2006 — 2010 |
Jordt, Sven-Eric |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sensory Neural Mechanisms of Pulmonary Agent and Vesicant Toxicity
[unreadable] DESCRIPTION (provided by applicant): Sensory nerve endings in the skin, airways, eyes and mucous membranes are activated by a wide range of hazardous chemicals. These include pulmonary chemical agents as well as vesicants and noxious industrial chemicals. Activation of sensory nerve endings in the nasal passages and airways induces pain, irritation and apnea. Extended chemical exposure promotes injury by causing the release of inflammatory neuropeptides that contribute to edema formation in the lung and skin, ocular damage, mucus hypersecretion, pulmonary obstruction, and blister formation. In animal models these effects can be strongly reduced by prior neural desensitization or denervation. Thus, pharmacological blockade of neural activation, as well as block of neuropeptide receptors in target tissues, could represent effective measures to prevent and alleviate the deleterious effects of pulmonary agents and vesicants. The molecular targets for pulmonary agents and vesicants on sensory neurons are largely unknown. Recently, a new class of sensory chemoreceptors, the TRP ion channels, was discovered. The founding member, TRPV1, is the receptor for capsaicin, the pungent and inflammatory ingredient in chili peppers that is used as an incapacitating agent. TRPA1, a novel TRP ion channel, is activated by mustard oil (allyl isothiocyanate), a potent irritant and neuroinflammatory agent. We found that TRPA1 is exclusively expressed in sensory fibers that are also sensitive to capsaicin. Mustard oil and other plant-derived activators of TRPA1 show intriguing structural similarities with sulfur mustard. In addition, we found that TRPA1 is strongly activated by hazardous industrial chemicals. These include a,p-unsaturated aldehydes such as acrolein, a pulmonary agent used in the First World War. Our functional and behavioral analysis of mice deficient in TRPA1 showed that TRPA1 is essential for sensory neural responses to mustard oil, acrolein and other chemical hazards. Thus TRPA1, and potentially other TRP channels, may represent effective targets to prevent and treat the toxic effects of pulmonary agents and vesicants. Our specific aims are to investigate the role of TRP channels in the response to pulmonary agents and vesicants in vitro and in vivo and to analyze the efficacy of TRP channel blockers and neuropeptide antagonists in the reduction of warfare agent toxicity. [unreadable] [unreadable] [unreadable]
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1 |
2006 |
Jordt, Sven-Eric |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Trpa1 Channels Sensory Neurons Environmental Irritants
[unreadable] DESCRIPTION (provided by applicant): [unreadable] The long term goal of our research is to reveal the molecular and cellular basis of sensory neural activation by hazardous environmental irritants. Sensory nerve endings in the lung, skin, eyes and mucous membranes are activated by environmental toxicants, including the alpha, beta-unsaturated aldehydes. Aldehydes such as acrolein (2-propenal) are severely irritating volatile compounds present in cigarette smoke, smoke from fires, automobile exhaust, and smog. In humans, acrolein exposure has been implicated in the pathogenesis of acute lung injury, chemical hypersensitivity, chronic pulmonary obstructive disease (COPD), and asthma. Despite its important role in human exposure health effects, the molecular targets of acrolein and other environmental irritants on sensory neurons remain unknown. [unreadable] [unreadable] Here, we propose to identify and characterize the molecular targets for acrolein and other environmental irritants on somatosensory neurons. Our specific aims are derived from our preliminary data that show that acrolein, and a different class of irritants, the isocyanates, activate neurons by stimulating Ca2+ influx through the ion channel TRPA1. TRPA1 recently has been identified through its sensitivity to allyl isothiocyanate (mustard oil), an irritant used to probe pain transduction pathways. We found that TRPA1 is exclusively expressed in sensory fibers that are also sensitive to capsaicin, the plant-derived irritant that activates the capsaicin receptor, TRPV1. These sensory fibers, the C-fibers, are known to mediate irritant effects and inflammatory pain. [unreadable] [unreadable] The objective of our application is to investigate whether TRPA1 is underlying acute and long-term irritant effects of acrolein and other environmental exposures in vivo. Our specific aims are to 1) investigate sensory neural responses to acrolein in TRPA1-deficient mice, 2) to elucidate the mechanism of activation and inflammatory sensitization of TRPA1, 3) study and compare the effects of industrial isocyanates on sensory neural activity, and 4) examine the effects of hazardous environmental toxicants on sensory neural activity and sensory neural receptors. Our experimental approaches will include the generation and analysis of transgenic mice, microscopic imaging of neural function, electrophysiological techniques and genetic and biochemical approaches. [unreadable] [unreadable] [unreadable] [unreadable]
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1 |
2007 — 2012 |
