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.
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