title: Febrile-range hyperthermia modifies endothelial and neutrophilic functions to promote extravasation.
abstract: Acute respiratory distress syndrome (ARDS) is a neutrophil (polymorphonuclear leukocyte; PMN)-driven lung injury that is associated with fever and heat-stroke, and involves approximately 40% mortality. In murine models of acute lung injury (ALI), febrile-range hyperthermia (FRH) enhanced PMN accumulation, vascular permeability, and epithelial injury, in part by augmenting pulmonary cysteine-x-cysteine (CXC) chemokine expression. To determine whether FRH increases chemokine responsiveness within the lung, we used in vivo and in vitro models that bypass the endogenous generation of chemokines. We measured PMN transalveolar migration (TAM) in mice after intratracheal instillations of the human CXC chemokine IL-8 in vivo, and of IL-8-directed PMN transendothelial migration (TEM) through human lung microvascular endothelial cell (HMVEC-L) monolayers in vitro. Pre-exposure to FRH increased in vivo IL-8-directed PMN TAM by 23.5-fold and in vitro TEM by 7-fold. Adoptive PMN transfer demonstrated that enhanced PMN TAM required both PMN donors and recipients to be exposed to FRH, suggesting interdependent effects on PMNs and endothelium. FRH exposure caused the activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase in lung homogenates and circulating PMNs, with an associated increase in HSP27 phosphorylation and stress-fiber formation. The inhibition of these signaling pathways with U0126 and SB203580 blocked the effects of FRH on PMN extravasation in vivo and in vitro. Collectively, these results (1) demonstrate that FRH augments chemokine-directed PMN extravasation through direct effects on endothelium and PMNs, (2) identify ERK and p38 signaling pathways in the effect, and (3) underscore the complex effects of physiologic temperature change on innate immune function and its potential consequences for lung injury.
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, School of Medicine, University of Maryland, 20 Penn St., Baltimore, MD 21201, USA.
authors.forename: Mohan E
authors.initials: ME
authors.lastname: Tulapurkar
authors.forename: Eid A
authors.initials: EA
authors.lastname: Almutairy
authors.forename: Nirav G
authors.initials: NG
authors.lastname: Shah
authors.forename: Ju-ren
authors.initials: JR
authors.lastname: He
authors.forename: Adam C
authors.initials: AC
authors.lastname: Puche
authors.forename: Paul
authors.initials: P
authors.lastname: Shapiro
authors.forename: Ishwar S
authors.initials: IS
authors.lastname: Singh
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hasday
mesh_terms: D000818:Animals; D004727:Endothelium / Q000473:pathology*; D005334:Fever / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D009504:Neutrophils / Q000473:pathology*