Acute high-level exposures to chemicals that damage the respiratory tract can cause life-threatening lung injury. Chlorine gas is a highly toxic respiratory irritant that when inhaled causes cellular injury, alveolar- capillary barrier disruption, inflammation, and pulmonary edema. We are investigating mechanisms by which G proteins, which are ubiquitous intracellular signaling molecules, regulate lung injury, inflammation, and repair. During the course of the proposed research we will investigate how G protein-mediated signaling pathways regulate injury and inflammation that are induced when lungs, or lung cells, are exposed to chlorine gas. We will then apply the information gained from these studies to develop novel treatment strategies based on modulation of G protein function to ameliorate acute lung injury. G protein coupled receptors (GPCRs), which control cellular homeostasis and responses to environmental stimuli, are activated by a variety of neuropeptides, inflammatory mediators, and hormones that are released following tissue injury. GPCRs activate intracellular signaling pathways by stimulating G proteins that have been classified into four families: Gq, Gs, Gj, and Gi2. We have observed that activation of Gq in lung epithelial cells stimulates proinflammatory gene expression, whereas activation of Gs promotes increased survival following injury. In the proposed experiments, we will use manipulation of Gq and Gs signaling pathways as potential therapeutic measures to treat acute lung injury induced by inhalation of chlorine gas.
In Specific Aim 1 we will examine mechanisms by which Gq signaling promotes activation of the proinflammatory transcription factor NF-KB and Gs inhibits chlorine toxicity in cultured epithelial and endothelial cells.
In Specific Aim 2, we will determine, using an inducible, cell-specific knockout mouse model, whether Gq signaling in lung epithelial cells is a therapeutic target for ameliorating acute lung injury.
In Specific Aim 3, we will develop treatment strategies, including cell-soluble Gq inhibitory peptides and Gq siRNA, for chlorine-induced lung injury based on inhibition of Gq function.
In Specific Aim 4, we will optimize the in vivo delivery of therapeutic agents for chlorine-induced lung injury based on inhibition of Gq function and stimulation signaling pathways downstream of Gs. This application is submitted in response to RFA-NS-06-004, """"""""Countermeasures Against Chemical Threats."""""""" The proposed experiments are designed to understand how inhalation of a toxic chemical injures the lung and, based on this information, to develop novel ways to treat or prevent acute lung injury. This type of research is sought through the RFA because of concerns that U. S. civilians could be adversely affected by highly toxic chemicals released intentionally in terrorist attacks or unintentionally in industrial accidents or natural disasters.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01ES015673-06
Application #
7851095
Study Section
Special Emphasis Panel (ZNS1-SRB-R (22))
Program Officer
Nadadur, Srikanth
Project Start
2006-09-29
Project End
2011-08-21
Budget Start
2010-06-01
Budget End
2011-08-21
Support Year
6
Fiscal Year
2010
Total Cost
$403,141
Indirect Cost
Name
University of Louisville
Department
Type
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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Summerhill, Eleanor M; Hoyle, Gary W; Jordt, Sven-Eric et al. (2017) An Official American Thoracic Society Workshop Report: Chemical Inhalational Disasters. Biology of Lung Injury, Development of Novel Therapeutics, and Medical Preparedness. Ann Am Thorac Soc 14:1060-1072
Hoyle, Gary W; Chen, Jing; Schlueter, Connie F et al. (2016) Development and assessment of countermeasure formulations for treatment of lung injury induced by chlorine inhalation. Toxicol Appl Pharmacol 298:9-18
Hoyle, Gary W; Svendsen, Erik R (2016) Persistent effects of chlorine inhalation on respiratory health. Ann N Y Acad Sci 1378:33-40
Chen, Jing; Mo, Yiqun; Schlueter, Connie F et al. (2013) Inhibition of chlorine-induced pulmonary inflammation and edema by mometasone and budesonide. Toxicol Appl Pharmacol 272:408-13
Chang, Weiyuan; Chen, Jing; Schlueter, Connie F et al. (2012) Inhibition of chlorine-induced lung injury by the type 4 phosphodiesterase inhibitor rolipram. Toxicol Appl Pharmacol 263:251-8
Hoyle, Gary W; Chang, Weiyuan; Chen, Jing et al. (2010) Deviations from Haber's Law for multiple measures of acute lung injury in chlorine-exposed mice. Toxicol Sci 118:696-703
Cheng, Yung Sung; Bowen, Larry; Rando, Roy J et al. (2010) Exposing animals to oxidant gases: nose only vs. whole body. Proc Am Thorac Soc 7:264-8
Hoyle, Gary W (2010) Mitigation of chlorine lung injury by increasing cyclic AMP levels. Proc Am Thorac Soc 7:284-9
Hoyle, Gary W; Hoyle, Christine I; Chen, Jing et al. (2010) Identification of triptolide, a natural diterpenoid compound, as an inhibitor of lung inflammation. Am J Physiol Lung Cell Mol Physiol 298:L830-6

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