Postexposure aerosolized heparin reduces lung injury in chlorine-exposed mice

Zarogiannis, Sotirios G.; Wagener, Brant M.; Basappa, Susanna; Doran, Stephen; Rodriguez, Christina M.; Jurkuvenaite, Asta; Pittet, Jean–François; Matalon, Sadis

doi:10.1152/ajplung.00152.2014

Cited by 29 publications

(19 citation statements)

References 57 publications

(77 reference statements)

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“…However, given that many of the anti-inflammatory properties of heparin appear to be broadly separable from its anticoagulant effects, related molecules that lack anticoagulant activity could prove to be more useful and acceptable in this situation. Furthermore, recent studies in mice demonstrated that heparin can reduce both the increased plasma protein levels and leukocyte infiltration into the lung elicited by exposure to chlorine gas (Zarogiannis et al, 2014) and can reduce the lung injury after smoke inhalation or burns (Miller et al, 2009(Miller et al, , 2014.…”

Section: A Acute Inflammatory Reactionsmentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs

et al. 2015

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Section: A Acute Inflammatory Reactionsmentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs

et al. 2015

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“…They predominantly damage the respiratory and alveolar epithelium, causing tracheitis, bronchitis, obliterative bronchiolitis, and acute respiratory distress syndrome (ARDS), which usually occurs within 24 h postexposure (19,24). Rodents exposed to chlorine gas also develop systemic injury, including cardiac dysfunction (52), systemic hypocoagulation (53), and inactivation of pulmonary arterial endothelial nitric oxide synthase (18) leading to hypertension, as well as increased susceptibility to fungal infections (12). Surviving animals develop subepithelial fibrosis and tracheal obstruction (30).…”

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confidence: 99%

Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury

Aggarwal

Lam

Bolisetty

et al. 2016

Antioxidants & Redox Signaling

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Aims: Exposure to irritant gases, such as bromine (Br 2 ), poses an environmental and occupational hazard that results in severe lung and systemic injury. However, the mechanism(s) of Br 2 toxicity and the therapeutic responses required to mitigate lung damage are not known. Previously, it was demonstrated that Br 2 upregulates the heme degrading enzyme, heme oxygenase-1 (HO-1). Since heme is a major inducer of HO-1, we determined whether an increase in heme and heme-dependent oxidative injury underlies the pathogenesis of Br 2 toxicity. Results: C57BL/6 mice were exposed to Br 2 gas (600 ppm, 30 min) and returned to room air. Thirty minutes postexposure, mice were injected intraperitoneally with a single dose of the heme scavenging protein, hemopexin (Hx) (3 lg/gm body weight), or saline. Twenty-four hours postexposure, saline-treated mice had elevated total heme in bronchoalveolar lavage fluid (BALF) and plasma and acute lung injury (ALI) culminating in 80% mortality after 10 days. Hx treatment significantly lowered heme, decreased evidence of ALI (lower protein and inflammatory cells in BALF, lower lung wet-to-dry weight ratios, and decreased airway hyperreactivity to methacholine), and reduced mortality. In addition, Br 2 caused more severe ALI and mortality in mice with HO-1 gene deletion (HO-1 -/-) compared to wild-type controls, while transgenic mice overexpressing the human HO-1 gene (hHO-1) showed significant protection. Innovation: This is the first study delineating the role of heme in ALI caused by Br 2 . Conclusion: The data suggest that attenuating heme may prove to be a useful adjuvant therapy to treat patients with ALI. Antioxid. Redox Signal. 24, 99-112.

