Even without signs of external injury, chemical exposure can produce severe trauma to internal target organs including the lungs, heart, gastrointestinal tract, eyes, and the central nervous system. Of these injuries, the extent of lung injury often is the most critical to survival. Chemical Induced Acute Lung Injury (CIALI) can be viewed as a molecular cascade mounting over hours and days subsequent to even a transient incident. Unfortunately, CIALI is a likely consequence of terrorist attacks of multiple possible scenarios including intentional detonation of chemical plants, railroad car derailment, or chemical truck hijacking. Chemicals of high concern include chlorine, phosgene, sulfuric acid, ammonia, and acrolein. Predictive strategies will require the monitoring of multiple biochemical indicators forming complex molecular signatures. Our goal is to understand the genetic, global transcriptomal, and molecular events that will provide insights into the mechanisms of CIALI and could redirect or strengthen current emergency clinical approaches to diagnosis and treatment. The objective of this application is to determine the molecular mechanism(s) and therapeutic efficacy of TGFalpha and FGF7 in enhancing survival in this condition. Our central hypothesis is that the interplay between TGFalpha, FGF7, and TGFbeta signaling determines survival and controls the susceptibility to sequelae from CIALI. To explore our hypothesis, we seek to: 1) Identify the genetic determinants and molecular mechanisms controlling CIALI common to exposure to 5 leading hazardous chemicals: chlorine, phosgene, sulfuric acid, ammonia, and acrolein, 2) Evaluate the therapeutic efficacy of TGFalpha and FGF7 induction and signaling during CIALI and determine whether pulmonary fibrosis is a necessary sequela as a consequence of protection, and 3) Identify the molecular mechanisms that are unique to each of the 5 leading hazardous chemicals during the early development of CIALI. At the completion of this project, we expect to: 1) Identify novel genetic differences that determine the susceptibility to CIALI, 2) Identify the events modulated during CIALI that are common to multiple agents 3) Evaluate the effectiveness of therapies by that lead to protection in CIALI, 4) Determine whether pulmonary fibrosis is an untoward consequence of activating TGFalpha/FGF7signaling during CIALI, 5) Develop an initial chemical specific database on the selective signatures of the 5 leading hazardous chemicals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01ES015675-05
Application #
7858079
Study Section
Special Emphasis Panel (ZNS1-SRB-R (22))
Program Officer
Nadadur, Srikanth
Project Start
2006-09-29
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$713,952
Indirect Cost
Name
University of Pittsburgh
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
George, Leema; Mitra, Ankita; Thimraj, Tania A et al. (2017) Transcriptomic analysis comparing mouse strains with extreme total lung capacities identifies novel candidate genes for pulmonary function. Respir Res 18:152
Latoche, Joseph D; Ufelle, Alexander Chukwuma; Fazzi, Fabrizio et al. (2016) Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice. Environ Health Perspect 124:1199-207
Moon, Kuk-Young; Lee, Pureun-Haneul; Kim, Byeong-Gon et al. (2015) Claudin 5 in a murine model of allergic asthma: Its implication and response to steroid treatment. J Allergy Clin Immunol 136:1694-1696.e5
Coon, Tiffany A; McKelvey, Alison C; Weathington, Nate M et al. (2014) Novel PDE4 inhibitors derived from Chinese medicine forsythia. PLoS One 9:e115937
Moon, Kuk-Young; Park, Moo-Kyun; Leikauf, George D et al. (2014) Diesel exhaust particle-induced airway responses are augmented in obese rats. Int J Toxicol 33:21-8
Ganguly, Koustav; Martin, Timothy M; Concel, Vincent J et al. (2014) Secreted phosphoprotein 1 is a determinant of lung function development in mice. Am J Respir Cell Mol Biol 51:637-51
Brant, Kelly A; Leikauf, George D (2014) Dysregulation of FURIN by prostaglandin-endoperoxide synthase 2 in lung epithelial NCI-H292 cells. Mol Carcinog 53:192-200
Fazzi, Fabrizio; Njah, Joel; Di Giuseppe, Michelangelo et al. (2014) TNFR1/phox interaction and TNFR1 mitochondrial translocation Thwart silica-induced pulmonary fibrosis. J Immunol 192:3837-46
Bein, Kiflai; Di Giuseppe, Michelangelo; Mischler, Steven E et al. (2013) LPS-treated macrophage cytokines repress surfactant protein-B in lung epithelial cells. Am J Respir Cell Mol Biol 49:306-15
Leikauf, George D; Concel, Vincent J; Bein, Kiflai et al. (2013) Functional genomic assessment of phosgene-induced acute lung injury in mice. Am J Respir Cell Mol Biol 49:368-83

Showing the most recent 10 out of 37 publications