Authors:
Address: Division of Pulmonary and Critical Care, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States.
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abstract

Acute Respiratory Distress Syndrome (ARDS) is a Neutrophil (PMN)-driven lung injury that is associated with fever and heat-stroke and has ~40% mortality. In mouse models of acute lung injury (ALI), Febrile-range Hyperthermia (FRH) enhanced PMN accumulation, vascular permeability, and epithelial injury, in part by augmenting pulmonary CXC chemokine expression. To determine whether FRH increases chemokine responsiveness within the lung, we utilized in vivo and in vitro models that bypass endogenous chemokine generation. We measured PMN transalveolar migration (TAM) in mice after intratracheal instillation of the human CXC chemokine IL-8 in vivo and 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 activation of ERK and p38 mitogen-activated protein kinase in lung homogenates and circulating PMNs with associated increase in HSP27 phosphorylation and stress fiber formation and 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) identifies ERK and p38 signaling pathways in the effect, and (3) underscores the complex effects of physiologic temperature change on innate immune function and the potential consequences for lung injury.

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