21st ESICM Annual Congress

INTRODUCTION.Host infection by pathogens triggers an innate immune response leading to a systemic inflammatory response, often followed by an immune dysfunction which can favour the emergence of secondary infections.Dendritic cells (DCs) have a unique ability to link innate and adaptive immunity and may be centrally involved in the regulation of sepsis-induced immune suppression.We previously reported that polymicrobial sepsis durably affects the functions of DCs and confers long-term susceptibility to P. aeruginosa pneumonia.In this study, we assessed the contribution of DCs to lung defence towards secondary P. aeruginosa pneumonia. METHODS.We used a murine model of sublethal polymicrobial sepsis through cecal ligature and puncture (CLP).In this model, a short course of antibiotics and volume resuscitation allows long-term survival of 70% of mice.Eight days after CLP, we induced a secondary pneumonia through intratracheal instillation of P. aeruginosa (serotype PAO1) in post-septic mice.Bone marrow-derived DCs (BMDCs) were generated through 7-day culture of medullar progenitors in medium supplemented with GM-CSF.Concomitant to bacterial inoculation, we intratracheally administrated exogenous BMDCs into post-septic mice.Bacterial lung clearance was evaluated through quantitative culture of bronchoalveolar lavage (BAL) fluid.The lung response was assessed 4 and 24 hours after instillation through quantification of protein level, inflammatory cells, myeloperoxydase (MPO) activity and cytokine levels in the BAL fluid.RESULTS.After intratracheal instillation of 5x10 6 CFUs of P. aeruginosa, all sham-operated mice survived while post-septic mice displayed high susceptibility with a 80-percent mortality rate.As compared to sham-operated mice, post-septic mice displayed marked lung damage with early recruitment of neutrophils, cytokine imbalance with decreased IL-12p70 production and increased IL-10 release, but no defective bacterial lung clearance.Co-administration of 10 6 exogenous BMDCs into post-septic mice challenged with P. aeruginosa dramatically improved the survival rate to 70%.Intratracheal instillation of BMDCs did not improve bacterial clearance, but delayed neutrophil recruitment and subsequently reduced the MPO activity in BAL fluid.In addition, BMDCs strongly attenuated the early peak of TNF-alpha and restored a positive Il-12p70/IL-10 balance.CONCLUSION.Adoptive transfer of BMDCs reverses sepsis-induced immune suppression in a relevant model of secondary P. aeruginosa pneumonia.Unexpectedly, the mechanism of action of BMDCs did not involve enhanced antibacterial activity, but occurred by dampening the pulmonary inflammatory response.

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