RESUMEN
During an infection, innate immune cells must adjust nature and strength of their responses to changing pathogen abundances. To determine how stimulation of the pathogen sensing TLR4 shapes subsequent macrophage responses, we systematically varied priming and restimulation concentrations of its ligand KLA. We find that different priming strengths have very distinct effects at multiple stages of the signaling response, including receptor internalization, MAPK activation, cytokine and chemokine production, and nuclear translocation and chromatin association of NFκB and IκB members. In particular, restimulation-induced TNF-α production required KLA doses equal to or greater than those used for prior exposure, indicating that macrophages can detect and adaptively respond to changing TLR4 stimuli. Interestingly, while such adaptation was dependent on the anti-inflammatory cytokine IL-10, exogenous concentrations of IL-10 corresponding to those secreted after strong priming did not exert suppressive effects on TNF-α without such prior priming, confirming the critical role of TLR4 stimulation history.
RESUMEN
On the basis of the impulse diagrams of various weapons and many audiometric tests, the CHABA impulse-noise damage-risk criteria (DRC) are compared with those of the Federal Republic of Germany. Both DRC indicate maximum permissible exposures in terms of peak-pressure level and of effective duration. Both DRC aim to protect 95% of the exposed population from permanent auditory damage. The computation of the effective duration differs between the CHABA DRC and the German DRC, and it generally results in a longer effective duration for CHABA. The current study is based on the results for more than 10 000 soldiers, who were audiometrically tested in a mobile monitoring station before firing practice and beginning 2 min after exposure until complete recovery. In a special study, it was possible to compare the results for 478 German soldiers and to evaluate the relative value of the CHABA DRC and the German DRC. This comparison showed that the CHABA DRC are too restrictive, permitting unnecessary "less maximum permissible load" than the German DRC. Moreover, owing to the large variability in TTS2, measurement of the whole recovery time beginning 2 min after exposure has a greater predictive value. Therefore, recovery time should be used in the evaluation of the DRC.