Mitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite

Yadav, Amit K.; Doran, Stephen; Samal, Andrey A.; Sharma, Ruchita; Vedagiri, Kokilavani; Postlethwait, Edward M.; Squadrito, G; Fanucchi, Michelle V.; Roberts, nd L. Jackson; Patel, Rakesh P.; Matalon, Sadis

doi:10.1152/ajplung.00278.2010

Cited by 48 publications

(62 citation statements)

References 37 publications

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“…Taken in aggregate, we believe we have provided convincing evidence for the existence of reactive intermediates in ATII cells after exposure to Cl 2 . We previously showed the presence of F2a-isoprostanes, a group of prostaglandin F2-like compounds derived from the nonenzymatic oxidation of arachidonic acid by HOCl or chloramines, in the lung tissue of rats exposed to 400 ppm Cl 2 for 30 minutes and returned to room air for 6 hours (48).…”

Section: Discussionmentioning

confidence: 99%

“…These findings offer significant insights into the mechanisms of lung injury and fluid accumulation after exposure to Cl 2 , and form the rational basis for the development of new strategies for mitigations of such injury. Indeed, we recently reported that the postexposure administration of low molecular weight oxidant scavengers (ascorbate and desferal) in mice exposed to lethal concentrations of Cl 2 increased their survival and decreased concentrations of lung MDA adducts (48).…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Alveolar Epithelial Na⁺ Channels by ERK1/2 in Chlorine-Breathing Mice

Lazrak¹,

Chen²,

Jurkuvenaite³

et al. 2012

Am J Respir Cell Mol Biol

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The mechanisms by which the exposure of mice to Cl 2 decreases vectorial Na 1 transport and fluid clearance across their distal lung spaces have not been elucidated. We examined the biophysical, biochemical, and physiological changes of rodent lung epithelial Na 1 channels (ENaCs) after exposure to Cl 2 , and identified the mechanisms involved. We measured amiloride-sensitive short-circuit currents (I amil ) across isolated alveolar Type II (ATII) cell monolayers and ENaC single-channel properties by patching ATII and ATI cells in situ. a-ENaC, g-ENaC, total and phosphorylated extracellular signalrelated kinase (ERK)1/2, and advanced products of lipid peroxidation in ATII cells were measured by Western blot analysis. Concentrations of reactive intermediates were assessed by electron spin resonance (ESR). Amiloride-sensitive Na 1 channels with conductances of 4.5 and 18 pS were evident in ATI and ATII cells in situ of air-breathing mice. At 1 hour and 24 hours after exposure to Cl 2 , the open probabilities of these two channels decreased. This effect was prevented by incubating lung slices with inhibitors of ERK1/2 or of proteasomes and lysosomes. The exposure of ATII cell monolayers to Cl 2 increased concentrations of reactive intermediates, leading to ERK1/2 phosphorylation and decreased I amil and a-ENaC concentrations at 1 hour and 24 hours after exposure. The administration of antioxidants to ATII cells before and after exposure to Cl 2 decreased concentrations of reactive intermediates and ERK1/2 activation, which mitigated the decrease in I amil and ENaC concentrations. The reactive intermediates formed during and after exposure to Cl 2 activated ERK1/2 in ATII cells in vitro and in vivo, leading to decreased ENaC concentrations and activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of Alveolar Epithelial Na⁺ Channels by ERK1/2 in Chlorine-Breathing Mice

Lazrak¹,

Chen²,

Jurkuvenaite³

et al. 2012

Am J Respir Cell Mol Biol

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“…Mice were exposed to Cl2 gas (400 ppm) in a cylindrical glass chamber for 30 min, as previously described (34,52,67,71), and returned to room air. Continuous measurements of Cl2 concentrations during the exposure were monitored with an Interscan (model RM34-1000 m) Cl 2 detector, connected to a data logger for data storage.…”

Section: Methodsmentioning

confidence: 99%

“…For lung injury analysis, 72 h post-A. fumigatus challenge, a bronchoalveolar lavage (BAL) was performed as previously described (34,52,67,71). The BAL fluid was spun at 150 g for 10 min at 4°C to pellet cells and cellular debris.…”

Section: Methodsmentioning

confidence: 99%

Chlorine gas exposure increases susceptibility to invasive lung fungal infection

Gessner¹,

Doran

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chlorine (Cl2) is a highly irritating and reactive gas with potential occupational and environmental hazards. Acute exposure to Cl2 induces severe epithelial damage, airway hyperreactivity, impaired alveolar fluid clearance, and pulmonary edema in the presence of heightened inflammation and significant neutrophil accumulation in the lungs. Herein, we investigated whether Cl2 exposure affected the lung antimicrobial immune response leading to increased susceptibility to opportunistic infections. Mice exposed to Cl2 and challenged intratracheally 24 h thereafter with the opportunistic mold Aspergillus fumigatus demonstrated an >500-fold increase in A. fumigatus lung burden 72 h postchallenge compared with A. fumigatus mice exposed to room air. Cl2-exposed A. fumigatus challenged mice also demonstrated significantly higher lung resistance following methacholine challenge and increased levels of plasma proteins (albumin and IgG) in the bronchoalveolar lavage fluid. Despite enhanced recruitment of inflammatory cells to the lungs of Cl2-exposed A. fumigatus challenged mice, these cells (>60% of which were neutrophils) demonstrated a profound impairment in generating superoxide. Significantly higher A. fumigatus burden in the lungs of Cl2 exposed mice correlated with enhanced production of IL-6, TNF-α, CXCL1, CCL2, and CCL3. Surprisingly, however, Cl2-exposed A. fumigatus challenged mice had a specific impairment in the production of IL-17A and IL-22 in the lungs compared with mice exposed to room air and challenged with A. fumigatus. In summary, our results indicate that Cl2 exposure markedly impairs the antimicrobial activity and inflammatory reactivity of myeloid cells in the lung leading to increased susceptibility to opportunistic pathogens.

