Diffuse alveolar damage (DAD) is a common, often lethal complication in the critically ill. The mechanisms underlying DAD are incompletely understood and the strategies to prevent and treat it are suboptimal. Fever is an ancient and conserved response, which augments neutrophil recruitment and accelerates pathogen clearance, but worsens tissue injury, especially in the lung. Prolonged exposure to febrile-range hyperthermia (FRH) increases activation of several genes that promote neutrophil recruitment and activation, including the ELR+ CXC chemokines, interleukin (IL)-8, and granulocyte-macrophage colony stimulating factor (GM-CSF) as well as increasing responsiveness to a preformed IL-8 gradient in vivo. Exposure to FRH activates the heat shock (HS) response in vivo and the p38 and ERK stress kinase pathways in vitro leading to activation of the transcription factors heat shock factor-1 (HSF1), ATF2, and Elk- 1. Most of the genes for the cytokines involved in neutrophil recruitment, including the family of ELR+ CXC chemokines and their common receptor, CXCR2, and GM-CSF have binding sites for these transcription factors within their promoters. Whereas HS increases IL-8 generation when accompanied by another proinflammatory stimulus, it is not sufficient to activate IL-8 expression. HYPOTHESIS: We propose that FRH increases neutrophil delivery by increasing expression of ELR+ CXC chemokines and GM-CSF, and enhancing neutrophil CXCR2 expression and chemotaxis potential through the actions of HSF1, p38->ATF2, and ERK->Elk-1.
SPECIFIC AIMS :
Aim #1 will delineate the role of HSF1 and ERK in augmenting IL-8 transcription in HS-exposed cells.
Aim #2 will determine how IL-8 translation bypasses the robust translational repression exerted by HS.
Aim #3 will extend the IL-8 analysis to evaluate the contributions of HSF1, p38, and ERK in regulating CXC chemokines and GM-CSF in vitro and in the mouse intratracheal LPS challenge model of diffuse bacterial pneumonia and analyze how FRH increases neutrophil responsiveness to FRH.
Antipyresis is difficult to achieve in the critically ill and exertional/environmental hyperthermia is often unavoidable. Ablating fever may eliminate its beneficial as well as its harmful effects. We expect that a better understanding of its molecular mechanisms will allow us to selectively block the harmful effects of fever/hyperthermia. ? ? ?
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