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.

Public Health Relevance

Chemical warfare agents and industrial chemicals oftentimes cause severe inflammation that aggravates the injuries and prevents healing. Our proposed research will investigate the therapeutic effects of a group of newly discovered natural drugs that terminate inflammation before it causes tissue damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES022875-02
Application #
8547809
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (55))
Program Officer
Nadadur, Srikanth
Project Start
2012-09-19
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$395,881
Indirect Cost
$127,281
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520