Jordt, Sven-Eric |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Trpa1 Channels in Sensory Neurons as Targets For Environmental Irritants
DESCRIPTION (provided by applicant): The long term goal of our research is to reveal the molecular and cellular basis of sensory neural activation by hazardous environmental irritants. Sensory nerve endings in the lung, skin, eyes and mucous membranes are activated by environmental toxicants, including the alpha, beta-unsaturated aldehydes. Aldehydes such as acrolein (2-propenal) are severely irritating volatile compounds present in cigarette smoke, smoke from fires, automobile exhaust, and smog. In humans, acrolein exposure has been implicated in the pathogenesis of acute lung injury, chemical hypersensitivity, chronic pulmonary obstructive disease (COPD), and asthma. Despite its important role in human exposure health effects, the molecular targets of acrolein and other environmental irritants on sensory neurons remain unknown. Here, we propose to identify and characterize the molecular targets for acrolein and other environmental irritants on somatosensory neurons. Our specific aims are derived from our preliminary data that show that acrolein, and a different class of irritants, the isocyanates, activate neurons by stimulating Ca2+ influx through the ion channel TRPA1. TRPA1 recently has been identified through its sensitivity to allyl isothiocyanate (mustard oil), an irritant used to probe pain transduction pathways. We found that TRPA1 is exclusively expressed in sensory fibers that are also sensitive to capsaicin, the plant-derived irritant that activates the capsaicin receptor, TRPV1. These sensory fibers, the C-fibers, are known to mediate irritant effects and inflammatory pain. The objective of our application is to investigate whether TRPA1 is underlying acute and long-term irritant effects of acrolein and other environmental exposures in vivo. Our specific aims are to 1) investigate sensory neural responses to acrolein in TRPA1-deficient mice, 2) to elucidate the mechanism of activation and inflammatory sensitization of TRPA1, 3) study and compare the effects of industrial isocyanates on sensory neural activity, and 4) examine the effects of hazardous environmental toxicants on sensory neural activity and sensory neural receptors. Our experimental approaches will include the generation and analysis of transgenic mice, microscopic imaging of neural function, electrophysiological techniques and genetic and biochemical approaches.
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1 |
2011 |
Jordt, Sven-Eric Morris, John B |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Counterirritation by Menthol: Molecular Targets and Role in Airway Disease
DESCRIPTION (provided by applicant): Menthol, the cooling terpene derived from peppermint, is widely used for the treatment of cough, respiratory irritation and pain. As a cigarette additive menthol is especially popular with beginning smokers and in minority populations disproportionally affected by COPD, lung cancer and hypertension. It is currently unclear whether menthol contributes to these disease conditions through inhibition of the respiratory irritation response mediated by chemosensory neurons. Recently, two sensory menthol receptors were identified: TRPM8, the cold/menthol receptor, and TRPA1, a reactive irritant receptor. TRPA1 is activated by acrolein and other irritants contained in tobacco smoke. Our preliminary studies show that inhalation of menthol potently inhibits the respiratory irritation response to acrolein vapor in mice. Mice inhaling smoke from mentholated cigarettes showed higher serum levels of the nicotine metabolite, cotinine, than mice exposed to non-mentholated smoke, suggesting increased exposure to nicotine. In electrophysiological and fluorescent imaging experiments we show that menthol inhibits acrolein-activated TRPA1 channels. We hypothesize that: 1.) Menthol acts as a counterirritant, blocking sensory neuronal responses to inhaled noxious chemicals through interaction with the menthol receptors TRPA1 or TRPM8, and 2) As a tobacco additive, menthol facilitates smoke inhalation through inhibition of neuronal irritant receptor signalling, thereby accelerating nicotine dependence and lung disease. The studies proposed in this application will use physiological, biochemical, molecular and behavioral approaches to: Aim 1.) Define the roles of TRPA1 and TRPM8 in menthol-induced inhibition of acute respiratory irritation. Aim 2.) Examine the pharmacological effects of menthol and menthol-related compounds on irritant-induced activation of sensory neurons. Aim 3.) Determine the effects of menthol inhalation on smoking-induced lung inflammation and emphysema. Our proposed research will provide new insights into neuronal mechanisms of airway irritation and remodeling, and define a scientific basis for regulatory efforts targeting menthol as a tobacco additive. PUBLIC HEALTH RELEVANCE: The natural product menthol is contained in medications against cold symptoms and pain, in food and in cigarettes. This application aims to reveal how menthol reduces irritation, and if menthol causes more severe smoking-related disease. Our work may aid the government in determining whether to regulate menthol as a cigarette additive, and may reveal new treatments for cough and pain.
