Mitigation of Chlorine Lung Injury by Increasing Cyclic AMP Levels

Hoyle, Gary W.

doi:10.1513/pats.201001-002sm

Cited by 28 publications

(25 citation statements)

References 76 publications

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“…This is followed by a postexposure injury phase occurring over a time span ranging from days to months, which affects the airways and pulmonary and systemic vasculature (9,11,20,25,26,30,37). Clinically, this presents as reactive airway syndrome, hypoxemia, noncardiogenic edema leading to acute lung injury, and development of acute respiratory distress syndrome, which chronically leads to reactive airway disease, increased sensitivity to pulmonary infections, fibrosis, and bronchiolitis obliterans, as well as dermal injury (9,10,12,17,24,26,28,30). Exciting recent studies are providing insights into the postexposure mechanisms that include increased oxidative stress, neurogenic and airway inflammation, fibrosis, loss of nitric oxide (NO) signaling homeostasis, and loss of endogenous airway repair mechanisms (2, 9 -11, 15, 20, 22, 25, 26, 36).…”

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confidence: 99%

Nitrite therapy improves survival postexposure to chlorine gas

Honavar

Doran

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Exposure to relatively high levels of chlorine (Cl2) gas can occur in mass-casualty scenarios associated with accidental or intentional release. Recent studies have shown a significant postexposure injury phase to the airways, pulmonary, and systemic vasculatures mediated in part by oxidative stress, inflammation, and dysfunction in endogenous nitric oxide homeostasis pathways. However, there is a need for therapeutics that are amenable to rapid and easy administration in the field and that display efficacy toward toxicity after chlorine exposure. In this study, we tested whether nitric oxide repletion using nitrite, by intramuscular injection after Cl2 exposure, could prevent Cl2 gas toxicity. C57bl/6 male mice were exposed to 600 parts per million Cl2 gas for 45 min, and 24-h survival was determined with or without postexposure intramuscular nitrite injection. A single injection of nitrite (10 mg/kg) administered either 30 or 60 min postexposure significantly improved 24-h survival (from ∼20% to 50%). Survival was associated with decreased neutrophil accumulation in the airways. Rendering mice neutropenic before Cl2 exposure improved survival and resulted in loss of nitrite-dependent survival protection. Interestingly, female mice were more sensitive to Cl2-induced toxicity compared with males and were also less responsive to postexposure nitrite therapy. These data provide evidence for efficacy and define therapeutic parameters for a single intramuscular injection of nitrite as a therapeutic after Cl2 gas exposure that is amenable to administration in mass-casualty scenarios.

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confidence: 99%

Nitrite therapy improves survival postexposure to chlorine gas

Honavar

Doran

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Also, in human studies, SAP was unaffected by roflumilast treatment (Louw et al, 2007). On the other hand, an increase in cAMP levels inhibited the pro-inflammatory and apoptotic responses and provided an anti-inflammatory milieu (Dastidar et al, 2009;Naderi et al, 2009;Hoyle, 2010;Kim et al, 2010). So, it could be concluded that inhibition of PDE-4 reversed the hypertension-induced cognitive deficits independent of blood pressure.…”

Section: Discussionmentioning

confidence: 97%

Phosphodiesterase-4 inhibitors ameliorates cognitive deficits in deoxycorticosterone acetate induced hypertensive rats via cAMP/CREB signaling system

Sumathy

Girish

et al. 2015

Brain Research

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“…Phosphodiesterase inhibitors including rolipram raise the intracellular levels of the second messenger cyclic AMP, which can have multiple beneficial effects in the lung following injury (Hoyle, 2010). Rolipram has been shown to inhibit lung injury in animals exposed to bleomycin (Pan et al, 2009), hyperoxia (Mehats et al, 2008), and Streptococcus pneumoniae (Tavares et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Development and assessment of countermeasure formulations for treatment of lung injury induced by chlorine inhalation

Hoyle

Jing

Schlueter

et al. 2016

Toxicology and Applied Pharmacology

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Chlorine is a commonly used, reactive compound to which humans can be exposed via accidental or intentional release resulting in acute lung injury. Formulations of rolipram (a phosphodiesterase inhibitor), triptolide (a natural plant product with anti-inflammatory properties), and budesonide (a corticosteroid), either neat or in conjunction with poly(lactic:glycolic acid) (PLGA), were developed for treatment of chlorine-induced acute lung injury by intramuscular injection. Formulations were produced by spray-drying, which generated generally spherical microparticles that were suitable for intramuscular injection. Multiple parameters were varied to produce formulations with a wide range of in vitro release kinetics. Testing of selected formulations in chlorine-exposed mice demonstrated efficacy against key aspects of acute lung injury. The results show the feasibility of developing microencapsulated formulations that could be used to treat chlorine-induced acute lung injury by intramuscular injection, which represents a preferred route of administration in a mass casualty situation.

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Mitigation of Chlorine Lung Injury by Increasing Cyclic AMP Levels

Cited by 28 publications

References 76 publications

Nitrite therapy improves survival postexposure to chlorine gas

Nitrite therapy improves survival postexposure to chlorine gas

Phosphodiesterase-4 inhibitors ameliorates cognitive deficits in deoxycorticosterone acetate induced hypertensive rats via cAMP/CREB signaling system

Development and assessment of countermeasure formulations for treatment of lung injury induced by chlorine inhalation

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