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Inhaling hydrogen sulfide (H2S) reduced energy expenditure resulting in hypothermia. Because the inflammatory effects of either hypothermia alone or H2S per se still are a matter of debate, we tested the hypothesis whether inhaled H2S amplifies the hypothermia-related modulation of the inflammatory response. Fifteen hours after cecal ligation and puncture or sham laparotomy, anesthetized and mechanically ventilated normothermic and hypothermic mice (core temperature kept at 38°C and 27°C, respectively) received either 100 ppm H2S or vehicle. In the sham-operated animals, inhaled H2S and hypothermia alone comparably reduced the plasma chemokine and IL-6 levels, but combining hypothermia and inhaled H2S had no additional effect. The lung tissue cytokine and chemokine patterns revealed a similar response. During sepsis, inhaled H2S reduced the blood cytokine concentrations only, without effects on the plasma chemokine or the lung tissue levels. Again, inhaled H2S had no major additional effect during hypothermia. With or without sepsis, inhaled H2S and hypothermia alone comparably reduced the lung tissue heme oxygenase 1 expression, whereas inhaled H2S had no additional effect during hypothermia. Lung tissue nuclear transcription factor κB activation was reduced by combining H2S with hypothermia in the sham-operated animals, whereas it was increased by inhaled H2S during sepsis. Hypothermia amplified this response. Hence, during anesthesia and mechanical ventilation, inhaled H2S exerted anti-inflammatory effects, which were, however, not amplified by adding deliberate hypothermia. Sepsis attenuated these anti-inflammatory effects of inhaled H2S, which were at least in part independent of the nuclear transcription factor κB pathway.

Activation of NF-κB is known to prevent apoptosis but may also act as proapoptotic factor in order to eliminate inflammatory cells. Here, we show that classical NF-κB activation in RAW 264.7 and bone marrow-derived macrophages upon short E. coil coculture is necessary to promote cell death at late time points. At 48 hours subsequent to short-term, E. coli challenge increased survival of NF-κB-suppressed macrophages was associated with pattern of autophagy whereas macrophages with normal NF-κB signalling die. Cell death of normal macrophages was indicated by preceding downregulation of autophagy associated genes atg5 and bedin1. Restimulation of macrophages with LPS at 48 hours after E. coil treatment results in augmented proinflammatory cytokine production in NF-κB-suppressed macrophages compared to control cells. We thus demonstrate that classical NF-κB activation inhibits autophagy and promotes delayed programmed cell death. This mechanism is likely to prevent the recovery of inflammatory cells and thus contributes to the resolution of inflammation. [ABSTRACT FROM AUTHOR]