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1 |
2012 — 2013 |
Jordt, Sven-Eric |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Accelerating Inflammation Resolution to Counteract Chemical Injury
DESCRIPTION (provided by applicant): Exposures to chemical threat agents oftentimes induce strong inflammatory tissue responses that contribute to morbidity and prevent tissue repair and recovery. Pulmonary exposures to chlorine trigger a potent inflammatory response resulting in vascular leakage, cardiopulmonary depression, neutrophil infiltration and a pulmonary and systemic hypercytokinemia comparable to the cytokine storm observed in sepsis. Similar inflammatory responses are observed after inhalation exposures to phosgene and acidic (HCl) or alkaline gases (ammonia) and reactive industrial chemicals such as acrolein, and to riot control agents (CS, CN or CR), and following cutaneous exposures to vesicants. Classical anti-inflammatory treatments against chemical injury have focused on interference with target pathways involved in the initiation and maintenance of inflammation. These strategies have only been partially successful, due to the large variety of pathways and pathologies involved. The inflammatory response is divided into three temporal phases, initiation, amplification and maintenance, and resolution. A new area of inflammation research has focused on the process of inflammation resolution, an active mechanism involving the activation of signaling pathways during inflammation initiation, and the later generation of omega 3 fatty-acid derived inflammation-resolving mediators that activate resolution mechanisms. In our preliminary studies we observe that post exposure treatment with Resolvin D1, an inflammation-resolving agent, strongly inhibited skin edema formation and inflammation in mice exposed to the vesicant, CEES, and the electrophilic riot control agent, CS. Our proposed studies are designed to 1: Examine the effects of inflammation-resolving agents in mouse models of cutaneous exposures to vesicants and electrophilic chemical threats and, 2: Study the effects of inflammation-resolving agents on pulmonary injury progression in mice exposed to chlorine and HCl.
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1 |
2012 — 2014 |
Jordt, Sven-Eric Morris, John B |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Counter-Irritation by Menthol: Molecular Targets and Role in Airway Disease
Project Summary Menthol, the cooling terpene derived from peppermint, is widely used for the treatment of cough, respiratory irritation and pain. As a cigarette additive menthol is especially popular with beginning smokers and in minority populations disproportionally affected by COPD, lung cancer and hypertension. It is currently unclear whether menthol contributes to these disease conditions through inhibition of the respiratory irritation response mediated by chemosensory neurons. Recently, two sensory menthol receptors were identified: TRPM8, the cold/menthol receptor, and TRPA1, a reactive irritant receptor. TRPA1 is activated by acrolein and other irritants contained in tobacco smoke. Our preliminary studies show that inhalation of menthol potently inhibits the respiratory irritation response to acrolein vapor in mice. Mice inhaling smoke from mentholated cigarettes showed higher serum levels of the nicotine metabolite, cotinine, than mice exposed to non-mentholated smoke, suggesting increased exposure to nicotine. In electrophysiological and fluorescent imaging experiments we show that menthol inhibits acrolein-activated TRPA1 channels. We hypothesize that: 1.) Menthol acts as a counterirritant, blocking sensory neuronal responses to inhaled noxious chemicals through interaction with the menthol receptors TRPA1 or TRPM8, and 2) As a tobacco additive, menthol facilitates smoke inhalation through inhibition of neuronal irritant receptor signalling, thereby accelerating nicotine dependence and lung disease. The studies proposed in this application will use physiological, biochemical, molecular and behavioral approaches to: Aim 1.) Define the roles of TRPA1 and TRPM8 in menthol-induced inhibition of acute respiratory irritation. Aim 2.) Examine the pharmacological effects of menthol and menthol-related compounds on irritant-induced activation of sensory neurons. Aim 3.) Determine the effects of menthol inhalation on smoking-induced lung inflammation and emhysema. Our proposed research will provide new insights into neuronal mechanisms of airway irritation and remodeling, and define a scientific basis for regulatory efforts targeting menthol as a tobacco additive.
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