Chlorine (C12) is a moderately soluble, highly reactive oxidant gas, used extensively for water purification, manufacturing of Pharmaceuticals and chemicals and as a potent disinfectant. Persons exposed to chlorine gas, may experience mild symptoms for the first 6-24 hours (h). However, following this latency period, severe lung injury, characterized by protein-rich edema and the onset of hypoxemia may develop. Presently, the cellular and biochemical events leading to this injury have not been elucidated. We propose that reactive oxygen-chloride and nitrogen intermediates (RONS), formed by the interaction of C12 and its hydrolysis products with nitric oxide (NO), initiate self-propagating chain reactions, the products of which damage alveolar epithelial cells decreasing their ability to produce and secrete surfactant, actively transport sodium (Na+) ions and maintain a tight, semi-permeable barrier. Thus, systemic administration of reactive species scavengers (such as ascorbate, N-acetyl-cysteine (NAC), and deferoxamine, as well as agents that augment surfactant levels, ion transport and paracellular resistance (such as albuterol (a long acting b-agonist) and a recently described peptide based on the lectin region of TNFa (tip peptide), shortly after exposure to C12 will decrease lung injury, morbidity and mortality. This hypothesis will be tested by exposing either confluent monolayers of rat alveolar type II (ATII) epithelial cells (SPECIFIC AIM # 1) or rats (SPECIFIC AIMS #2) to C12 (50-200 ppm for 30 min) and measure the following indices at 0.5, 6, 12 and 24 h post exposure: physiological and biochemical indices of lung function (including surfactant function and composition), ability of the lungs to transport ions in vivo and in vitro and clear pulmonary edema in vivo, levels of inflammatory cytokines in the rat alveolar space and in the plasma, arterial blood gases and pH, as well as levels of low reactive species scavengers (ascorbate, NAC) at 0.5, 6, 12, 24 and 48 h post exposure. These measurements will be repeated following intravenous injections of NAC, ascorbate and deferoxamine as well as albuterol and the tip peptide, every 6 h post exposure for 48 h.
In SPECIFIC AIM #3 , we will assess the efficacy of intratracheally instilled ascorbate, NAC, deferoxamine, Infasurf (a surfactant replacement mixture), albuterol and the tip peptide, as well as aerosolized albuterol, in prolonging survival of rats with respiratory failure post C12 exposure. The subject matter of this research is both timely and important: more than 25 million tons of chlorine is manufactured annually in the United States and the majority of this gas is transported by rail and can be used as a chemical weapon. ? ? ?
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