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.
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.
|Hasday, Jeffrey D (2017) The author replies. Crit Care Med 45:e1203|
|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|
|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|
|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|
|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|
|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|
|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|
|Netzer, Giora; Dowdy, David W; Harrington, Thelma et al. (2013) Fever is associated with delayed ventilator liberation in acute lung injury. Ann Am Thorac Soc 10:608-15|
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