2019 — 2021 |
Achanta, Satyanarayana Jordt, Sven-Eric [⬀] 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. |
Advanced Trpa1 Inhibitor For the Treatment of Chlorine Inhalation Injury
Summary Chlorine gas has been used as a terrorist weapon, in warfare and has injured many Americans in transportation or industrial accidents. Despite its devastating effects, no mechanism-based treatment has been developed. In this application, we hypothesize that targeting the TRPA1 ion channel post-exposure will ameliorate the acute pulmonary, cardiovascular and neurological effects of chlorine, leading to decreased morbidity and improved recovery. TRPA1 is a chemical irritant receptor eliciting pain, edema, vasodilation, cardiac arrhythmia, inflammation and leukocyte infiltration. Our preliminary studies in mice show that TRPA1 inhibitors, when administered post-chlorine exposure, prevent the chlorine-induced decline of blood oxygenation, improve pulmonary function and mitigate inflammation. Here, we propose to test the efficacy of a 3rd generation TRPA1 inhibitor, found to block mouse, human and porcine TRPA1, in mouse and pig models of chlorine inhalation injury, with the goal to develop this compound as a future human countermeasure. The following aims are proposed: Aim 1: Screen potential therapeutic effects of a 3rd generation TRPA1 inhibitor in mouse models of Cl2 gas inhalation injury. Aim 2: Determine the pharmacokinetic and toxicological properties of TRPA1 inhibitor in pigs. Aim 3: Test the TRPA1 inhibitor in a pig model of chlorine gas inhalation injury
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2020 — 2021 |
Achanta, Satyanarayana Jordt, Sven-Eric (co-PI) [⬀] |
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.) |
Specialized Pro-Resolving Mediators as Potential Medical Countermeasures in a Pig Model of Chlorine Gas-Induced Acute Lung Injury
Chlorine is a highly utilized chemical in the U.S. with more than 10 million metric tons produced annually for purposes including water treatment, paper bleaching, and chemical manufacturing. Unfortunately, however, chlorine is also a toxic inhalant. Exposure to chlorine gas can cause immediate and sustained injury to the respiratory tract with the severity of injury depends on both concentration and duration of exposure. Whereas exposure to chlorine gas is typically accidental, it has been used as a chemical weapon since World War I. Despite its known chemical threat potencies since World War I, there is no specific antidote for chlorine gas-induced injuries. Recent studies in our laboratory revealed that post-exposure treatment with specialized pro-resolving mediators (SPMs), such as Resolvin D1 and Protectin D1 strongly improved lung injury outcomes in mice exposed to chlorine and hydrochloric acid (HCl). These SPMs are endogenous lipid derivatives produced during inflammation cascade that subsequently accelerates the resolution phase of inflammation. In the proposed grant application, we want to test these novel potential therapeutic agents in our well-established pig model of chlorine gas-induced acute lung injury following the FDA's animal rule.
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2021 |
Achanta, Satyanarayana |
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.) |
Inhibition of Soluble Epoxide Hydrolase Protects Against Phosgene-Induced Lung Injuries
Summary Phosgene gas has been used as a terrorist weapon, in warfare and has injured many Americans in transportation or industrial accidents. Despite its devastating effects, no mechanism-based treatment has been developed. Soluble epoxide hydrolase (sEH) enzyme mediates the degradation of beneficial epoxyeicosatrienoic acids (EETs) and other fatty acid epoxides such as ?-3 docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) that mediate anti-inflammatory pathways and stimulate pro-resolving mechanisms. sEH enzyme levels and its downstream products have significantly increased in pulmonary disease models. Phosgene gas causes lipid peroxidation and membrane disruption that leads to alveolar-capillary barrier dysfunction. Soluble epoxide hydrolase inhibitors (sEHI) mitigated lipopolysaccharide (LPS), hyperoxia, and angiotensin II-induced acute lung injury (ALI). Further, sEHI also ameliorated chronic obstructive pulmonary disease (COPD), asthma, bleomycin-induced pulmonary fibrosis, and smoke-induced chronic lung injuries. In addition to pulmonary indications, sEHIs have shown beneficial therapeutic benefits in inflammatory diseases, destructive bone diseases, sepsis, cardiovascular diseases, neurodegenerative diseases, and pain. Some of the sEHI have been tested in clinical trials with encouraging outcomes and no potential side effects. While the therapeutic effects of sEHIs hold great promise as a broad-spectrum treatment candidate, these inhibitors have not yet been tested in pulmonary chemical injuries. In this application, we hypothesize that inhibiting soluble epoxide hydrolase ameliorates phosgene gas-induced lung injury, leading to decreased morbidity and improved recovery. Here, we propose to test the efficacy of three highly potent and selective sEHIs in mouse models of phosgene inhalation injury, with the goal to identify a lead therapeutic drug candidate as a future human medical countermeasure. The following aims are proposed: Aim 1: Assess the therapeutic effects of sEH inhibitors in a mouse model of phosgene gas-induced acute lung injury; Aim 2: Determine the pharmacokinetic profile of the most potent sEH inhibitor in naïve and phosgene gas-exposed mice; Aim 3: Assess the therapeutic efficacy of most potent sEH inhibitor in reducing mortality in a mouse model of phosgene gas-induced lung injury.
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