030031 and A-967079) and a CGRP inhibitor (MK-8825) reduced skin edema, pro-inflammatory cytokines (IL-1ß, CXCL1/KC), MMP-9, a protease implicated in skin damage, and improved histopathological outcomes. These findings suggest that TRPA1 and neurogenic inflammation contribute to the deleterious effects of vesicants in vivo, activated either directly by alkylation, or indirectly, by reactive intermediates or pro-inflammatory mediators. TRPA1 and CGRP inhibitors represent new leads that could be considered for validation and further development in other vesicant injury models.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Sustancias para la Guerra Química/toxicidad , Gas Mostaza/análogos & derivados , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/prevención & control , Canal Catiónico TRPA1/antagonistas & inhibidores , Acetanilidas/farmacología , Animales , Biomarcadores/análisis , Vesícula/patología , Citocinas/biosíntesis , Oído Externo/patología , Queratinocitos/efectos de los fármacos , Masculino , Metaloproteinasa 9 de la Matriz/biosíntesis , Ratones , Ratones Endogámicos C57BL , Gas Mostaza/toxicidad , Purinas/farmacología , Piridinas/farmacología , Piel/patología , Enfermedades de la Piel/patología , Compuestos de Espiro/farmacología
10.
PLoS One ; 11(11): e0165200, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27812120

RESUMEN

Oxidation products of the naturally occurring phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphatidylcholine (PAPC), which are known as OxPAPC, accumulate in atherosclerotic lesions and at other sites of inflammation in conditions such as septic inflammation and acute lung injury to exert pro- or anti-inflammatory effects. It is currently unknown whether OxPAPC also contributes to inflammatory pain and peripheral neuronal excitability in these conditions. Here, we observed that OxPAPC dose-dependently and selectively activated human TRPA1 nociceptive ion channels expressed in HEK293 cells in vitro, without any effect on other TRP channels, including TRPV1, TRPV4 and TRPM8. OxPAPC agonist activity was dependent on essential cysteine and lysine residues within the N-terminus of the TRPA1 channel protein. OxPAPC activated calcium influx into a subset of mouse sensory neurons which were also sensitive to the TRPA1 agonist mustard oil. Neuronal OxPAPC responses were largely abolished in neurons isolated from TRPA1-deficient mice. Intraplantar injection of OxPAPC into the mouse hind paw induced acute pain and persistent mechanical hyperalgesia and this effect was attenuated by the TRPA1 inhibitor, HC-030031. More importantly, we found levels of OxPAPC to be significantly increased in inflamed tissue in a mouse model of chronic inflammatory pain, identified by the binding of an OxPAPC-specific antibody. These findings suggest that TRPA1 is a molecular target for OxPAPC and OxPAPC may contribute to chronic inflammatory pain through TRPA1 activation. Targeting against OxPAPC and TRPA1 signaling pathway may be promising in inflammatory pain treatment.


Asunto(s)
Canales de Calcio/metabolismo , Dolor Crónico/inducido químicamente , Dolor Crónico/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Fosfatidilcolinas/farmacología , Canales de Potencial de Receptor Transitorio/metabolismo , Animales , Canales de Calcio/genética , Dolor Crónico/complicaciones , Dolor Crónico/patología , Relación Dosis-Respuesta a Droga , Ganglios Espinales/patología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/genética , Nocicepción/efectos de los fármacos , Fosfatidilcolinas/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Canal Catiónico TRPA1 , Canales de Potencial de Receptor Transitorio/agonistas , Canales de Potencial de Receptor Transitorio/genética
11.
Pain ; 154(10): 2169-2177, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23820004

RESUMEN

Menthol, the cooling natural product of peppermint, is widely used in medicinal preparations for the relief of acute and inflammatory pain in sports injuries, arthritis, and other painful conditions. Menthol induces the sensation of cooling by activating TRPM8, an ion channel in cold-sensitive peripheral sensory neurons. Recent studies identified additional targets of menthol, including the irritant receptor, TRPA1, voltage-gated ion channels and neurotransmitter receptors. It remains unclear which of these targets contribute to menthol-induced analgesia, or to the irritating side effects associated with menthol therapy. Here, we use genetic and pharmacological approaches in mice to probe the role of TRPM8 in analgesia induced by L-menthol, the predominant analgesic menthol isomer in medicinal preparations. L-menthol effectively diminished pain behavior elicited by chemical stimuli (capsaicin, acrolein, acetic acid), noxious heat, and inflammation (complete Freund's adjuvant). Genetic deletion of TRPM8 completely abolished analgesia by L-menthol in all these models, although other analgesics (acetaminophen) remained effective. Loss of L-menthol-induced analgesia was recapitulated in mice treated with a selective TRPM8 inhibitor, AMG2850. Selective activation of TRPM8 with WS-12, a menthol derivative that we characterized as a specific TRPM8 agonist in cultured sensory neurons and in vivo, also induced TRPM8-dependent analgesia of acute and inflammatory pain. L-menthol- and WS-12-induced analgesia was blocked by naloxone, suggesting activation of endogenous opioid-dependent analgesic pathways. Our data show that TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain. In contrast to menthol, selective TRPM8 agonists may produce analgesia more effectively, with diminished side effects.


Asunto(s)
Dolor Agudo/tratamiento farmacológico , Analgesia/métodos , Mentol/uso terapéutico , Dimensión del Dolor/métodos , Canales Catiónicos TRPM/fisiología , Dolor Agudo/fisiopatología , Animales , Células Cultivadas , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Masculino , Mentol/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Dimensión del Dolor/efectos de los fármacos
12.
Int J Clin Exp Med ; 1(2): 130-44, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-19079667

RESUMEN

On August 29, 2005, Hurricane Katrina made landfall along the Gulf Coast as a Category 3 hurricane. The associated storm surge and heavy rainfall resulted in major flooding throughout the New Orleans area. As the flood waters receded, thick sediment was left covering the ground and coating the interior of homes. This sediment was dispersed into the air and inhaled as dust by returning residents and workers. Our objective in this study was to evaluate the potential pulmonary effects associated with the respirable particulate matter (PM) derived from Hurricane Katrina (HK-PM) in mice. Samples of PM were collected from several locations along the Gulf Coast on September 30 and October 2, 2005 and had a mean aerodynamic diameter ranging from 3-5 mum). Chemical analysis and cytotoxicity assays were performed for all HK-PM samples. A few samples with varying levels of cytotoxicity were chosen for an acute inhalation exposure study. Airborne PM10 levels recorded in the New Orleans area post-Katrina were variable, ranging from 70 mug/m3 in Gentilly to 688 mug/m3 in Lakeview (residential areas). Mice exposed to one of these samples developed significant pulmonary inflammation and airways resistance and hyperresponsiveness to methacholine challenge. These studies demonstrate that dispersion of certain Katrina sediment samples through either natural (e.g., wind) or mechanical (e.g., vehicles) processes promotes airflow obstruction in mice.

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