Inhibition of chlorine-induced lung injury by the type 4 phosphodiesterase inhibitor rolipram

Chang, Weiyuan; Chen, Jing; Schlueter, Connie F.; Rando, Roy J.; Pathak, Yashwant; Hoyle, Gary W.

doi:10.1016/j.taap.2012.06.017

Cited by 41 publications

(40 citation statements)

References 43 publications

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“…Neutrophil deficiency/dysfunction is the hallmark predisposing factor for the development of invasive fungal infection caused by A. fumigatus (6,24). However, recruitment of neutrophils to the lung is a hallmark of Cl 2 gas exposure (16,57,71). Indeed, we observed that Cl 2 -exposed mice challenged with A. fumigatus had much higher neutrophil levels than either air-exposed mice challenged with A. fumigatus or mice exposed to Cl 2 alone.…”

Section: Discussionmentioning

confidence: 67%

“…It would be important in future studies to determine the extent by which Cl 2 affects assembly of the NADPH oxidase complex in neutrophils. Although neutrophils are often documented to be part of the lung response to Cl 2 gas exposure, and thus deemed a harmful contributor to lung injury, experimental studies have shown that some therapeutic interventions after Cl 2 exposure may ameliorate lung injury and/or lung function without having a significant impact on neutrophil numbers (16,52,67). This would suggest that some aspects of Cl 2 -induced lung injury are not mediated by neutrophils.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

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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“…The promotion of cAMP in ALI inhibited edema, inflammation, and hyperreactivity [40]. The effects of phosphatiosomes on pulmonary edema and neutrophil infiltration were thought to be related to the stimulation of cAMP.…”

Section: Discussionmentioning

confidence: 97%

Passive targeting of phosphatiosomes increases rolipram delivery to the lungs for treatment of acute lung injury: An animal study

Fang

Wen

Aljuffali

et al. 2015

Journal of Controlled Release

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“…Pulmonary function and airway reactivity to methacholine were measured by forced oscillation by using a FlexiVent system (SCIREQ, Montreal, Quebec, Canada) as described (5,13).…”

Section: Methodsmentioning

confidence: 99%

Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis

Chen

Schlueter

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Mo Y, Chen J, Schlueter CF, Hoyle GW. Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis. Am J Physiol Lung Cell Mol Physiol 304: L92-L102, 2013. First published November 21, 2012 doi:10.1152/ajplung.00272.2012.-Chlorine is a reactive gas that is considered a chemical threat agent. Humans who develop acute lung injury from chlorine inhalation typically recover normal lung function; however, a subset can experience chronic airway disease. To examine pathological changes following chlorine-induced lung injury, mice were exposed to a single high dose of chlorine, and repair of the lung was analyzed at multiple times after exposure. In FVB/NJ mice, chlorine inhalation caused pronounced fibrosis of larger airways that developed by day 7 after exposure and was associated with airway hyperreactivity. In contrast, A/J mice had little or no airway fibrosis and had normal lung function at day 7. Unexposed FVB/NJ mice had less keratin 5 staining (basal cell marker) than A/J mice in large intrapulmonary airways where epithelial repair was poor and fibrosis developed after chlorine exposure. FVB/NJ mice had large areas devoid of epithelium on day 1 after exposure leading to fibroproliferative lesions on days 4 and 7. A/J mice had airways covered by squamous keratin 5-stained cells on day 1 that transitioned to a highly proliferative reparative epithelium by day 4 followed by the reappearance of ciliated and Clara cells by day 7. The data suggest that lack of basal cells in the large intrapulmonary airways and failure to effect epithelial repair at these sites are factors contributing to the development of airway fibrosis in FVB/NJ mice. The observed differences in susceptibility to chlorine-induced airway disease provide a model in which mechanisms and treatment of airway fibrosis can be investigated. acute lung injury; airway hyperreactivity; basal cells CHLORINE IS A WIDELY USED industrial chemical and is one the top ten chemicals produced by gross weight (9). Chlorine gas is considered a chemical threat agent and is a highly toxic respiratory irritant that when inhaled causes cellular injury, alveolar-capillary barrier disruption, inflammation, pulmonary edema, and, at very high levels of exposure, death (9,21,39,44). Human exposure to chlorine has occurred from both intentional and accidental releases of chlorine (9,17,33,41,43). Humans exposed to high levels of chlorine develop acute lung injury, but most individuals recover from these acute effects (17, 43). However, additional follow-up studies suggest the existence of a subset of exposed individuals who experience chronic impairment of pulmonary function, which may include airway hyperreactivity, airway obstruction, or decreased residual volumes (1,18,23,33). Long-term effects of chlorine inhalation have been studied in the context of acute irritant-induced asthma (2, 23). Patients who developed irritant-induced asthma as a result of chemical exposure (most commonly chlorine) had evidence of airway obstruction, fibrosis, and hyper...

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Inhibition of chlorine-induced lung injury by the type 4 phosphodiesterase inhibitor rolipram

Cited by 41 publications

References 43 publications

Chlorine gas exposure increases susceptibility to invasive lung fungal infection

Chlorine gas exposure increases susceptibility to invasive lung fungal infection

Passive targeting of phosphatiosomes increases rolipram delivery to the lungs for treatment of acute lung injury: An animal study

Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis

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