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“…Spillage of Cl 2 in the environment during accidents or terrorist acts may result in significant morbidity and mortality to animals and humans (2,15,34,38). Exposure of animals to Cl 2 at concentrations comparable to the vicinity of industrial accidents damages airway epithelia and results in sloughing of airway mucosa, increased alveolar permeability, decreased ability of alveolar epithelial cells to clear fluid, damage to the pulmonary surfactant system (2,5,18,33), coagulation abnormalities (42), and extensive systemic injury (1,28). Animals surviving the initial exposure show significant structural and functional abnormalities, including the presence of foamy alveolar macrophages, patchy areas of ciliated airway cells (25,26), the presence of excess amounts of goblet cells, hyperplasia and airway hyperreactivity (11), and inability to clear inhaled fungi (15).…”

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confidence: 99%

Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness

Song

Doran

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Exposure to chlorine (Cl2) damages airway and alveolar epithelia resulting in acute lung injury and reactive airway hyperresponsiveness (AHR) to methacholine. However, little is known about the effect of preexisting respiratory disease on Cl2-induced lung injury. By using a murine respiratory syncytial virus (RSV) infection model, we found that preexisting RSV infection increases Cl2 (187 ppm for 30 min)-induced lung inflammation and airway AHR at 24 h after exposure (5 days after infection). RSV infection and Cl2 exposure synergistically induced oxygen desaturation and neutrophil infiltration and increased MCP-1, MIP-1␤, IL-10, IFN-␥, and RANTES concentrations in the bronchoalveolar lavage fluid (BALF). In contrast, levels of type 2 cytokines (i.e., IL-4, IL-5, IL-9, and IL-13) were not significantly affected by either RSV infection or Cl2 exposure. Cl2 exposure, but not RSV infection, induced AHR to methacholine challenge as measured by flexiVent. Moreover, preexisting RSV infection amplified BALF levels of hyaluronan (HA) and AHR. The Cl2-induced AHR was mitigated by treatment with inter-␣-trypsin inhibitor antibody, which inhibits HA signaling, suggesting a mechanism of HA-mediated AHR from exacerbated oxidative injury. Our results show for the first time that preexisting RSV infection predisposes the lung to Cl2-induced injury. These data emphasize the necessity for further research on the effects of Cl2 in vulnerable populations and the development of appropriate treatments. flexiVent; methacholine; bronchoalveolar lavage; cytokines; inflammatory cells CHLORINE (Cl 2 ) is an irritant and reactive gas with significant occupational and environmental hazard concerns due to its wide industrial and domestic usage. Spillage of Cl 2 in the environment during accidents or terrorist acts may result in significant morbidity and mortality to animals and humans (2,15,34,38). Exposure of animals to Cl 2 at concentrations comparable to the vicinity of industrial accidents damages airway epithelia and results in sloughing of airway mucosa, increased alveolar permeability, decreased ability of alveolar epithelial cells to clear fluid, damage to the pulmonary surfactant system (2, 5, 18, 33), coagulation abnormalities (42), and extensive systemic injury (1, 28). Animals surviving the initial exposure show significant structural and functional abnormalities, including the presence of foamy alveolar macrophages, patchy areas of ciliated airway cells (25,26), the presence of excess amounts of goblet cells, hyperplasia and airway hyperreactivity (11), and inability to clear inhaled fungi (15). These injuries may result from chemical reactions of Cl 2 and hypochlorous acid (HOCl), as well as various secondary reaction products, like chloramines (1, 33), chlorinated fatty acid, and low-molecular-weight hyaluronan (HA), a proinflammatory fragment generated by the fractionation of HA (19,21).Currently, little is known about the effects of previous existing respiratory infections on the subsequent Cl 2 -induced lung injury. Herein...

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Postexposure aerosolized heparin reduces lung injury in chlorine-exposed mice

Abstract: Zarogiannis SG, Wagener BM, Basappa S, Doran S, Rodriguez CA, Jurkuvenaite A, Pittet JF, Matalon S. Postexposure aerosolized heparin reduces lung injury in chlorine-exposed mice.

Cited by 29 publications

References 57 publications

Pharmacology of Heparin and Related Drugs

Pharmacology of Heparin and Related Drugs

Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury

Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness

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