Heat-shock Response Increases Lung Injury Caused by Pseudomonas aeruginosa via an Interleukin-10-dependent Mechanism in Mice

Abstract

Background The heat shock response (HSR) protects from insults, such as ischemia-reperfusion injury, by inhibiting signaling pathways activated by sterile inflammation. However, the mechanisms by which the HSR activation would modulate lung damage and host response to a bacterial lung infection remain unknown. Methods HSR was activated with whole body hyperthermia or by intraperitoneal geldanamycin in mice that had their lungs instilled with Pseudomonas (P.) aeruginosa 24 h later (at least six mice per experimental group). Four hours after instillation, lung endothelial and epithelial permeability, bacterial counts, protein levels in bronchoalveolar lavage fluid and lung myeloperoxidase activity were measured. Mortality rate 24 h after P. aeruginosa instillation was recorded. The HSR effect on the release of interleukin (IL)-10 and killing of P. aeruginosa bacteria by a mouse alveolar macrophage cell line and on neutrophil phagocytosis was also examined. Results HSR activation worsened lung endothelial (42%) and epithelial permeability (50%) to protein, decreased lung bacterial clearance (71%) and increased mortality (50%) associated with P. aeruginosa pneumonia, an effect that was not observed in Hsp72 null mice. HSR-mediated decrease in neutrophil phagocytosis (69%) and bacterial killing (38%) by macrophages was IL-10-dependent, a mechanism confirmed by increased lung bacterial clearance and decreased mortality (70%) caused by P. aeruginosa pneumonia in heat-shocked IL-10 null mice. Conclusions Prior HSR activation worsens lung injury associated with P. aeruginosa pneumonia in mice via Hsp72 and IL-10-dependent mechanisms. These results provide a novel mechanism for the immunosuppression observed after severe trauma that is known to activate HSR in humans.

Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study

“…The mouse pneumonia model was performed as we previously described [ 56 ]. Mice were instilled with P .…”

NLRP3 Inflammasome Mediates Dormant Neutrophil Recruitment following Sterile Lung Injury and Protects against Subsequent Bacterial Pneumonia in Mice

“…These results are in line with the findings of Matthay et al, who in 1989 observed that leukotriene B4 instillation in human volunteer lungs resulted in the recruitment of non-damaging neutrophils ( 49 ). Furthermore, Carles et al reported worsened lung injury from pseudomonal pneumonia when sterile inflammation was dampened through the induction of a heat-shock response ( 50 ). These reports are consistent with our findings that inflammation generated by lung IR can augment the host defensive response against bacterial infection.…”

Hydrocortisone Prevents Immunosuppression by Interleukin-10+ Natural Killer Cells After Trauma-Hemorrhage

“…However, effects of IL-10 on the immune response are highly dependent of the timing and in healthy volunteers challenged with endotoxin, IL-10 displays antiinflammatory properties when it is administered early, but proinflammatory effects when it is injected late (29)(30)(31). Recently, Carles et al (32) demonstrated that heat shock proteins increase the lung injury associated with posttraumatic pneumonia via an IL-10-dependent mechanism. These results are in line with ours because we found an association between high levels of IL-10 after hemorrhage and an overwhelming inflammatory lung response during subsequent pneumonia.…”