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1.  Ascorbate and Deferoxamine Administration after Chlorine Exposure Decrease Mortality and Lung Injury in Mice 
Chlorine (Cl2) gas exposure poses an environmental and occupational hazard that frequently results in acute lung injury. There is no effective treatment. We assessed the efficacy of antioxidants, administered after exposure, in decreasing mortality and lung injury in C57BL/6 mice exposed to 600 ppm of Cl2 for 45 minutes and returned to room air. Ascorbate and deferoxamine were administered intramuscularly every 12 hours and by nose-only inhalation every 24 hours for 3 days starting after 1 hour after exposure. Control mice were exposed to Cl2 and treated with vehicle (saline or water). Mortality was reduced fourfold in the treatment group compared with the control group (22 versus 78%; P = 0.007). Surviving animals in the treatment group had significantly lower protein concentrations, cell counts, and epithelial cells in their bronchoalveolar lavage (BAL). Lung tissue ascorbate correlated inversely with BAL protein as well as with the number of neutrophils and epithelial cells. In addition, lipid peroxidation was reduced threefold in the BAL of mice treated with ascorbate and deferoxamine when compared with the control group. Administration of ascorbate and deferoxamine reduces mortality and decreases lung injury through reduction of alveolar–capillary permeability, inflammation, and epithelial sloughing and lipid peroxidation.
doi:10.1165/rcmb.2010-0432OC
PMCID: PMC3175564  PMID: 21131440
acute lung injury; oxidative stress; survival; aerosols; antioxidants
2.  Postexposure Administration of a β2-Agonist Decreases Chlorine-Induced Airway Hyperreactivity in Mice 
Exposure to chlorine (Cl2) damages airway and alveolar epithelia, resulting in acute lung injury and reactive airway dysfunction syndrome. We evaluated the efficacy and mechanisms by which arformoterol, a long-term β2-agonist, administered after exposure, mitigated the extent of this injury. Exposure of C57BL/6 mice to 400 ppm Cl2 for 30 minutes increased respiratory system resistance and airway responsiveness to aerosolized methacholine (assessed by FlexiVent) up to 6 days after exposure, and decreased Na+-dependent alveolar fluid clearance (AFC). Inducible Nitric Oxide Synthase (iNOS) knockout mice developed similar degrees of airway hyperreactivity as wild-type controls after Cl2 exposure, indicating that reactive intermediates from iNOS do not contribute to Cl2-induced airway dysfunction in our model. Intranasal administration of arformoterol mitigated the Cl2 effects on airway reactivity and AFC, presumably by increasing lung cyclic AMP level. Arformoterol did not modify the inflammatory responses, as evidenced by the number of inflammatory cells and concentrations of IL-6 and TNF-α in the bronchoalveolar lavage. NF-κB activity (assessed by p65 Western blots and electrophoretic mobility shift assay) remained at control levels up to 24 hours after Cl2 exposure. Our results provide mechanistic insight into the effectiveness of long-term β2-agonists in reversing Cl2-induced reactive airway dysfunction syndrome and injury to distal lung epithelial cells.
doi:10.1165/rcmb.2010-0226OC
PMCID: PMC3145072  PMID: 20855648
alveolar fluid clearance; cAMP; iNOS; NF-κB; lung injury
3.  Mechanisms and Modification of Chlorine-induced Lung Injury in Animals 
Chlorine (Cl2) is a reactive oxidant gas used extensively in industrial processes. Exposure of both humans and animals to high concentrations of Cl2 results in acute lung injury, which may resolve spontaneously or progress to acute respiratory failure. Injury to airway and alveolar epithelium may result from chemical reactions of Cl2, from HOCl (the hydrolysis product of Cl2), and/or from the various reaction products, such as chloramines, that are formed from the reactions of these chlorinating species with biological molecules. Subsequent reactions may initiate self-propagating reactions and induce the production of inflammatory mediators compounding injury to pulmonary surfactant, ion channels, and components of lung epithelial and airway cells. Low-molecular-weight antioxidants, such as ascorbate, glutathione, and urate, present in the lung epithelial lining fluid and tissue, remove Cl2 and HOCl and thus decrease injury to critical target biological targets. However, levels of lung antioxidants of animals exposed to Cl2 in concentrations likely to be encountered in the vicinity of industrial accidents decrease rapidly and irreversibly. Our measurements show that prophylactic administration of a mixture containing ascorbate and desferal N-acetyl-cysteine, a precursor of reduced glutathione, prevents Cl2-induced injury to the alveolar epithelium of rats exposed to Cl2. The clinical challenge is to deliver sufficient quantities of antioxidants noninvasively, after Cl2 exposure, to decrease morbidity and mortality.
doi:10.1513/pats.201001-009SM
PMCID: PMC3136964  PMID: 20601632
ascorbate; N-acetyl-cysteine; chlorine; alveolar epithelium; hypochlorous acid

Results 1-3 (3)