We showed that exposure to febrile range hyperthermia (FRH) markedly accelerates onset and progression of pulmonary oxygen toxicity by augmenting accumulation of neutrophils (PMN) within lung interstitium. FRH activates G-CSF expression, expands the circulating PMN pool, enhances transendothelial migration, and augments generation of the CXC chemokines, KC and LIX, within the hyperoxic lung. Preliminary data suggest that the heat shock response, usually thought to be protective in stressed cells, contributes to the augmented lung injury in the hyperthermic, hyperoxic lung. We hypothesize that the convergence of FRH and hyperoxia causes early and extensive lung injury mediated, in part, by processes that are not activated by either stimulus alone. We will use our hyperoxia-exposed, temperature-controlled mouse model and mouse and human cell culture systems to elucidate the mechanisms underlying the synergism between FRH and hyperoxia in causing lung injury. Specifically, we will: [unreadable] [unreadable] 1) Determine how FRH expands and primes the circulating PMN pool, (years 1-4): identify the source of excess G-CSF in hyperthermic mice and elucidate the molecular mechanisms of its increased expression; analyze the contributions of PMN demargination, increased granulopoiesis, and prolonged PMN survival; and determine whether FRH primes circulating PMN for recruitment and cytotoxicity. [unreadable] [unreadable] 2) Elucidate the mechanisms through which FRH augments PMN delivery to and alters PMN distribution within the hyperoxic lung (years 1-4): identify cellular sources of KC and LIX and elucidate the molecular mechanisms of their increased expression and of the redistribution of PMN to lung interstitium; and determine if FRH inhibits PMN apoptosis, and increases PMN necrosis and cytotoxic granule release. [unreadable] [unreadable] 3) Determine how activation of heat shock in the hyperthermic, hyperoxic lung paradoxically worsens lung injury (years 2-5): determine if generation of intracellular heat shock proteins (HSP) within PMN contribute to shift from PMN apoptosis to necrosis; and whether extracellular HSP-60 or -70 released from injured cells augments lung injury through their TLR4-dependent proinflammatory actions. The proposed studies will provide new insights about the unanticipated consequences of fever in critically ill patients, and expand our knowledge about the mechanisms through which fever modifies the immune response.
NIH ExPorter
NIH ExPorter