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: ? ? 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. ? ? 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. ? ? 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069057-02
Application #
6706994
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Harabin, Andrea L
Project Start
2003-03-01
Project End
2007-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
2
Fiscal Year
2004
Total Cost
$371,250
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Potla, Ratnakar; Tulapurkar, Mohan E; Luzina, Irina G et al. (2018) Exposure to febrile-range hyperthermia potentiates Wnt signalling and epithelial-mesenchymal transition gene expression in lung epithelium. Int J Hyperthermia 34:1-10
Slack, Donald F; Corwin, Douglas S; Shah, Nirav G et al. (2017) Pilot Feasibility Study of Therapeutic Hypothermia for Moderate to Severe Acute Respiratory Distress Syndrome. Crit Care Med 45:1152-1159
Shah, Nirav G; Tulapurkar, Mohan E; Ramarathnam, Aparna et al. (2017) Novel Noncatalytic Substrate-Selective p38?-Specific MAPK Inhibitors with Endothelial-Stabilizing and Anti-Inflammatory Activity. J Immunol 198:3296-3306
Hasday, Jeffrey D (2017) The author replies. Crit Care Med 45:e1203
Scheraga, Rachel G; Thompson, Christopher; Tulapurkar, Mohan E et al. (2016) Activation of heat shock response augments fibroblast growth factor-1 expression in wounded lung epithelium. Am J Physiol Lung Cell Mol Physiol 311:L941-L955
Potla, Ratnakar; Singh, Ishwar S; Atamas, Sergei P et al. (2015) Shifts in temperature within the physiologic range modify strand-specific expression of select human microRNAs. RNA 21:1261-73
Tulapurkar, Mohan E; Ramarathnam, Aparna; Hasday, Jeffrey D et al. (2015) Bacterial lipopolysaccharide augments febrile-range hyperthermia-induced heat shock protein 70 expression and extracellular release in human THP1 cells. PLoS One 10:e0118010
Roche, Joseph A; Tulapurkar, Mohan E; Mueller, Amber L et al. (2015) Myofiber damage precedes macrophage infiltration after in vivo injury in dysferlin-deficient A/J mouse skeletal muscle. Am J Pathol 185:1686-98
Bridges, Tiffany M; Scheraga, Rachel G; Tulapurkar, Mohan E et al. (2015) Polymorphisms in human heat shock factor-1 and analysis of potential biological consequences. Cell Stress Chaperones 20:47-59
Hasday, Jeffrey D; Thompson, Christopher; Singh, Ishwar S (2014) Fever, immunity, and molecular adaptations. Compr Physiol 4:109-48

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