title: 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 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-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 heat-shock protein-72-null mice. HSR-mediated decrease in neutrophil phagocytosis (69%) and bacterial killing (38%) by macrophages was interleukin-10 dependent, a mechanism confirmed by increased lung bacterial clearance and decreased mortality (70%) caused by P. aeruginosa pneumonia in heat-shocked interleukin-10-null mice.
  
  
  CONCLUSIONS
  Prior HSR activation worsens lung injury associated with P. aeruginosa pneumonia in mice via heat-shock protein-72- and interleukin-10-dependent mechanisms. These results provide a novel mechanism for the immunosuppression observed after severe trauma that is known to activate HSR in humans.
authors.affiliation: From the Department of Anesthesiology, University of Nice-Sophia-Antipolis, Nice, France (M.C.); French Institute of Health and Medical Research U1065, University of Nice-Sophia-Antipolis, Nice, France (J.-E.R.); Department of Anesthesiology, University of California San Francisco, San Francisco, California (M.L., J.R.); and Departments of Anesthesiology (B.M.W., K.I., D.L., C.A.R., N.A., J.-F.P.), Environmental Health Sciences (K.I.), Surgery (J.-F.P.), Medicine (J.Z.) and Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama (J.-F.P.).
authors.forename: Michel
authors.initials: M
authors.lastname: Carles
authors.forename: Brant M
authors.initials: BM
authors.lastname: Wagener
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lafargue
authors.forename: Jérémie
authors.initials: J
authors.lastname: Roux
authors.forename: Karen
authors.initials: K
authors.lastname: Iles
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Cilina Ann
authors.initials: CA
authors.lastname: Rodriguez
authors.forename: Naseem
authors.initials: N
authors.lastname: Anjum
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Zmijewski
authors.forename: Jean-Ehrland
authors.initials: JE
authors.lastname: Ricci
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Pittet
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D050884:HSP72 Heat-Shock Proteins / Q000502:physiology*; D018869:Heat-Shock Response / Q000276:immunology; D016753:Interleukin-10 / Q000378:metabolism / Q000502:physiology*; D055370:Lung Injury / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011552:Pseudomonas Infections / Q000276:immunology / Q000378:metabolism*; D011550:Pseudomonas aeruginosa; D011897:Random Allocation; D012756:Sheep; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D050884:HSP72 Heat-Shock Proteins; C556062:IL10 protein, mouse; D016753:Interleukin-10