Pathological Studies on the Protective Effect of a Macrolide Antibiotic, Roxithromycin, against Sulfur Mustard Inhalation Toxicity in a Rat Model

Gao, Xiugong; Anderson, Dana R.; Brown, A. C.; Lin, Hsiuling; Amnuaysirikul, Jack; Chua, Aileen L.; Holmes, Wesley W.; Ray, Prabhati

doi:10.1177/0192623311422079

Cited by 20 publications

(8 citation statements)

References 22 publications

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“…These human reports correlate with our findings presented here, where we used a nose inhalation model of CEES in rats, with pseudomembranes further defined as fibrin-containing casts of plastic bronchitis. 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).…”

Section: Discussionmentioning

confidence: 97%

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: Discussionmentioning

confidence: 97%

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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“…In cultured human airway epithelial cells and monocytes, macrolides suppress mustard-induced expression of pro-inflammatory cytokines and iNOS (Gao et al, 2007, 2008, 2010). Roxithromycin treatment of animals before and after SM inhalation also reduces upper airway pathology (Gao et al, 2011). Moreover, administration of clarithromycin in combination with NAC to humans with chronic SM-induced lung injury improves pulmonary function and decreases cough and sputum production (Ghanei et al, 2004).…”

Section: Targeting Inflammatory Cells and Tnfαmentioning

confidence: 99%

Mustard vesicant-induced lung injury: Advances in therapy

Weinberger

Malaviya

Sunil

et al. 2016

Toxicology and Applied Pharmacology

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Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine, which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant.

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“…Prior animal models of SM inhalation have been focused on the acute and subacute injuries that occur within the first 7 days of exposure (41)(42)(43)46). In acute/subacute injury (,14 d after insult), cell necrosis and sloughing occur, as well as increased inflammation and airway wall edema resulting from increased bronchovascular permeability.…”

Section: Discussionmentioning

confidence: 99%

Bronchiolitis Obliterans and Pulmonary Fibrosis after Sulfur Mustard Inhalation in Rats

McGraw

Dysart

Hendry‐Hofer

et al. 2018

Am J Respir Cell Mol Biol

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Inhalation of powerful chemical agents, such as sulfur mustard (SM), can have debilitating pulmonary consequences, such as bronchiolitis obliterans (BO) and parenchymal fibrosis (PF). The underlying pathogenesis of disorders after SM inhalation is not clearly understood, resulting in a paucity of effective therapies. In this study, we evaluated the role of profibrotic pathways involving transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) in the development of BO and PF after SM inhalation injury using a rat model. Adult Sprague-Dawley rats were intubated and exposed to SM (1.0 mg/kg), then monitored daily for respiratory distress, oxygen saturation changes, and weight loss. Rats were killed at 7, 14, 21, or 28 days, and markers of injury were determined by histopathology; pulmonary function testing; and assessment of TGF-β, PDGF, and PAI-1 concentrations. Respiratory distress developed over time after SM inhalation, with progressive hypoxemia, respiratory distress, and weight loss. Histopathology confirmed the presence of both BO and PF, and both gradually worsened with time. Pulmonary function testing demonstrated a time-dependent increase in lung resistance, as well as a decrease in lung compliance. Concentrations of TGF-β, PDGF, and PAI-1 were elevated at 28 days in lung, BAL fluid, and/or plasma. Time-dependent development of BO and PF occurs in lungs of rats exposed to SM inhalation, and the elevated concentrations of TGF-β, PDGF, and PAI-1 suggest involvement of these profibrotic pathways in the aberrant remodeling after injury.

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Pathological Studies on the Protective Effect of a Macrolide Antibiotic, Roxithromycin, against Sulfur Mustard Inhalation Toxicity in a Rat Model

Cited by 20 publications

References 22 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

Mustard vesicant-induced lung injury: Advances in therapy

Bronchiolitis Obliterans and Pulmonary Fibrosis after Sulfur Mustard Inhalation in Rats

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