In critical care and trauma patients, dysregulated neutrophil (PMN) chemotaxis contributes to sepsis and multi-organ failure. The underlying mechanisms are only partially understood, which is a major hurdle in the search for effective therapeutic interventions that improve the treatment of sepsis and critical care patients. Chemotaxis is a complex process that allows PMNs to locate and eliminate invading bacteria. Dysfunctional chemotaxis impairs not only host defense but can also contribute to collateral host tissue damage. Our previous work has demonstrated that PMN chemotaxis requires autocrine purinergic signaling mechanisms that involve localized release of cellular ATP at the leading edge and complex pull-push mechanisms that involve different purinergic receptor subtypes at the front and back of cells. Recently we found that rapid activation of mitochondrial ATP formation triggers these purinergic signaling mechanisms. In addition, we found that sepsis is accompanied by the release of systemic ATP, which interferes with the autocrine purinergic navigation systems of PMNs. Based on this evidence, we hypothesize that therapeutic strategies that support mitochondrial ATP production or eliminate the interfering effects of systemic ATP will improve PMN chemotaxis and host defense and that clinical strategies based on these concepts may sooner or later diminish morbidity and mortality in critically care, sepsis, and trauma patients.
Specific Aim 1. Mechanisms that regulate PMN chemotaxis: We will study the mechanisms that regulate the production of ATP which fuels autocrine purinergic signaling at the front and back of cells. Special emphasis will be placed on mTOR and AMPK and their roles in regulating mitochondrial function.
Specific Aim 2. Impaired PMN chemotaxis in patients: We will study how oxygen and glucose supply and systemic ATP affect PMN chemotaxis and we will investigate how these factors contribute to impaired PMN chemotaxis in critically care patients. Specifically, we will test how these variables affect mitochondrial function and PMN chemotaxis in ICU patients.
Specific Aim 3. Therapeutic strategies to restore PMN chemotaxis and host defense: Finally, we will use a mouse sepsis model to test novel therapeutic strategies to improve PMN chemotaxis and host defenses. We will focus on approaches that improve mitochondrial ATP production and reduce the disruptive influence of systemic ATP levels on PMN chemotaxis in other functional responses. We anticipate that our findings will advance scientific knowledge of the mechanisms by which PMN chemotaxis is regulated and that this knowledge will reveal novel therapeutic strategies that may ultimately lead to improvements in the care of trauma, sepsis, and critical patients.

Public Health Relevance

Trauma and sepsis cause excessive neutrophil activation and impair neutrophil chemotaxis. We discovered that mitochondria fuels purinergic signaling mechanisms that regulate neutrophil activation and chemotaxis and that trauma and sepsis disrupt these regulatory mechanisms. In this project, we will study these mechanisms and test the potential of novel therapeutic strategies to support mitochondrial ATP function and restore proper PMN chemotaxis in order to improve outcome in trauma, sepsis, and critical care patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM116162-06S1
Application #
9275758
Study Section
Program Officer
Somers, Scott D
Project Start
2009-06-15
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Sumi, Yuka; Ledderose, Carola; Li, Linglin et al. (2018) Plasma Adenylate Levels are Elevated in Cardiopulmonary Arrest Patients and May Predict Mortality. Shock :
Lee, Albert H; Ledderose, Carola; Li, Xiaoou et al. (2018) Adenosine Triphosphate Release is Required for Toll-Like Receptor-Induced Monocyte/Macrophage Activation, Inflammasome Signaling, Interleukin-1? Production, and the Host Immune Response to Infection. Crit Care Med 46:e1183-e1189
Ledderose, Carola; Liu, Kaifeng; Kondo, Yutaka et al. (2018) Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration. J Clin Invest 128:3583-3594
Li, Xiaoou; Kondo, Yutaka; Bao, Yi et al. (2017) Systemic Adenosine Triphosphate Impairs Neutrophil Chemotaxis and Host Defense in Sepsis. Crit Care Med 45:e97-e104
Ledderose, Carola; Bao, Yi; Kondo, Yutaka et al. (2016) Purinergic Signaling and the Immune Response in Sepsis: A Review. Clin Ther 38:1054-65
Ledderose, Carola; Bao, Yi; Ledderose, Stephan et al. (2016) Mitochondrial Dysfunction, Depleted Purinergic Signaling, and Defective T Cell Vigilance and Immune Defense. J Infect Dis 213:456-64
Chen, Yu; Bao, Yi; Zhang, Jingping et al. (2015) Inhibition of Neutrophils by Hypertonic Saline Involves Pannexin-1, CD39, CD73, and Other Ectonucleotidases. Shock 44:221-7
Ledderose, C; Bao, Y; Zhang, J et al. (2015) Novel method for real-time monitoring of ATP release reveals multiple phases of autocrine purinergic signalling during immune cell activation. Acta Physiol (Oxf) 213:334-45
Bao, Yi; Ledderose, Carola; Graf, Amelie F et al. (2015) mTOR and differential activation of mitochondria orchestrate neutrophil chemotaxis. J Cell Biol 210:1153-64
Bao, Yi; Ledderose, Carola; Seier, Thomas et al. (2014) Mitochondria regulate neutrophil activation by generating ATP for autocrine purinergic signaling. J Biol Chem 289:26794-803

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