Bromine (Br2) is a halogen used as a water disinfectant, for bleaching fibers, in the manufacture of antiepileptic drugs, dyestuffs, flame retardants, insecticides, drilling fluids, and gasoline additives When inhaled at higher concentrations, as may occur during transportation accidents, transfers among containers or acts of terrorisms, Br2 has caused death from respiratory failure. There are very few published studies evaluating acute and chronic sequelae of Br2 inhalation;treatment remains symptomatic and no effective countermeasures exist. Our exciting and highly novel preliminary data show that mice overexpressing the human form of the heme oxygenase (HO)-1 gene and protein (hHO-1 BAC) exhibit significantly lower mortality when returned to room air post Br2 exposure as compared to their wild-type littermate controls. In contrast, mice deficient in the HO-1 gene (HO-1-/-), display markedly increased mortality following Br2 exposure. We have also identified five compounds that are potent inducers of the human HO-1 gene using high-throughput screening. The goals of this application are: (1) to establish the role of HO-1 in protecting mice from Br2 induced injury and (2) test the efficacy of these compounds, administered in mice systemically, post Br2 exposure, to upregulate HO-1, and decrease mortality and lung injury. SA #1. We will expose hHO-1 BAC, HO-1-/- mice and their wild-type littermates to Br2 (600 ppm for 30 min) in environmental chambers, and return them to room air and measure mortality and lung injury for two weeks. SA #2: (i) We will expose confluent monolayers of human airway Clara-cell like cells (H441) to Br2 and return them to room air;we will then test the efficacy of the five compounds identified by high throughput screening, to increase HO-1 and decrease Br2 induced cellular necrosis and apoptosis. (ii) We will profile these compounds to determine those with the best pharmacokinetic properties related to intramuscular dosing. (iii) We will inject hHO-1 BAC and wild-type mice intramuscularly with the compound that exhibits the best cytoprotective effects in vitro and measure lung mRNA and hHO-1 activity at two, 24 and 72 post injection. (iv) We will expose hHO-1 BAC, HO- 1-/- mice and their wild-type littermates (all in C57BL/6 background) to Br2 (600 ppm for 30 min), return them to room air and inject them intramuscularly starting at 2 h post-exposure with this compound. We will measure mortality in all groups and indices of lung injury and lung hHO1 activity for 14 d as described in SA #1.
Accidental exposure to bromine gas may result in significant morbidity and mortality. Based on preliminary data, we propose that upregulation of lung heme oxygenase will decrease mortality and morbidity when given post exposure.
|Lam, Adam; Vetal, Nilam; Matalon, Sadis et al. (2016) Role of heme in bromine-induced lung injury. Ann N Y Acad Sci 1374:105-10|
|Bali, Vedrana; Lazrak, Ahmed; Guroji, Purushotham et al. (2016) Mechanistic Approaches to Improve Correction of the Most Common Disease-Causing Mutation in Cystic Fibrosis. PLoS One 11:e0155882|
|Ford, David A; Honavar, Jaideep; Albert, Carolyn J et al. (2016) Formation of chlorinated lipids post-chlorine gas exposure. J Lipid Res 57:1529-40|
|Bali, Vedrana; Lazrak, Ahmed; Guroji, Purushotham et al. (2016) A synonymous codon change alters the drug sensitivity of Î”F508 cystic fibrosis transmembrane conductance regulator. FASEB J 30:201-13|
|Aggarwal, Saurabh; Lam, Adam; Bolisetty, Subhashini et al. (2016) Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury. Antioxid Redox Signal 24:99-112|
|Carlisle, Matthew; Lam, Adam; Svendsen, Erik R et al. (2016) Chlorine-induced cardiopulmonary injury. Ann N Y Acad Sci 1374:159-67|
|Surolia, Ranu; Karki, Suman; Kim, Hyunki et al. (2015) Heme oxygenase-1-mediated autophagy protects against pulmonary endothelial cell death and development of emphysema in cadmium-treated mice. Am J Physiol Lung Cell Mol Physiol 309:L280-92|
|Jurkuvenaite, Asta; Benavides, Gloria A; Komarova, Svetlana et al. (2015) Upregulation of autophagy decreases chlorine-induced mitochondrial injury and lung inflammation. Free Radic Biol Med 85:83-94|
|Song, Weifeng; Yu, Zhihong; Doran, Stephen F et al. (2015) Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness. Am J Physiol Lung Cell Mol Physiol 309:L205-10|
|Matalon, Sadis; Bartoszewski, Rafal; Collawn, James F (2015) Role of epithelial sodium channels in the regulation of lung fluid homeostasis. Am J Physiol Lung Cell Mol Physiol 309:L1229-38|
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