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Principal Investigator: ALISON K BAUER
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2023
Award: $462,501
Funding agency: National Institute of Environmental Health Sciences
Project Abstract
The Department of Homeland Security considers numerous chemical threat agents a concern for human health,
specifically those that are acute pulmonary toxicants. In acute lung injury, inflammation is critical thus we propose
that inflammation is a common mechanism of lung injury caused by chemical threat agents due to mast cell
activation through non-IgE mechanisms. We and others have shown mast cell activation to be critical in response
to a wide range of xenobiotics including nitrogen mustard, ozone, diesel exhaust, insecticides/herbicides,
cigarette smoke, heavy metals and nanoparticles as examples. Mast cells are a logical cell type to study in
pulmonary injury from chemical threat agents due to 1) their location at interfaces with the external environment
(e.g., lung); 2) their roles as sensors for initiating both innate and adaptive immune responses; and 3) their
immediate response to danger signals through degranulation and release of preformed mediators. We have
demonstrated that mast cell activation is a major contributor to the pulmonary toxicity and inflammation observed
following nitrogen mustard (NM) exposure, a surrogate of sulfur mustard. Currently there are few shared
mechanisms which have been identified between these chemical threat agents, thus identification of common
pathways would be beneficial for future therapeutic targets and biomarkers of exposure. We propose to examine
common mechanisms using three specific classes of chemicals (alkylating agents (NM), pesticides (chloropicrin),
and industrial chemicals (formaldehyde)). Our overall hypothesis is that activation of mast cells by nitrogen
mustard, formaldehyde, and chloropicrin is a common initiating step in recruitment and propagation of
immune responses in the lung. In aims 1 and 2 we will use mast cell deficient mice to investigate pulmonary
inflammation and injury and in aim 3 a human mast cell line to further examine mechanisms by which these
agents lead to mast cell activation. In aim 1, we will determine the in vivo contribution of mast cells in pulmonary
injury, toxicity, and altered function resulting from chemical threat exposures using WT and mast cell deficient
mice. In aim 2 we will examine bioactive lipid profiles and their contribution to pulmonary injury and toxicity from
chemical threat exposures from aim 1 plasma and bronchoalveolar lavage samples based on published data
with NM that shows increased pro-inflammatory bioactive lipid release upon exposure. Lastly, in aim 3 we will
elucidate the role non-IgE mast cell activation through the Mas-Related G-Protein Coupled Receptor
(MRGPRX2), in mast cells exposed chemical threat exposures using ROSA cells deficient in MRPGRX2 to
identify a novel target. Collectively, our goal is to establish activation of mast cells via MRPGRX2 as a common
mechanism across several chemical classes which are linked with pulmonary toxicity. Secondly, we will identify
novel therapeutic targets for prevention and/or treatment of the effects of these potential chemical warfare agents
through targeting of mast cells and/or the MRGPRX2 receptor.
Terms: <Acute><Acute Lung Injury><Acute Pulmonary Injury><Alkylating Agents><Alkylators><Biological Markers><Bis(beta-chloroethyl) Sulfide><Blood Plasma><Body Tissues><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchoalveolar Lavage Fluid><Bronchopulmonary Lavage><Cell Body><Cell Communication and Signaling><Cell Degranulation><Cell Line><Cell Signaling><Cell model><CellLine><Cells><Cellular model><Chemical Exposure><Chemical Warfare Agents><Chemicals><Chemotactic Cytokines><Chloramin><Chlorethazine><Chlormethine><Data><Di-2-chloroethyl Sulfide><Dichlorodiethyl Sulfide><Diesel Exhaust><Eicosanoids><Environment><Exposure to><Fatty Acids><Formaldehyde><Formic Aldehyde><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Goals><HN-2><HN2><Health><Heavy Metals><Herbicides><Histamine Liberation><Histamine Release><Homologous Chemotactic Cytokines><Human><Immune><Immune Surveillance><Immune response><Immune system><Immunes><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunological response><Immunosurveillance><In Vitro><Individual><Industrialization><Inflammation><Inflammatory><Injury><Innate Immune Response><Insecticides><Intercrines><Intervention><Intervention Strategies><Intracellular Communication and Signaling><LC/MS><Lead><Link><Lipids><Location><Lung><Lung Inflammation><Lung Lavage><Lung Respiratory System><Lung damage><Marrow Mast Cell><Mechlorethamine><Mediating><Mediator><Methods><Methyl Aldehyde><Methylchlorethamine><Mice><Mice Mammals><Modern Man><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Mustard Gas><Mustine><Nitrogen Mustard><O3><Oxomethane><Ozone><Pathway interactions><Pb element><Pesticides><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Plasma><Plasma Serum><Play><Pneumonitis><Prevention><Production><Prophylactic treatment><Prophylaxis><Publishing><Pulmonary Inflammation><Pulmonary Pathology><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Reticuloendothelial System, Serum, Plasma><Riots><Risk><Role><SIS cytokines><Safety><Sampling><Security><Signal Transduction><Signal Transduction Systems><Signaling><Strains Cell Lines><Sulfur Mustard><Surface><Terrorism><Testing><Therapeutic><Tissue Basophils><Tissues><Toxic effect><Toxicities><Wild Type Mouse><Xenobiotics><Yellow Cross Liquid><Yperite><adaptive immune response><bio-markers><biologic marker><biological signal transduction><biomarker><bronchopulmonary lavage therapy><cell type><chemical threat><chemical warfare substances><chemoattractant cytokine><chemokine><chloromethine><cigarette smoke><cultured cell line><cytokine><heavy metal Pb><heavy metal lead><host response><immune system response><immunoresponse><in vivo><injuries><interventional strategy><lipid mediator><liquid chromatography mass spectrometry><lung injury><lung pathology><mast cell><mastocyte><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathway><pharmaceutical><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><receptor><recruit><response><sensor><social role><targeted agent><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><terrorist attack><therapeutic biomarker><therapeutic marker><therapeutic target><toxicant><transcriptome sequencing><transcriptomic sequencing><treatment effect><wildtype mouse>