Exposure–response effects of inhaled sulfur mustard in a large porcine model: a 6-h study

Fairhall, Sarah; Jugg, Bronwen; Read, Robert W.; Stubbs, Sue; Rutter, S. J.; Smith, A. J.; Mann, T.; Jenner, John; Sciuto, Alfred M.

doi:10.3109/08958378.2010.527398

Cited by 16 publications

(25 citation statements)

References 24 publications

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“…In regard to other animal models, when ethanolic SM vapor was delivered to glass catheter-intubated rats, the same type of injury in the conducting airways occurred, with fibrin-containing casts present in the bronchi and bronchioles (39). In the porcine SM model, where high-dose SM was delivered as a neat vapor via nasal inhalation, gas exchange abnormalities mirroring our findings were noted, but more importantly, airway-obstructive lesions caused mortality in 40% of the pigs in less than 6 hours from initial SM exposure (40). Thus, an injury affecting the conducting airways has been reported in both humans and animal models of SM inhalation, just as we have found in our CEES inhalation model.…”

Section: Discussionsupporting

confidence: 50%

Tissue Plasminogen Activator Prevents Mortality from Sulfur Mustard Analog–Induced Airway Obstruction

Veress

Hendry‐Hofer²,

Loader³

et al. 2013

Am J Respir Cell Mol Biol

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Sulfur mustard (SM) inhalation causes the rare but life-threatening disorder of plastic bronchitis, characterized by bronchial cast formation, resulting in severe airway obstruction that can lead to respiratory failure and death. Mortality in those requiring intubation is greater than 80%. To date, no antidote exists for SM toxicity. In addition, therapies for plastic bronchitis are solely anecdotal, due to lack of systematic research available to assess drug efficacy in improving mortality and/or morbidity. Adult rats exposed to SM analog were treated with intratracheal tissue plasminogen activator (tPA) (0.15-0.7 mg/kg, 5.5 and 6.5 h), compared with controls (no treatment, isoflurane, and placebo). Respiratory distress and pulse oximetry were assessed (for 12 or 48 h), and arterial blood gases were obtained at study termination (12 h). Microdissection of fixed lungs was done to assess airway obstruction by casts. Optimal intratracheal tPA treatment (0.7 mg/kg) completely eliminated mortality (0% at 48 h), and greatly improved morbidity in this nearly uniformly fatal disease model (90-100% mortality at 48 h). tPA normalized plastic bronchitis-associated hypoxemia, hypercarbia, and lactic acidosis, and improved respiratory distress (i.e., clinical scores) while decreasing airway fibrin casts. Intratracheal tPA diminished airwayobstructive fibrin-containing casts while improving clinical respiratory distress, pulmonary gas exchange, tissue oxygenation, and oxygen utilization in our model of severe chemically induced plastic bronchitis. Most importantly, mortality, which was associated with hypoxemia and clinical respiratory distress, was eliminated.Keywords: plastic bronchitis; tissue plasminogen activator; airway obstruction; sulfur mustard; fibrin Sulfur mustard (bis(2-chloroethyl)sulfide; SM) is a vesicant and chemical weapon used in warfare during much of the twentieth century, and which remains in the stockpiles of multiple nations today (Syria, Iran, North Korea, Libya, the United States, and possibly others). SM exposure affects the eyes, skin, upper airways, and lungs. After a brief latent period, respiratory failure and death can develop within 12 to 48 hours. Despite a century of study, the mechanisms responsible for SM's toxic effects remain unsolved, and clinically effective rescue therapies or antidotes are not available.Initial reports of human SM inhalation toxicity in the early 1900s described the presence of airway-obstructive necrotic debris/ mucosa, or "pseudomembranes," in the large airways of victims, and these were more recently confirmed in the victims of the IranIraq war (1, 2). Such severe lesions have been reported to lead to respiratory compromise, with need for artificial ventilation, and death in 80% of those needing intubation (2). Furthermore, chronic conducting airway lesions, such as bronchiolitis obliterans, tracheal/bronchial stenosis, and chronic bronchitis, are commonly found in survivors of SM inhalation months to years after exposure (2, 3), whereas chronic alveolar or paren...

