Lung Cysteine/cystine Redox Potential Increase Is Associated with Worse Inflammation and Disrupted Metabolism during H1N1 Infection and Exposure to Dietary Levels of Cadmium

Influenza A virus subtype H1N1 is seasonally active in the United States, affecting millions of people each year and claiming tens of thousands of lives since the 2009 pandemic. Public health efforts have focused on vaccination, but exposed individuals who become sick face severe inflammation and possibly death. Cadmium (Cd) is a ubiquitous heavy metal that interacts with thiols such as metallothionein and GSH. Public dietary exposure has remained steadily constant, potentially worsening health risks. Emerging evidence suggests Cd may worsen lung disease at levels achievable in the diet. To assess the role of dietary Cd in lung inflammation, mice were exposed to 1 mg/l CdCl 2 in drinking water for 16 weeks. 10 days prior to study completion, mice were intranasally given sub-lethal H1N1 or sterile saline. H1N1 caused a 20% body weight loss and 7-fold increase in airway enhanced pause after 10 days, and Cd exposure caused a 4.8-fold increase in lung tissue Cd without detectable changes in urine or plasma. Infected and Cd-exposed mice had worse lung inflammation, which was comprised of neutrophils, monocytes and T cells, and increased KC, IP-10, IFN-γ and IL-6. Lung tissue cysteine/cystine redox potential (Eh[CySS]) was progressively increased by Cd, H1N1 and the combination, unlike glutathione redox potential (Eh[GSSG]). A similar, less significant trend was observed in plasma Eh[GSSG]. Reducing Eh[CySS] clustered with myogenesis and complement pathway genes by associating with inflammation-sensitive metabolism such as kynurenine conversion to anthranilic acid. These data suggest lung Eh[CySS] coordinates tissue responses to viral-induced inflammation and that ingested Cd may significantly worsen lung inflammation during respiratory infections.