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Intratracheal heparin improves plastic bronchitis due to sulfur mustard analog.

ABSTRACT: Inhalation of sulfur mustard (SM) and SM analog, 2-chloroethyl ethyl sulfide (CEES), cause fibrinous cast formation that occludes the conducting airways, similar to children with Fontan physiology-induced plastic bronchitis. These airway casts cause significant mortality and morbidity, including hypoxemia and respiratory distress. Our hypothesis was that intratracheal heparin, a highly cost effective and easily preserved rescue therapy, could reverse morbidity and mortality induced by bronchial cast formation.Sprague-Dawley rats were exposed to 7.5% CEES via nose-only aerosol inhalation to produce extensive cast formation and mortality. The rats were distributed into three groups: non-treated, phosphate-buffered saline (PBS)-treated, and heparin-treated groups. Morbidity was assessed with oxygen saturations and clinical distress. Blood and bronchoalveolar lavage fluid (BALF) were obtained for analysis, and lungs were fixed for airway microdissection to quantify the extent of airway cast formation.Heparin, given intratracheally, improved survival (100%) when compared to non-treated (75%) and PBS-treated (90%) controls. Heparin-treated rats also had improved oxygen saturations, clinical distress and airway cast scores. Heparin-treated rats had increased thrombin clotting times, factor Xa inhibition and activated partial thromboplastin times, indicating systemic absorption of heparin. There were also increased red blood cells (RBCs) in the BALF in 2/6 heparin-treated rats compared to PBS-treated control rats.Intratracheal heparin 1 hr after CEES inhalation improved survival, oxygenation, airway obstruction, and clinical distress. There was systemic absorption of heparin in rats treated intratracheally. Some rats had increased RBCs in BALF, suggesting a potential for intrapulmonary bleeding if used chronically after SM inhalation.

SUBMITTER: Houin PR

PROVIDER: S-EPMC4182164 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Intratracheal heparin improves plastic bronchitis due to sulfur mustard analog.

Houin Paul R PR Veress Livia A LA Rancourt Raymond C RC Hendry-Hofer Tara B TB Loader Joan E JE Rioux Jacqueline S JS Garlick Rhonda B RB White Carl W CW

Pediatric pulmonology 20140401 2

<h4>Background</h4>Inhalation of sulfur mustard (SM) and SM analog, 2-chloroethyl ethyl sulfide (CEES), cause fibrinous cast formation that occludes the conducting airways, similar to children with Fontan physiology-induced plastic bronchitis. These airway casts cause significant mortality and morbidity, including hypoxemia and respiratory distress. Our hypothesis was that intratracheal heparin, a highly cost effective and easily preserved rescue therapy, could reverse morbidity and mortality in ...[more]

PMID: 24692161

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Project description:Sulfur mustard (SM) is a chemical weapon stockpiled today in volatile regions of the world. SM inhalation causes a life-threatening airway injury characterized by airway obstruction from fibrin casts, which can lead to respiratory failure and death. Mortality in those requiring intubation is more than 80%. No therapy exists to prevent mortality after SM exposure. Our previous work using the less toxic analog of SM, 2-chloroethyl ethyl sulfide, identified tissue plasminogen activator (tPA) an effective rescue therapy for airway cast obstruction (Veress, L. A., Hendry-Hofer, T. B., Loader, J. E., Rioux, J. S., Garlick, R. B., and White, C. W. (2013). Tissue plasminogen activator prevents mortality from sulfur mustard analog-induced airway obstruction. Am. J. Respir. Cell Mol. Biol. 48, 439-447). It is not known if exposure to neat SM vapor, the primary agent used in chemical warfare, will also cause death due to airway casts, and if tPA could be used to improve outcome.Adult rats were exposed to SM, and when oxygen saturation reached less than 85% (median: 6.5?h), intratracheal tPA or placebo was given under isoflurane anesthesia every 4?h for 48?h. Oxygen saturation, clinical distress, and arterial blood gases were assessed. Microdissection was done to assess airway obstruction by casts.Intratracheal tPA treatment eliminated mortality (0% at 48?h) and greatly improved morbidity after lethal SM inhalation (100% death in controls). tPA normalized SM-associated hypoxemia, hypercarbia, and lactic acidosis, and improved respiratory distress. Moreover, tPA treatment resulted in greatly diminished airway casts, preventing respiratory failure from airway obstruction.tPA given via airway more than 6?h after exposure prevented death from lethal SM inhalation, and normalized oxygenation and ventilation defects, thereby rescuing from respiratory distress and failure. Intra-airway tPA should be considered as a life-saving rescue therapy after a significant SM inhalation exposure incident.

Project description:Sulfur mustard (SM) is a potent vesicant that targets epithelial cells and tissues. Most vesicant research has been performed using bona fide SM; however, some studies have used simulants, most notably half mustard (2-chloroethyl ethylsulfide; CEES) and nitrogen mustard (mechlorethamine; NM). Although CEES and NM have similarities to SM and can cause vesication, there are distinct differences in the chemical structures and physical properties of these compounds that may impact their toxic effects. Microarray analysis of cultured primary human epidermal keratinocytes (HEK) exposed to each of these vesicants was performed to directly compare the transcriptional responses induced by these vesicants. HEK were exposed in triplicate to concentrations ranging from 0-1000 µM for SM and NM and 0-4000 µM for CEES. Cells were harvested at 1, 2, 4, 8, 16, and 24 h and the RNA isolated for microarray analysis. Transcriptional responses were phenotypically anchored to cell morphology. The dataset was filtered by exposure and timepoint, and an analysis of variance was performed using dose as the factor. The top 500 genes ranked by p-value were analyzed using gene ontology algorithms to identify biological pathways significantly affected by each vesicant. At 2 h post-exposure, p53 signaling, Erk/MAPK signaling, and BMP signaling were significantly affected by all three vesicants. At 4 h post-exposure, p53 signaling , B cell activating factor, and glucocorticoid receptor signaling were significantly affected by all three vesicants. At 8 h post-exposure, there were no significant pathways commonly affected by all three vesicants. These results suggest that, although there are similarities in the transcriptional responses to each of these vesicants, the transcriptional responses appear to differ over time. Thus, extrapolation of results obtained with one vesicant to other vesicants may be complex and may have important implications for the development of vesicant therapeutics.

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Intratracheal heparin improves plastic bronchitis due to sulfur mustard analog.

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Intratracheal heparin improves plastic bronchitis due to sulfur mustard analog.

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