Delayed toxic effects of sulfur mustard on respiratory tract of Iranian veterans

Balali-Mood, Mahdi; Afshari, Reza; Zojaji, Ramin; Kahrom, Hadi; Kamrani, Maedeh; Attaran, Davood; Mousavi, Seyed Reza; Zare, Gholam Ali

doi:10.1177/0960327110389501

Cited by 45 publications

(29 citation statements)

References 21 publications

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“…Common lower respiratory diseases include chronic obstructive pulmonary disease (84%), bronchiectasis (44.1%), and lung fibrosis (7.7%) (Balali-Mood et al, 2011). High resolution lung CT scans in victims 18-23 years after exposure show significant air trapping and parenchymal attenuation patterns (Idani et al, 2012).…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

Mustard vesicant-induced lung injury: Advances in therapy

Weinberger

Malaviya

Sunil

et al. 2016

Toxicology and Applied Pharmacology

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“…The lung is a major target and pulmonary toxicity is the main cause of mortality and long term morbidity following sulfur mustard exposure (Ghanei and Harandi, 2007). Both acute and chronic effects of sulfur mustard inhalation have been described, including pulmonary inflammation and disruption of the alveolar epithelial barrier, as well as bronchitis, and pulmonary fibrosis (Balali-Mood et al, 2011; Ghanei et al, 2008; Weinberger et al, 2011). Toxicity is attributed to the lipophilic nature of sulfur mustard which allows it to rapidly penetrate target tissues and cells and alkylate DNA, resulting in cytotoxicity, apoptosis and autophagy.…”

Section: Introductionmentioning

confidence: 99%

Role of reactive nitrogen species generated via inducible nitric oxide synthase in vesicant-induced lung injury, inflammation and altered lung functioning

Sunil

Shen

Patel-Vayas

et al. 2012

Toxicology and Applied Pharmacology

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Pulmonary toxicity induced by vesicants is associated with oxidative stress. In the present studies we analyzed the role of reactive nitrogen species (RNS) generated via inducible nitric oxide synthase (iNOS) in lung injury and inflammation induced by vesicants using 2-chloroethyl ethyl sulfide (CEES) as a model. C57Bl/6 (WT) and iNOS−/− mice were sacrificed 3 d or 14 d following intratracheal administration of CEES (6 mg/kg) or control. CEES intoxication resulted in transient (3 d) increases in bronchoalveolar lavage (BAL) cell and protein content in WT, but not iNOS−/− mice. This correlated with expression of Ym1, a marker of oxidative stress in alveolar macrophages and epithelial cells. In contrast, in iNOS−/− mice, Ym1 was only observed 14 d post exposure in enlarged alveolar macrophages, suggesting that they are alternatively activated. This is supported by findings that lung tumor necrosis factor and lipocalin Lcn2 expression, mediators involved in tissue repair were also upregulated at this time in iNOS−/− mice. Conversely, CEES-induced increases in the proinflammatory genes, monocyte chemotactic protein-1 and cyclooxygenase-2, were abrogated in iNOS−/− mice. In WT mice, CEES treatment also resulted in increases in total lung resistance and decreases in compliance in response to methacholine, effects blunted by loss of iNOS. These data demonstrate that RNS, generated via iNOS play a role in the pathogenic responses to CEES, augmenting oxidative stress and inflammation and suppressing tissue repair. Elucidating inflammatory mechanisms mediating vesicant-induced lung injury is key to the development of therapeutics to treat mustard poisoning.

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“…The surviving SM victims of the Iran-Iraq war continue to suffer from chronic respiratory complication of SM exposure [7]. In humans, respiratory exposure to mustard agents (sulfur and nitrogen mustards) produces acute lung injury followed by chronic progressive lung fibrosis [6, 7, 26, 29, 30].…”

Section: Discussionmentioning

confidence: 99%

“…In humans, respiratory exposure to mustard agents (sulfur and nitrogen mustards) produces acute lung injury followed by chronic progressive lung fibrosis [6, 7, 26, 29, 30]. Moreover, the SM-exposed patients show persistent signs of immune dysfunction and accumulation of CD8 + cells in the lung [10–13].…”

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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Delayed toxic effects of sulfur mustard on respiratory tract of Iranian veterans

Cited by 45 publications

References 21 publications

Mustard vesicant-induced lung injury: Advances in therapy

Mustard vesicant-induced lung injury: Advances in therapy

Role of reactive nitrogen species generated via inducible nitric oxide synthase in vesicant-induced lung injury, inflammation and altered lung functioning

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

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