Lung epithelium is critical to normal gas exchange and maintenance of a physical and immu- nologic barrier against environmental dangers. Acute loss of epithelium can have devastating consequences, including loss of gas exchange, surfactant synthesis, airway obstruction, and increased susceptibility to secondary infections. The processes that regulate epithelial cell sur- vival are critical to how lung epithelium responds to acute and chronic environmental challenges with important consequences for lung function and host survival. We have identified new path- ways by which hyperthermia, such as occurs in fever, clinical hyperthermia syndromes and en- vironmental exposures, accelerate apoptosis in lung epithelium and worsen lung injury. The overall objective of this application is to elucidate the mechanisms by which hyperthermia within the febrile range modifies lung epithelial injury and recovery. Our central hypothesis is that ex- posure to hyperthermia concurrent with activation of death receptors (e.g. TNF Receptor- 1/TNFR1 or fas) accelerates assembly of the death inducing signaling complexes, augments downstream pro-apoptotic pathways, and inhibits anti-apoptotic factors. The rationale for our hypothesis is based on our recent studies demonstrating that (1) co-exposure to hyperthermia in the HS (42C) or febrile (39.5C) range greatly increases and accelerates caspase-3 activation and apoptosis in mouse MLE15 lung epithelial cells after TNF treatment or fas activation and is independent of NFB and the major heat activated transcription factor, HSF-1, and (2) there is a limited time window following TNF treatment but not fas activation after which cells are pro- tected from HS-augmented apoptosis (discussed in the Preliminary Data section). We will utilize MLE-15 mouse lung epithelial cells, BEAS2B human lung epithelial cells, and primary cultured human small airway epithelial cells (SAECs), and an in vivo intratracheal LPS-induced mouse ALI model to pursue the following specific aims: (1) determine how hyperthermia alters TNF- and fas-activated death-inducing signaling complexes, their composition, and function and the consequences for cell survival vs. death;(2) delineate the effect of hyperthermia on JNK MAP kinase signaling and the consequences for cells survival vs. death in cells TNF-treated cells;(3) analyze the mechanisms of hyperthermia-enhanced apoptosis in human lung epithelial cells, and (4) analyze the contribution of accelerated epithelial apoptosis to LPS-induced lung injury. We expect that the results of the proposed studies will identify new pathophysiologic pathways that contribute to lung injury under clinically relevant conditions. The pharmacologic studies in aim 4 will provide new preclinical data that may lead to future therapies in patients with ALI.
We have shown that fever and other causes of hyperthermia (elevated body temperature) worsen acute lung injury and increase mortality. We have recently discovered that this effect is caused, at least in part, by accelerating programmed cell death (apoptosis) in lung epithelium. This project is focused on understanding how hyperthermia increases epithelial death and identifying potential targets for preventing cell death that may reduce lung injury. If successful, these studies will help us develop new protocols and drugs that can reduce lung injury during febrile illnesses and heat exposure and better understand the consequences of hyperthermia in multiple settings, including febrile illnesses, heat-stroke, strenuous exercise, Bikram yoga (hot yoga), and during therapeutic hyperthermia for treatment of cancer and muscle injuries.
|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|
|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|
|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|
|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|
|Singh, Ishwar S; Hasday, Jeffrey D (2013) Fever, hyperthermia and the heat shock response. Int J Hyperthermia 29:423-35|
|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|