This proposal seeks support for the evaluation and development of a therapeutic portfolio (TP) of novel agents that represent the first molecules proven effective in the resuscitation of a pre-clinical model of acute chlorine inhalational injury (CILI). The TP comprises 4 technologies that address key pathophysiological targets and have proven effective in a broad range of acute lung injuries: 1) R-503, a bifunctional poly (ADP-ribose) polymerase (""""""""PARP"""""""") inhibitor- lipoic acid conjugate;2) R-100, a bifunctional organic nitrate and pyrollidine nitroxide;3) R-801, a bifunctional mitochondrial potassium-ATP channel opener and pyrollidine nitroxide;and 4) R-901, a cell-permeable thioredoxin mimetic. In a murine model of CILI (400 ppm X 30 min), single-agent delivery of R-503, R-801, or R-901 initiated 15 min AFTER the end of chlorine inhalation reduced the elevation in neutrophil infiltration by 50-82% (p<0.0001) and histologic injury by 43-72% (p<0.001). R-100 has likewise effectively resuscitated acute lung injury in regional and systemic models of inflammation.
Aim #1 : Establish the optimal combination of TP agents, confirm their mechanism of action, and define the therapeutic time window of opportunity for resuscitation of murine CILI. Lungs will be scored for histologic injury, neutrophil infiltration, lipid peroxidation, reductant concentrations, and the expression of pro- and anti-inflammatory signaling species. These parameters will be correlated with the concentrations of the TP agents in plasma and lung tissue to construct a pharmacodynamic profile that will guide large animal and clinical dosing. The optimal agent will be designated as the TP candidate and advanced to large animal studies.
Aim #2 : Confirm the efficacy of the TP candidate as a rescue therapy in an ovine model of CILI, as assessed by the impact on pulmonary vascular resistance, peak inspiratory pressure, pulmonary shunt, lung lymph flow, and histologic and biochemical parameters of lung tissue.
Aim #3 : Establish the acute safety, stability, and tolerance of the TP candidate in toxicology, ADME/PK, and safety pharmacology IND-enabling studies. Demonstration of potent resuscitation and safety in the pre-clinical setting will provide the foundation for development of a clinical therapeutic for CILI.
A set of novel antidotes has been identified that block damage to the lung after inhaling toxic quantities of chlorine gas. Further testing in mice and sheep will guide the selection of the most effective drug candidate from among this set. Additional studies of this candidate are intended to lay the foundation for its testing and introduction into humans, as the first approved drug for treatment of acute chlorine inhalational injury.