Exposure to toxic inhaled chemicals like sulfur mustard (SM) can cause injuries to the respiratory system, eyes, skin and also frequently leads to death. The pathogenesis of sulfur mustard-induced injury is incompletely understood and a search for effective treatment regimens has been a challenge. SM-induced toxicities activate several pathways that include the coagulation and inflammatory pathways. Extracellular RNA (exRNA) and hypoxic signaling events drive several factors implicated in these pathways. This proposal focuses on understanding the role of extracellular RNA and associated inflammatory pathways in SM-induced injuries. These studies will be carried out using CEES, a surrogate of sulfur mustard as well as sulfur mustard. We hypothesize that CEES/SM exposures release exRNA that causes activation of the coagulation pathway and also inhibition of HIFs that in turn activate proinflammatory pathways. And that blocking of exRNA and stabilization of HIFs can alleviate toxicity and lung injury. The proposed studies are divided into three aims.
Aim 1 will test whether blockage of exRNA using RNase or synthetic cationic polymers can mitigate CEES/SM-induced injury.
The second aim will test whether activation of the hypoxia- inducible transcription factor will decrease inflammation and mitigate CEES-induced injury.
Aim 3 will determine mechanisms by which CEES causes injury.
This aim will also test whether therapeutic inhibition of exRNA from other chemical inhalations like chlorine can reduce injury. Since previous studies from our group and others have indicated a beneficial effect with combination therapies this aim will also test whether combining the two therapies tested in Aims 1 and 2 above can provide a better protection. Results of the proposed research will help identify treatment options for sulfur mustard exposures as well as other potentially toxic chemical inhalations associated with increased exRNA and metabolic poisoning.

Public Health Relevance

The purpose of this U01 is to develop specific medical countermeasures that can be used to rescue victims of civilian disaster, acts of terrorism, and military attack after exposures to toxic inhaled gases. This proposal is aimed at testing certain rescue agents after inhalation of toxic gasses like sulfur mustard.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01ES025069-01A1
Application #
8733958
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (50))
Program Officer
Nadadur, Srikanth
Project Start
2014-09-25
Project End
2019-05-31
Budget Start
2014-09-25
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$513,713
Indirect Cost
$178,817
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045