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“…Peripheral oxygen saturations and respiratory rates were measured before and after chlorine gas (Cl 2 ) exposure and aerosol administrations (26). Saline or freshly prepared ascorbic acid (80 mg/kg) and deferoxamine mesylate (15 mg/kg), at 0.2-ml volume, were administered intravenously within 5 minutes after chlorine exposure.…”

Section: Methodsmentioning

confidence: 99%

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

Fanucchi¹,

Bracher

Doran

et al. 2012

Am J Respir Cell Mol Biol

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We assessed the safety and efficacy of combined intravenous and aerosolized antioxidant administration to attenuate chlorine gasinduced airway alterations when administered after exposure. Adult male Sprague-Dawley rats were exposed to air or 400 parts per million (ppm) chlorine (a concentration likely to be encountered in the vicinity of industrial accidents) in environmental chambers for 30 minutes, and returned to room air, and they then received a single intravenous injection of ascorbic acid and deferoxamine or saline. At 1 hour and 15 hours after chlorine exposure, the rats were treated with aerosolized ascorbate and deferoxamine or vehicle. Lung antioxidant profiles, plasma ascorbate concentrations, airway morphology, and airway reactivity were evaluated at 24 hours and 7 days after chlorine exposure. At 24 hours after exposure, chlorine-exposed rats had significantly lower pulmonary ascorbate and reduced glutathione concentrations. Treatment with antioxidants restored depleted ascorbate in lungs and plasma. At 7 days after exposure, in chlorineexposed, vehicle-treated rats, the thickness of the proximal airways was 60% greater than in control rats, with twice the amount of mucosubstances. Airway resistance in response to methacholine challenge was also significantly elevated. Combined treatment with intravenous and aerosolized antioxidants restored airway morphology, the amount of airway mucosubstances, and airway reactivity to control levels by 7 days after chlorine exposure. Our results demonstrate for the first time, to the best of our knowledge, that severe injury to major airways in rats exposed to chlorine, as characterized by epithelial hyperplasia, mucus accumulation, and airway hyperreactivity, can be reversed in a safe and efficacious manner by the postexposure administration of ascorbate and deferoxamine.Keywords: epithelial injury; epithelial repair; mucosubstances; ascorbate; deferoxamine; aerosol Chlorine is essential to global industry and to global public health. According to the World Chlorine Council (http://www. worldchlorine.org), 14.4 million metric tons were produced in North America in 2008, and 62.8 million metric tons were produced globally. Water treatment makes up only 5% of the world's use of chlorine. The majority of chlorine is used in the production of plastics such as polyvinyl chloride (1). It is also used as a bleaching agent for pulp and paper production, as feedstock in the production of chlorinated solvents used in metalworking, in dry cleaning, in electronics, and in pharmaceutical production (1-6).Only 20 American states contain facilities that produce chlorine, but every American state has facilities that use chlorine. This results in the shipping of chlorine by railcar, and increases the potential for large-scale accidents. According to the Environmental Protection Agency, chlorine gas was related to 518 serious accidents over a 5-year period during the 1990s (1). Multiple-casualty exposures to chlorine have resulted from industrial accidents involving chlorine ta...

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Mitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite

Abstract: Yadav AK, Doran SF, Samal AA, Sharma R, Vedagiri K, Postlethwait EM, Squadrito GL, Fanucchi MV, Roberts LJ 2nd, Patel RP, Matalon S. Mitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite.

Cited by 48 publications

References 37 publications

Regulation of Alveolar Epithelial Na⁺ Channels by ERK1/2 in Chlorine-Breathing Mice

Regulation of Alveolar Epithelial Na⁺ Channels by ERK1/2 in Chlorine-Breathing Mice

Chlorine gas exposure increases susceptibility to invasive lung fungal infection

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

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Mitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite

Abstract: Yadav AK, Doran SF, Samal AA, Sharma R, Vedagiri K, Postlethwait EM, Squadrito GL, Fanucchi MV, Roberts LJ 2nd, Patel RP, Matalon S. Mitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite.

Cited by 48 publications

References 37 publications

Regulation of Alveolar Epithelial Na+ Channels by ERK1/2 in Chlorine-Breathing Mice

Regulation of Alveolar Epithelial Na+ Channels by ERK1/2 in Chlorine-Breathing Mice

Chlorine gas exposure increases susceptibility to invasive lung fungal infection

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

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Regulation of Alveolar Epithelial Na⁺ Channels by ERK1/2 in Chlorine-Breathing Mice

Regulation of Alveolar Epithelial Na⁺ Channels by ERK1/2 in Chlorine-Breathing Mice