The National Institutes of Health (NIH) has awarded our Center a five-year grant in 2016, which includes a $16 million grant to the University of Colorado Denver located in Aurora, Colorado (with subcontracts to MRIGlobal, Duke University, University of Texas at Tyler, South Dakota State University, University of California, Irvine and University of California, San Diego). This Center of Excellence was developed to focus on toxic inhaled chemicals, with an emphasis on sulfur mustard toxicity in the lung and skin, and, more recently, to include inhalation effects of methyl isocynate (MIC) and methyl mercaptan. The long-term goal of the Center is to develop an effective treatment for mustard gas-induced injury in lung to treat sulfur mustard poisoning, a potent chemical warfare vesicant, and to develop similarly effective rescue agents for MIC and methyl mercaptan inhalation. There is an increasing emphasis on the acute, life-threatening effects of these agents.
The collaborative studies are contained in three basic and translational projects and an Photonics Modeling Imaging Core is based both at University of Colorado Denver, University of California, San Diego and at University of California, Irvine. Projects 1 & 2 are based at University of Colorado Denver, Project 3 at University of California, San Diego, and Photonics Core at Beckman Laser Institute, University of California, Irvine. Administrative and Educational Cores are based at University of Colorado Denver.
Members of the Center are establishing optimal compounds, route and mode of delivery for rescue agents, and research projects are ongoing to determine countermeasures that will provide specific interventions needed to treat mustard gas-induced injury, and for chlorine gas inhalation.
The Center members include the overall director Carl W. White, MD University of Colorado Denver; Livia A. Veress, MD University of Colorado Denver, Gerry Boss, MD University of California San Diego, and Matthew Brenner, MD University of California Irvine.
Develop new therapeutic measures to enhance our medical response capabilities in the event of an emergency, specifically sulfur mustard poisoning resulting in acute and chronic lung injury, as well as for Methyl isocynate (MIC; “Bhopol agent”. An additional interest is acute cardiopulmonary collapse after inhalation of methyl mercaptan. A longterm goal of the Denver program is to attain FDA approval for the most effective countermeasures discovered.
The research is based on animal models of toxic chemical inhalation. The goal fo the work is to develop medical countermeasures to interrupt or prevent acute and/or chronic lung injuries due to toxic inhaled chemicals (TICs). IN Project 1, a new model of acute methyl isocyanate (MIC) inhalation has been developed. The pathogenesis of airways injury after MIC vapor inhalation has been discovered. At least two new promising approaches to improve the acute MIC inhalation illness have been discovered. These include fibrinolytic drugs and TRP channel antagonists. Investigations of the pathogenesis of injury and search for new biomarkers, as well as biomarker metabolite(s) of MIC continue. In Project 2, the Denver-based team headed by Drs. Veress and White have discovered a new model for chronic lung injury after sulfur mustard (SM) inhalation. Two lung disease processes, bronchiolitis obliterans (BO) and pulmonary fibrosis (PF), both of which occur in human survivors of sulfur mustard inhalation, have been found in rats exposed to acutely sublethal SM by inhalation. Studies of antifibrotic drugs and antibiotic therapies are in progress, and work pertaining to the airway epithelial cell response are in progress. Although there are now FDA-approved drugs available for treatment of PF, there are no known successful therapies for BO. IN Project 3, Dr. Gerry Boss and his team at UCSD are actively studying the mitochondrial toxic substance methyl mercaptan after acute inhalation. From simple in vitro chemical studies, to cell based models, to fruit fly models, to acute mouse model, the team has taken creative approaches to study the disease pathogenesis. Dr. Boss’ team has discovered a promising line of therapy using cobalamin analogues to mitigate mitochondrial toxicity. The Photonics and Imaging Core headed by Dr. Matt Brenner and Sari Mohan at UC Irvine contributes novel imaging tools that allow less invasive mapping of airway pathology and continuous lactate sensing in small animals. These provide innovative methods for visualizing airway disease related to each toxic gas, and lactate sensing provides a minimally invasive approach to metabolic studies after toxic inhalation.
Dr. Brian Logue is identifying specific metabolites that can be used to confirm exposure and exposure level. Dr. Steven Idell and his group are working collaboratively with the Denver team to define mechanisms of extravascular coagulation triggered by MIC and SM. Dr. Sven Jordt and his group are contributing their knowledge of TRP channel activation in acute toxic chemical inhalation and the potential of antagonists of TRP channels to reverse airways disease related to MIC, and potentially other TICs.