Lipopolysaccharide suppresses IgE-mast cell-mediated reactions.

BACKGROUND: Clinical and experimental analyses have identified a central role for IgE/FcεRI/mast cells in promoting IgE-mediated anaphylaxis. Recent data from human studies suggest that bacterial infections can alter susceptibility to anaphylaxis. OBJECTIVE: We examined the effect of LPS exposure on the induction of IgE-mast cell (MC) mediated reactions in mice. METHODS: C57BL/6 WT, tlr4-/- and IL10-/- mice were exposed to LPS, and serum cytokines (TNF and IL-10) were measured. Mice were subsequently treated with anti-IgE, and the symptoms of passive IgE-mediated anaphylaxis, MC activation, Ca2+ -mobilization and the expression of FcεRI on peritoneal MCs were quantitated. RESULTS: We show that LPS exposure of C57BL/6 WT mice constraints IgE-MC-mediated reactions. LPS-induced suppression of IgE-MC-mediated responses was TLR-4-dependent and associated with increased systemic IL-10 levels, decreased surface expression of FcεRI on MCs and loss of sensitivity to IgE activation. Notably, LPS-induced desensitization of MCs was short term with MC sensitivity to IgE reconstituted within 48 hours, which was associated with recapitulation of FcεRI expression on the MCs. Mechanistic analyses revealed a requirement for IL-10 in LPS-mediated decrease in MC FcεRI surface expression. CONCLUSIONS & CLINICAL RELEVANCE: Collectively, these studies suggest that LPS-induced IL-10 promotes the down-regulation of MC surface FcεRI expression and leads to desensitization of mice to IgE-mediated reactions. These studies indicate that targeting of the LPS-TLR-4-IL-10 pathway may be used as a therapeutic approach to prevent adverse IgE-mediated reactions.

Prediction and assessment of the severity of post-operative pain and of satisfaction with management.

A prospective observational study of cohorts of patients undergoing hip replacement (30), knee replacement (31), and spinal nerve root decompressive surgery (30) were interviewed pre-operatively to identify factors which might correlate with and potentially predict severe post-operative pain and dissatisfaction with analgesic management. The hip patients comprised 33% females and averaged 64 years, while the knee patients were 45% female and older (mean 71 years) and the spinal patients were 43% female and averaged 50 years. The three groups were similar with respect to all other pre-operative variables. Pain intensity was assessed mainly by self-report using the Present Pain Intensity (PPI) and Visual Analogue Scales (VAS) of the McGill Pain Questionnaire. The PPI was preferred by patients and nurses and, as there were no analytical advantages for the VAS, the PPI data are presented. The average post-operative pain during routine management mainly with patient controlled intravenous opiate, was mild to moderate and declined over days 1-5, declined further at discharge but rose slightly 1 month after discharge. The hip replacement patients experienced significantly (P < 0.01) less pain overall than the patients in the other two groups. Nurses' assessments of pain severity from observed behaviour were low and agreed poorly with the patients' self reports. Assessed on Likert Scales (0-6), the patients generally indicated good or excellent pain control, better than expected pain experience, and high levels of satisfaction with analgesic management. Significant (P < or = 0.01) multivariate correlates of severe post-operative pain assessed by logistic regression analysis of 11 variables were female gender, high pre-operative pain severity, and younger age. Significant (P < or = 0.01) multivariate correlates of both worse than expected pain experience and low satisfaction were female gender, high pre-operative pain severity, high anxiety about risks and problems, low expected pain severity, age (younger) and high willingness to report pain. These variables may reasonably be tested in further studies as potential predictors of adverse post-operative pain experience.