title: Febrile-range hyperthermia augments neutrophil accumulation and enhances lung injury in experimental gram-negative bacterial pneumonia.
abstract: We previously demonstrated that exposure to febrile-range hyperthermia (FRH) accelerates pathogen clearance and increases survival in murine experimental Klebsiella pneumoniae peritonitis. However, FRH accelerates lethal lung injury in a mouse model of pulmonary oxygen toxicity, suggesting that the lung may be particularly susceptible to injurious effects of FRH. In the present study, we tested the hypothesis that, in contrast with the salutary effect of FRH in Gram-negative peritonitis, FRH would be detrimental in multilobar Gram-negative pneumonia. Using a conscious, temperature-clamped mouse model and intratracheal inoculation with K. pneumoniae Caroli strain, we showed that FRH tended to reduce survival despite reducing the 3 day-postinoculation pulmonary pathogen burden by 400-fold. We showed that antibiotic treatment rescued the euthermic mice, but did not reduce lethality in the FRH mice. Using an intratracheal bacterial endotoxin LPS challenge model, we found that the reduced survival in FRH-treated mice was accompanied by increased pulmonary vascular endothelial injury, enhanced pulmonary accumulation of neutrophils, increased levels of IL-1beta, MIP-2/CXCL213, GM-CSF, and KC/CXCL1 in the bronchoalveolar lavage fluid, and bronchiolar epithelial necrosis. These results suggest that FRH enhances innate host defense against infection, in part, by augmenting polymorphonuclear cell delivery to the site of infection. The ultimate effect of FRH is determined by the balance between accelerated pathogen clearance and collateral tissue injury, which is determined, in part, by the site of infection.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Penelope
authors.initials: P
authors.lastname: Rice
authors.forename: Erica
authors.initials: E
authors.lastname: Martin
authors.forename: Ju-Ren
authors.initials: JR
authors.lastname: He
authors.forename: Mariah
authors.initials: M
authors.lastname: Frank
authors.forename: Louis
authors.initials: L
authors.lastname: DeTolla
authors.forename: Lisa
authors.initials: L
authors.lastname: Hester
authors.forename: Timothy
authors.initials: T
authors.lastname: O'Neill
authors.forename: Cheu
authors.initials: C
authors.lastname: Manka
authors.forename: Ivor
authors.initials: I
authors.lastname: Benjamin
authors.forename: Ashish
authors.initials: A
authors.lastname: Nagarsekar
authors.forename: Ishwar
authors.initials: I
authors.lastname: Singh
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hasday
mesh_terms: D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005334:Fever / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis; D007710:Klebsiella Infections / Q000276:immunology* / Q000473:pathology; D007711:Klebsiella pneumoniae / Q000472:pathogenicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D055370:Lung Injury; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha