Abstract
BackgroundLethal B. anthracis infection produces high proinflammatory peptidoglycan (PGN) burdens in hosts. We investigated whether the lethality and inflammation anthrax PGN can produce are related.MethodsAt 6 h before and the start of 24 h anthrax PGN infusions, rats (n = 198) were treated with diluent (controls) or one of three IV-doses of either hydrocortisone (125, 12.5 or 1.25 mg/kg) or TNF-soluble receptor (TNFsr; 2000, 1000 or 333 μg/kg), non-selective and selective anti-inflammatory agents, respectively.ResultsCompared to controls, hydrocortisone 125 and 12.5 mg/kg each decreased 7-day lethality (p ≤ 0.004). Hydrocortisone 125 mg/kg decreased IL-1β, IL-6, TNFα, MCP, MIP-1α, MIP-2, RANTES and nitric oxide (NO) blood levels at 4 and 24 h after starting PGN (except MCP at 24 h). Each decrease was significant at 4 h (except MIP-1α that was significant at 24 h) (p ≤ 0.05). Similarly, hydrocortisone 12.5 mg/kg decreased each measure at 4, 24 and 48 h (except TNFα at 24 h and MIP-1α at 24 and 48 h and NO at 48 h). Decreases were significant for IL-6 and NO at 4 h and RANTES at 48 h (p ≤ 0.05). Hydrocortisone 1.25 mg/kg had non-significant effects. Each TNFsr dose decreased lethality but non-significantly. However, when doses were analyzed together, TNFsr decreased lethality in a potential trend (p = 0.16) and IL-6 and NO significantly at 4 h (p = 0.05).ConclusionsPeptidoglycan-stimulated host inflammation may contribute to B. anthracis lethality.
Highlights
Outbreaks and isolated cases of Bacillus anthracis (B. anthracis) infection in the UnitedStates and Europe over the past 15 years and this bacterium’s weaponization potential, have raised persistent concerns [1–3]
Increasing evidence suggests that the B. anthracis cell wall and its peptidoglycan (PGN) component may contribute to shock and lethality with this bacterium, in part by stimulating maladaptive inflammatory responses [5, 9]
Excessive inflammation is implicated in the pathogenesis of cell wall components from other bacteria, it may be more important during B. anthracis infection which produces exceptionally high bacteria burdens in blood and tissue and provides a potentially large PGN reservoir [17–19]
Summary
Animal care This study was approved by the Animal Care and Use Committee of the Clinical Center of the National Institutes of Health, protocol #ASP CCM 1801. Weekly experiment, animals were randomized to receive the dose of anti-inflammatory agent being studied (n = 4 to 6) or diluent (control, n = 4 to 6) administered 6 h before (T-6) and at the time the PGN infusion was started (T0). Following preparation of each PGN batch, a survival dose response study was performed, and the PGN dose producing a lethality rate of 40 to 80% was employed in subsequent experiments. This dose was found to be 80 mg/kg administered at 3.3 mg/kg/h for 24 h for all experiments.
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