title: Febrile-range hyperthermia augments pulmonary neutrophil recruitment and amplifies pulmonary oxygen toxicity.
abstract: Febrile-range hyperthermia (FRH) improves survival in experimental infections by accelerating pathogen clearance, but may also increase collateral tissue injury. We hypothesized that FRH would worsen the outcome of inflammation stimulated by a non-replicating agonist and tested this hypothesis in a murine model of pulmonary oxygen toxicity. Using a conscious, temperature-controlled mouse model, we showed that maintaining a core temperature at FRH (39 degrees C to 40 degrees C) rather than at euthermic levels (36.5 degrees C to 37 degrees C) during hyperoxia exposure accelerated lethal pulmonary vascular endothelial injury, reduced the inspired oxygen threshold for lethality, induced expression of granulocyte-colony stimulating factor, and expanded the circulating neutrophil pool. In these same mice, FRH augmented pulmonary expression of the ELR(+) CXC chemokines, KC and LPS-induced CXC chemokine, enhanced recruitment of neutrophils, and changed the histological pattern of lung injury to a neutrophilic interstitial pneumonitis. Immunoblockade of CXC receptor-2 abrogated neutrophil recruitment, reduced pulmonary vascular injury, and delayed death. These combined data demonstrate that FRH may enlist distinct mediators and effector cells to profoundly shift the host response to a defined injurious stimulus, in part by augmenting delivery of neutrophils to sites of inflammation, such as may occur in infections. In certain conditions, such as in the hyperoxic lung, this process may be deleterious.
authors.affiliation: Divisions of Pulmonary and Critical Care Medicine, Department of Pathology, University of Maryland, Baltimore, Maryland 21201, USA. jhasday@umaryland.edu
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hasday
authors.forename: Allen
authors.initials: A
authors.lastname: Garrison
authors.forename: Ishwar S
authors.initials: IS
authors.lastname: Singh
authors.forename: Theodore
authors.initials: T
authors.lastname: Standiford
authors.forename: Garrettson S
authors.initials: GS
authors.lastname: Ellis
authors.forename: Srinivas
authors.initials: S
authors.lastname: Rao
authors.forename: Ju-Ren
authors.initials: JR
authors.lastname: He
authors.forename: Penny
authors.initials: P
authors.lastname: Rice
authors.forename: Mariah
authors.initials: M
authors.lastname: Frank
authors.forename: Simeon E
authors.initials: SE
authors.lastname: Goldblum
authors.forename: Rose M
authors.initials: RM
authors.lastname: Viscardi
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001831:Body Temperature; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D018496:Hyperoxia / Q000503:physiopathology*; D006979:Hyperthermia, Induced / Q000009:adverse effects*; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology / Q000473:pathology*; D017563:Lung Diseases, Interstitial / Q000209:etiology* / Q000276:immunology / Q000401:mortality; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000473:pathology; D015996:Survival Rate; D013997:Time Factors
chemical_list: D016207:Cytokines