ABSTRACT
Hypoxia and bacterial infection frequently co-exist, in both acute and chronic clinical settings, and typically result in adverse clinical outcomes. To ameliorate this morbidity, we investigated the interaction between hypoxia and the host response. In the context of acute hypoxia, both S. aureus and S. pneumoniae infections rapidly induced progressive neutrophil mediated morbidity and mortality, with associated hypothermia and cardiovascular compromise. Preconditioning animals through longer exposures to hypoxia, prior to infection, prevented these pathophysiological responses and profoundly dampened the transcriptome of circulating leukocytes. Specifically, perturbation of HIF pathway and glycolysis genes by hypoxic preconditioning was associated with reduced leukocyte glucose utilisation, resulting in systemic rescue from a global negative energy state and myocardial protection. Thus we demonstrate that hypoxia preconditions the innate immune response and determines survival outcomes following bacterial infection through suppression of HIF-1α and neutrophil metabolism. The therapeutic implications of this work are that in the context of systemic or tissue hypoxia therapies that target the host response could improve infection associated morbidity and mortality.
ABSTRACT
BACKGROUND: Acute mountain sickness may be caused by cerebrovascular fluid leakage due to oxidative damage to the endothelium. This may be reduced by oral antioxidant supplementation. AIM: To assess the effectiveness of antioxidant supplementation for the prevention of acute mountain sickness (AMS). DESIGN: A parallel-group double blind, randomized placebo-controlled trial. METHODS: The study was conducted in a university clinical research facility and a high altitude research laboratory. Eighty-three healthy lowland volunteers ascended to 5200 m on the Apex 2 high altitude research expedition. The treatment group received a daily dose of 1 g l-ascorbic acid, 400 IU of alpha-tocopherol acetate and 600 mg of alpha-lipoic acid (Cultech Ltd., Wales, UK) in four divided doses. Prevalence of AMS was measured using the Lake Louise Consensus score sheet (LLS). Secondary outcomes were AMS severity measured using a novel visual analogue scale, arterial oxygen saturation and pulmonary artery systolic pressure (PASP). RESULTS: Forty-one subjects were allocated to the antioxidant group, and 42 to the placebo group. There was no difference in AMS incidence or severity between the antioxidant and placebo groups using the LLS at any time at high altitude. At the pre-determined comparison point at Day 2 at 5200 m, 69% of the antioxidant group (25/36) and 66% of the placebo group (23/35) had AMS using the LLS criteria (P = 0.74). No differences were observed between the groups for PASP, oxygen saturation, presence of a pericardial effusion or AMS assessed by VAS. CONCLUSION: This trial found no evidence of benefit from antioxidant supplementation at high altitude. TRIAL REGISTRATION NUMBER: NCT00664001.
