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.
Chlorine (Cl2) is utilized worldwide for a diverse range of industrial applications, including pulp bleaching, sanitation, and pharmaceutical development. Though Cl2 has widespread use, little is known regarding the mechanisms of toxicity associated with Cl2 exposure, which occurs during industrial accidents or acts of terrorism. Previous instances of Cl2 exposure have led to reported episodes of respiratory distress that result in high morbidity and mortality. Furthermore, studies suggest that acute Cl2 exposure also results in systemic vascular injury and subsequent myocardial contractile dysfunction. Here we review both lung and cardiac pathology associated with acute Cl2 inhalation and discuss recently published data that suggests that mitochondrial dysfunction underlies the pathogenesis of Cl2-induced toxicity. Lastly, we discuss our findings that suggest that upregulation of autophagy protects against Cl2-induced lung inflammation and can be a potential therapeutic target for ameliorating the toxic effects of Cl2 exposure.
Aims
Implantable cardioverter‐defibrillator (ICD) therapy reduces mortality in patients with heart failure and current guidelines advise implantation of ICDs in patients with a life expectancy of >1 year. We examined trends in all‐cause mortality in patients who underwent primary or secondary prevention ICD placement in the Veterans Affairs (VA) Health System.
Methods and results
US veterans receiving a new ICD placement for primary or secondary prevention of sudden cardiac death between January 2007 and January 2015, who had heart failure with reduced ejection fraction (HFrEF) were included in the analysis. We assessed all‐cause mortality 1 year post‐ICD implantation. ICD implantation and HFrEF diagnosis were established with associated ICD‐9 codes. The VA death registry was utilized to identify mortality rates following ICD placement. Results were subsequently age‐stratified. There were 17 901 veterans with HFrEF with ICD placement nationwide. There was no statistically significant difference in 1‐year mortality from 2007 (13.1%) to 2014 (13.4%, P > 0.05). There was a significant increase in 1‐year mortality in patients in the oldest age quartile (81.6 years, 32.3% mortality) compared to the youngest quartile (55.5 years, 7% mortality). The finding of diverging clinical outcomes extended to the 30‐day but also 8‐year mark.
Conclusions
Our data suggest there is a high 1‐year mortality in aging HFrEF patients undergoing primary and secondary prevention ICD placement. This highlights the importance of developing better predictive models for mortality in our ICD eligible patient population.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.