This is a competitive renewal application to extend ongoing research by the co-Principal Investigators that is focused on the effects of fever and fever suppression on acute lung injury (ALI). Despite the general acceptance of low tidal volume ventilation for support of patients with ALI, mortality in such patients remains ~40%. We identified fever/hyperthermia as another potentially important contributor to ARDS pathogenesis. Fever is reported to occur in about half of patients admitted to intensive care units and in up to 90% of those with ALI/ARDS. ARDS is characterized by neutrophil-rich inflammation, loss of endothelial barrier, and epithelial injury. Our previous studies show that exposure to hyperthermia in the febrile range (FRH, ~39.5oC) profoundly augments each of these pathogenic processes. The current application proposes a mechanistic study that focuses on the role of p38 mitogen-activated protein kinase (MAPK)-dependent mechanisms of FRH- augmented ALI. We have shown that exposure to FRH augments innate immune function in part by enhancing neutrophil (PMN) recruitment. This effect accelerates pathogen clearance, but also increases collateral tissue injury, especially in the lung. Based on new data, this proposal focuses on the central role of pulmonary vascular endothelium and the stress-activated MAPK, p38. Preliminary data suggests that (1) FRH directly activates p38 at least in part through autophosphorylation and (2) that FRH directly alters p38 conformation, kinase activity, cellular localization, and substrate selectivity. This proposal will test the following hypotheses: (1) FRH activates p38 through multiple pathways including through a conformational change in p38 that facilitates its autophosphorylation and by activating upstream kinases;(2) the FRH-induced conformational changes in p38 will result in distinct patterns of p38 intermolecular docking, subcellular distribution, and downstream signaling events, which will uniquely modify downstream substrate phosphorylation patterns with important consequences for lung inflammation and injury;and (3) in the patient with ALI and fever, inhibition of p38 or downstream signaling pathways will improve outcome better than suppressing fever. We will use primary cultured HMVEC- Ls and mouse models of ALI to: (1) elucidate the molecular mechanisms by which FRH activates p38, (2) analyze how FRH modifies p38 subcellular distribution and substrate phosphorylation profile, and (3) test the potential of p38 signaling pathway blockade to reduce FRH-augmented lung injury without impairing pathogen clearance. We expect that the results of these studies will clarify the mechanisms of FRH-induced p38 signaling relevant to ALI and provide essential information about disproportionate substrate phosphorylation that will identify alternative therapeutic targets to test in ALI/ARDS. We expect that these findings will have wider applications in mitigating inflammation and injury in other tissues as well.

Public Health Relevance

We have shown that fever and other causes of hyperthermia (elevated body temperature) worsen acute lung injury and increase mortality and have recently discovered that an important signaling pathway, p38 MAPK, plays an important role in these effects. The objectives of this project are to understand how hyperthermia activates p38 and develop therapies for lung injury that target hyperthermia-specific pathways leading to p38 activation and downstream signaling events. If successful, these studies will help us develop new protocols that can reduce organ injury during febrile illnesses and heat stroke and better understand the consequences of hyperthermia in multiple settings, including febrile illnesses, heat-stroke, Bikram yoga (hot yoga), and therapeutic hyperthermia for treatment of cancer and muscle injuries.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL069057-10
Application #
8690132
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Harabin, Andrea L
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Hasday, Jeffrey D; Thompson, Christopher; Singh, Ishwar S (2014) Fever, immunity, and molecular adaptations. Compr Physiol 4:109-48
Gupta, Aditi; Cooper, Zachary A; Tulapurkar, Mohan E et al. (2013) Toll-like receptor agonists and febrile range hyperthermia synergize to induce heat shock protein 70 expression and extracellular release. J Biol Chem 288:2756-66
Singh, Ishwar S; Hasday, Jeffrey D (2013) Fever, hyperthermia and the heat shock response. Int J Hyperthermia 29:423-35
Tulapurkar, Mohan E; Almutairy, Eid A; Shah, Nirav G et al. (2012) Febrile-range hyperthermia modifies endothelial and neutrophilic functions to promote extravasation. Am J Respir Cell Mol Biol 46:807-14
Hasday, Jeffrey D; Shah, Nirav; Mackowiak, Phillip A et al. (2011) Fever, hyperthermia, and the lung: it's all about context and timing. Trans Am Clin Climatol Assoc 122:34-47
Maity, Tapan K; Henry, Michael M; Tulapurkar, Mohan E et al. (2011) Distinct, gene-specific effect of heat shock on heat shock factor-1 recruitment and gene expression of CXC chemokine genes. Cytokine 54:61-7
Tulapurkar, Mohan E; Hasday, Jeffrey D; Singh, Ishwar S (2011) Prolonged exposure to hyperthermic stress augments neutrophil recruitment to lung during the post-exposure recovery period. Int J Hyperthermia 27:717-25
Sareh, Houtan; Tulapurkar, Mohan E; Shah, Nirav G et al. (2011) Response of mice to continuous 5-day passive hyperthermia resembles human heat acclimation. Cell Stress Chaperones 16:297-307
Greenberg, Rachel S; Chen, Hegang; Hasday, Jeffrey D (2010) Acetaminophen has limited antipyretic activity in critically ill patients. J Crit Care 25:363.e1-7
Shah, Nirav G; Tulapurkar, Mohan E; Singh, Ishwar S et al. (2010) Prostaglandin E2 potentiates heat shock-induced heat shock protein 72 expression in A549 cells. Prostaglandins Other Lipid Mediat 93:1-7

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