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Section: Discussionsupporting

confidence: 50%

Tissue Plasminogen Activator Prevents Mortality from Sulfur Mustard Analog–Induced Airway Obstruction

Veress

Hendry‐Hofer²,

Loader³

et al. 2013

Am J Respir Cell Mol Biol

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“…Apoptosis is believed to have contributed to the lung injury in Iranian victims of SM exposure [43]. Increased LDH activity (cell death) was observed in guinea pig lungs [44] and tracheal epithelial cells of pigs exposed to SM inhalation [45]. If the cell injury/death involves an apoptotic process, the nuclear condensation of apoptotic cells can be visualized by TUNEL staining [46].…”

Section: Discussionmentioning

confidence: 99%

Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: Possible role of Th17 cells in chronic lung pathology

Mishra

Rir-sima-ah

Grotendorst

et al. 2012

International Immunopharmacology

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Sulfur mustard (SM) is a highly toxic chemical warfare agent that remains a threat to human health. The immediate symptoms of pulmonary distress may develop into chronic lung injury characterized by progressive lung fibrosis, the major cause of morbidity among the surviving SM victims. Although SM has been intensely investigated, little is known about the mechanism(s) by which SM induces chronic lung pathology. Increasing evidence suggests that IL-17+ cells are critical in fibrosis, including lung fibrotic diseases. In this study we exposed F344 rats and cynomolgus monkeys to SM via inhalation and determined the molecular and cellular milieu in their lungs at various times after SM exposure. In rats, SM induced a burst of pro-inflammatory cytokines/chemokines within 72 h, including IL-1β, TNF-α, IL-2, IL-6, CCL2, CCL3, CCL11, and CXCL1 that was associated with neutrophilic infiltration into the lung. At 2 wk and beyond (chronic phase), lymphocytic infiltration and continued elevated expression of cytokines/chemokines were sustained. TGF-β, which was undetectable in the acute phase, was strongly upregulated in the chronic phase; these conditions persisted until the animals were sacrificed. The chronic phase was also associated with myofibroblast proliferation, collagen deposition, and presence of IL-17+ cells. At 30 days, SM inhalation promoted the accumulation of IL-17+ cells in the inflamed areas of monkey lungs. Thus, SM inhalation causes acute and chronic inflammatory responses; the latter is characterized by the presence of TGF-β, fibrosis, and IL-17+ cells in the lung. IL-17+ cells likely play an important role in the pathogenesis of SM-induced lung injury.

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“…Anderson et al (1996) described the pathogenesis of HD-induced lesions in the rat respiratory tract. More recent studies in the pig model, Fairhall et al (2010) found significant changes in shunt fraction from 3 to 6 hours post-exposure, increased hypoxia, respiratory acidosis, and pathological finding of necrosis and erosions in the tracheal epithelium.…”

Section: Introductionmentioning

confidence: 88%

A novel sulfur mustard (HD) vapor inhalation exposure system for accurate inhaled dose delivery

Perry

Benson

Kohne

et al. 2015

Journal of Pharmacological and Toxicological Methods

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Introduction A custom designed HD exposure system was used to deliver controlled inhaled doses to an animal model through an endotracheal tube. Methods Target HD vapor challenges were generated by a temperature controlled bubbler/aerosol trap, while concentration was monitored near real-time by gas chromatography. Animal breathing parameters were monitored real-time by an in-line pneumotach, pressure transducer, and Buxco pulmonary analysis computer/software. For each exposure, the challenge atmosphere was allowed to stabilize at the desired concentration while the anesthetized animal was provided humidity controlled clean air. Once the target concentration was achieved and stable, a portion of the challenge atmosphere was drawn past the endotracheal tube, where the animal inhaled the exposure ad libitum. During the exposure, HD vapor concentration and animal weight were used to calculate the needed inhaled volume to achieve the target inhaled dose (μg/kg). The exposures were halted when the inhaled volume was achieved. Results The exposure system successfully controlled HD concentrations from 22.2 to 278 mg/m3 and accurately delivered inhaled doses between 49.3 and 1120 μg/kg with actual administered doses being within 4% of the target level. Discussion This exposure system administers specific HD inhaled doses to evaluate physiological effects and for evaluation of potential medical countermeasure treatments.

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Exposure–response effects of inhaled sulfur mustard in a large porcine model: a 6-h study

Abstract: These findings are consistent with those seen in the early stages of acute lung injury (ALI).

Cited by 16 publications

References 24 publications

Tissue Plasminogen Activator Prevents Mortality from Sulfur Mustard Analog–Induced Airway Obstruction

Tissue Plasminogen Activator Prevents Mortality from Sulfur Mustard Analog–Induced Airway Obstruction

Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: Possible role of Th17 cells in chronic lung pathology

A novel sulfur mustard (HD) vapor inhalation exposure system for accurate inhaled dose delivery

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