Neutrophil activation and trauma - Neutrophils (PMN) cause the systemic inflammatory response (SIRS) and multi-organ failure syndromes (MOFS) that damage host tissues. Approaches to block PMN can reduce SIRS and MOFS, but detailed knowledge of the mechanisms involved in PMN activation is still missing. The purpose of this proposal is to continue our work elucidating these mechanisms. Over the last several years, our research has revealed that hypertonic saline (HS) resuscitation can markedly suppress PMN activation. We identified that ATP release and autocrine signaling via purinergic receptors is the underlying molecular mecha- nism by which HS can suppress but also enhance PMN responses. An unexpected finding of our work has been that ATP release and autocrine purinergic signaling is a much more fundamental mechanism that is re- quired for PMN activation in general. We discovered that PMN require two separate signals for appropriate cell activation: (1) qualitative signals through receptors that recognize specific extracellular danger mediators, and (2) quantitative signals, generated by autocrine purinergic signaling, that regulate subsequent cellular re- sponses. Based on these important findings and our exciting preliminary data, we hypothesize that trauma influences the autocrine signaling system of PMN in several ways, which leads to excessive PMN activation, SIRS, and MOFS. The release of large amounts of ATP from damaged tissues disrupts the autocrine puriner- gic signaling system of PMN. Trauma changes purinergic receptor expression and distort PMN responses, re- sulting in inflammation, SIRS, MOFS, and sepsis. Modulating purinergic signaling can prevent this progression.
Specific Aim 1) Autocrine purinergic regulation of PMN: We will deepen our understanding of the autocrine purinergic signaling mechanisms that regulate PMN by studying upstream pathways leading to ATP release, mechanisms of ATP release and conversion of ATP to adenosine, and the roles of all puriner- gic receptors expressed by PMN.
Specific Aim 2) Effect of sepsis on purinergic signaling of PMN: We will study how septic shock influences the autocrine purinergic signaling system of PMN for example by changing the expression of purinergic re- ceptors and overloading the autocrine purinergic system of PMN by ATP that is released from injured and in- flamed tissues.
Specific Aim 3) Purinergic signaling as a therapeutic target: Finally, we will evaluate the feasibility of tar- geting purinergic signalin to improve outcome after sepsis. We anticipate that the proposed work will lead to entirely novel therapeutic strategies to block PMN activation and reduce SIRS and MOFS in critically ill patients.

Public Health Relevance

Neutrophil activation and trauma - We have discovered that ATP release and autocrine signaling via purinergic receptors are fundamental processes required for neutrophil (PMN) activation. However, large quantities of ATP are also released from damaged tissues in response to major injury, inflammation, and sepsis. Our data show that this additional ATP overloads the autocrine purinergic signaling system of PMN, resulting in excessive PMN activation and aggravated host organ damage. We propose to fully define the autocrine purinergic signaling mechanisms that regulate PMN, how these mechanisms are affected in critically ill patients, and how novel therapeutic strategies targeting purinergic signaling can be used to prevent PMN activation, inflammation, organ damage, and sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060475-11
Application #
8601091
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2001-02-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
11
Fiscal Year
2014
Total Cost
$458,055
Indirect Cost
$194,805
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Weihs, Anna M; Fuchs, Christiane; Teuschl, Andreas H et al. (2014) Shock wave treatment enhances cell proliferation and improves wound healing by ATP release-coupled extracellular signal-regulated kinase (ERK) activation. J Biol Chem 289:27090-104
Ledderose, Carola; Bao, Yi; Lidicky, Markus et al. (2014) Mitochondria are gate-keepers of T cell function by producing the ATP that drives purinergic signaling. J Biol Chem 289:25936-45
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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Bao, Yi; Chen, Yu; Ledderose, Carola et al. (2013) Pannexin 1 channels link chemoattractant receptor signaling to local excitation and global inhibition responses at the front and back of polarized neutrophils. J Biol Chem 288:22650-7
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Junger, Wolfgang G (2011) Immune cell regulation by autocrine purinergic signalling. Nat Rev Immunol 11:201-12
Inoue, Yoshiaki; Tanaka, Hiroshi; Sumi, Yuka et al. (2011) A3 adenosine receptor inhibition improves the efficacy of hypertonic saline resuscitation. Shock 35:178-83

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