The role of iron in Libby amphibole-induced acute lung injury and inflammation

Shannahan, Jonathan H.; Ghio, Andrew J.; Schladweiler, Mette C.; McGee, John K.; Richards, Judy H.; Gavett, Stephen H.; Kodavanti, Urmila P.

doi:10.3109/08958378.2011.569587

Cited by 16 publications

(20 citation statements)

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“…However, excessive heme catalyzes the formation of free radicals, resulting in oxidative stress and cellular injury (16). Elevated heme levels have also been reported to underlie the endothelial injury after lipopolysaccharide exposure (26), lung injury after Libby amphibole asbestos exposure (40), as well as hyperoxia-induced lung injury (9), suggesting that the attenuation of heme may have broader implications in ameliorating lung oxidative damage.…”

Section: Innovationmentioning

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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Section: Innovationmentioning

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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“…It was postulated that LA-induced acute and long-term lung injury (Padilla-Carlin et al 2011;Shannahan et al 2011b) might increase systemic microvascular thrombogenic activity. In this series of studies an attempt to examine acute and chronic alterations in platelet activity resulting from exposure to LA was conducted.…”

Section: Discussionmentioning

confidence: 99%

“…The median fiber length of this LA is smaller than the mean length, suggesting that there is likely a larger proportion of fibers that is smaller than the mean length. LA fiber size distribution and surface chemical properties were described in recent publications (Shannahan et al 2011a;2011b).…”

Section: Libby Amphibolementioning

confidence: 99%

“…Since asbestos fibers are known to deposit within the lung and produce lung injury, chronic inflammation, fibrosis, and mesothelioma, these fibers provide an interesting test material for study of systemic, prothrombotic, and vascular effects. It was postulated that LA fibers, which are shorter than classical asbestos fibers such as amosite (Shannahan et al 2011b), might facilitate a prothrombotic state, increase circulating cytokines, and produce vascular alterations similar to those produced by PM in healthy and CVD compromised rats. In order to test this hypothesis, samples obtained from three independent studies were examined.…”

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confidence: 97%

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Vascular and Thrombogenic Effects of Pulmonary Exposure to Libby Amphibole

Shannahan

Schladweiler

Thomas

et al. 2012

Journal of Toxicology and Environmental Health, Part A

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Exposure to Libby amphibole (LA) asbestos is associated with increased incidences of human autoimmune disease and mortality related to cardiovascular diseases. However, the systemic and vascular impacts are less well examined because of the dominance of pulmonary disease. It was postulated that regardless of the type of exposure scenario, LA exposure might produce systemic and vascular inflammogenic and thrombotic alterations in healthy and cardiovascular compromised rat models. Samples from three independent studies were examined. In the first study, male Wistar Kyoto (WKY), spontaneously hypertensive (SH), and SH heart failure (SHHF) rats were intratracheally instilled once with 0 (vehicle), 0.25, or 1 mg/rat of LA. In the second study, F344 rats were instilled with vehicle or LA at 0.5, 1.5, or 5 mg/rat. In the third study, F344 rats were instilled with the same mass concentrations of LA delivered by biweekly multiple instillations over 3 mo to simulate an episodic subchronic exposure. Complete blood count, platelet aggregation, serum cytokines, and biomarkers of systemic and aortic effects were examined. LA reduced adenosine diphosphate (ADP)-induced platelet aggregation and decreased circulating platelets in WKY (1 mg/rat) and F344 (5 mg/rat) at the 3-mo time point but did not do so in SH or SHHF rats. A decline in circulating lymphocytes with age appeared to be exacerbated by LA exposure in F344 rats but the differences were not significant. Aorta mRNA expression for biomarkers of oxidative stress (HO-1, LOX-1), inflammation (MIP-2), and thrombosis (tPA, PAI-1, vWf) were increased at baseline in SH and SHHF relative to WKY. LA exposure upregulated several of these biomarkers and also those involved in aortic contractility of WKY rats at 3 mo, suggesting thrombogenic, vasocontractile, and oxidative stress-mediated impairments. The aorta changes in F344 rats were less remarkable than changes noted in WKY following LA exposure. In conclusion, exposure to LA decreased circulating platelets and platelet coagulability while increasing the expression of oxidative stress, thrombosis, and vasoconstriction biomarkers in the aorta of healthy rats. These changes were similar to those noted at baseline in SH and SHHF rats, suggesting that LA-induced pulmonary injury might increase the risk of developing cardiovascular disease in healthy individuals.

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“…A detailed description of fiber analysis was reported in Shannahan et al (2011). LA is a mixture of amphibole fibers comprised of winchite (84%), richterite (11%), and tremolite (6%), and was obtained from the Rainy Creek Complex near Libby, Montana in 2007 by the US Geological Survey, similar to a previous collection in 2000 (Meeker et al, 2003).…”

Section: Amphibole Asbestosmentioning

confidence: 99%

Evaluation of anti-nuclear antibodies and kidney pathology in Lewis rats following exposure to Libby amphibole asbestos

Salazar

Copeland²,

Wood³

et al. 2012

Journal of Immunotoxicology

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The prevalence of anti-nuclear antibodies (ANA) and self-reported systemic autoimmune diseases were increased in residents of Libby, MT, as was the incidence of ANA in Lewis rats exposed to Libby amphibole (LA) asbestos. However, rats induced to develop rheumatoid arthritis (RA) did not develop autoantibodies associated with RA, nor was RA exacerbated by LA exposure, suggesting that increased ANA expression might be related to some other autoimmune process. Libby residents self-reported increased numbers of physician-diagnosed cases of systemic lupus erythematosus (SLE). Thus, the goal of this study was to determine if the increased incidence of ANA in Lewis rats exposed to LA is related to the development of SLElike disease. Female Lewis rats were intratracheally instilled bi-weekly for 13 weeks with total doses of 0.15, 0.5, 1.5, or 5.0 mg of LA or 0.5 or 1.5 mg of a positive control fiber, amosite. ANA incidence was significantly increased in all asbestos dose groups, although no dose response was observed. The occurrence of proteinuria was increased in LA 0.5, LA 5.0, and amosite 0.5 dose groups; however, the microscopic appearance of the kidneys was normal, no binding of autoimmune complexes to glomerular surfaces was observed, and antibodies to doublestranded DNA were not elevated. Therefore, an increased prevalence of ANA in rats exposed to asbestos does not appear to correlate with disease markers typically observed in SLE. Analysis of ANA specificity for extractable nuclear antigens (ENA) determined that 98% of ENA þ samples were specific for the Jo-1 antigen. Autoantibodies to Jo-1 have been reported in patients with interstitial lung disease, suggesting that autoantibodies to Jo-1 may be a biomarker for asbestos-related pulmonary disease.

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The role of iron in Libby amphibole-induced acute lung injury and inflammation

Cited by 16 publications

References 50 publications

Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury

Heme Attenuation Ameliorates Irritant Gas Inhalation-Induced Acute Lung Injury

Vascular and Thrombogenic Effects of Pulmonary Exposure to Libby Amphibole

Evaluation of anti-nuclear antibodies and kidney pathology in Lewis rats following exposure to Libby amphibole asbestos

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