In vitro the lethal factor component of B. anthracis LeTx inactivated mitogen-activated protein kinases and inhibited TNF alpha and NO release in response to LPS and IFN gamma. Whether these anti-inflammatory effects are relevant to the pathogenicity of B. anthracis infection is not known. If they are however, we hypothesized that sublethal doses of LeTx might also have anti-inflammatory effects in vivo during lethal LPS challenge. In experiments, 3 hours before a 24 hour infusion with LPS, Sprague-Dawley rats with venous and arterial catheters were randomized to receive injections of low, medium, or high sublethal doses of LeTx or diluent only. During LPS infusion, mean arterial blood pressure (MAP) (q1h) and plasma cytokines (IL-1 alpha and beta, IL-2, 4, 6, and 10, IFN gamma, TNF alpha, GM-CSF, MIP1,2 and 3 alpha, and RANTES) and NO levels (2, 8, and 24 hours) were measured. Animals were observed for 168 hours. Compared to high doses of LeTx, medium and low doses caused decreases in the hazards ratio of survival approaching significance (p=0.08 for high vs low and medium doses combined). Compared to diluent only, LeTx decreased 10 of 12 cytokines at 2 hours (none significantly), all 13 cytokines, 4 of them significantly or approaching it (IL-6, IL-10, IFN alpha, MIP2 gamma, p less than 0.08) at 8 hours, and NO levels significantly from 2 to 24 hours (p=0.02 for the effect of LeTx across time) and increased MAP significantly over the 24 hours (p=0.001). Thus, consistent with in vitro data, sublethal LeTx decreased cytokine and NO levels in LPS challenged rats. This was associated with increased blood pressure and, with low and medium doses, beneficial survival trends. Whether these same anti-inflammatory effects with LeTx would be beneficial or instead impair host defense during bacterial infection has been studied in rats challenged with intrabronchial E. coli. As with LPS challenge, LeTx pretreatment decreased cytokine levels. However, with E. coli, this was associated with worsened survival. Reduced lung lavage leukocyte counts suggests that LeTx may have altered host defense. This work has been presented in abstract Am J Respir Crit Care Med. 2005; 171: A39. A manuscript has been submitted for review.
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