Acute lung injury (ALI) is a common, often lethal, complication in the critically ill. We have made the novel observation that febrile range hyperthermia (FRH) exacerbates ALI by greatly increasing recruitment of neutrophils (PMNs) to the lung. By measuring trans-alveolar PMN recruitment in response to intratracheal IL-8, we demonstrated that exposing mice to FRH for 16-24 h increased subsequent IL-8-directed trans-alveolar PMN recruitment 10-23-fold. The priming effect of FRH lasted for >48h and was blocked by inhibitors of ERK and p38. Using a novel adoptive PMN transfer technique, we showed that FRH likely exerts priming effects on both PMNs and the pulmonary vasculature. Our preliminary results demonstrate that exposing mice to FRH increases mRNA levels for some of these molecules in lung (junctional adhesion molecule-A) and circulating leukocytes (CD18). HYPOTHESIS: We propose that FRH modifies endothelium and PMNs to increase CAPACITY for TEM. We postulate a central role for p38 and ERK, regulation of critical adhesion molecule expression, and modification of endothelial and PMN cytoskeleton.
SPECIFIC AIMS : The overall objective of these studies is to understand the mechanisms by which FRH augments PMN-dependent ALI.
In aim 1, we will use our in vivo trans-alveolar PMN recruitment model to fill in gaps in our understanding of the process.
In aims 2 and 3, we will use in vitro and in vivo models to define the molecular events in endothelium and PMNs through which FRH increases CAPACITY for trans-alveolar PMN recruitment, focusing on p38- and ERK-dependent gene activation.

Public Health Relevance

Antipyresis is difficult to achieve in the critically ill and exertional/environmental hyperthermia is often unavoidable. Ablating fever may eliminate its beneficial as well as its harmful effects. A better understanding of its molecular mechanisms will allow us to selectively block the harmful effects of fever/hyperthermia and exploit the beneficial effects.

Public Health Relevance

. Exposure to elevated body temperatures as occurs during fever or heat stroke changes the blood vessels and white blood cells to increase movement of white blood cells from the blood to the lung. During infections this effect can help eliminate bacteria, but it can also cause severe lung injury. Since blocking fever may eliminate its beneficial as well as its harmful effects, a better understanding of how high temperatures cause these changes will allow us to selectively block the harmful effects of fever. The same knowledge will help us develop better therapies to prevent the complications of heat stroke, a growing global health problem.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069057-08
Application #
8102930
Study Section
Special Emphasis Panel (ZRG1-RES-B (04))
Program Officer
Harabin, Andrea L
Project Start
2001-12-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
8
Fiscal Year
2011
Total Cost
$375,000
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
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

Showing the most recent 10 out of 36 publications