In response to inflammatory stimuli, neutrophils (PMN) remodel cell membranes to generate bioactive lipid-derived signals that serve as intra- or extracellular mediators for the transduction of functional responses. We recently identified polyisoprenyl phosphates (PIPP) as novel, intracellular counter- regulatory signals in PMN. One of these PIPP's, presqualene diphosphate (PSDP), is present in unstimulated cells and, upon cell stimulation, undergoes rapid dephosphorylation with a reciprocal increase in its monophosphate form, PSMP, PSDP, but not PSMP or closely related compounds, inhibits agonist-induced superoxide anion generation and phospholipase D (PLD). Here, the proposed experiments will test the hypothesis that polyisoprenyl phosphates are novel intracellular signals that counteract processes initiated by phosphoinositide signaling. The scientific community has become accustomed to thinking of receptor-ligand interacts as leading to the rapid elaboration of pro-inflammatory intracellular signals, such as phosphoinositol biphosphate (PIP2) and phosphoinositol trisphosphate (PIPS). It is also possible that counter-regulatory lipid signals (e.g., PSDP) are held at a set point in resting cells to provide regulated negative signaling that is rapidly decreased upon cell stimulation. This new paradigm would introduce the notion that inflammatory responses may result, in part, from the release of biochemical """"""""brakes"""""""" rather than activation of biochemical """"""""accelerators."""""""" To test our hypothesis, we propose three specific aims: 1. determine the key domains and residues in PLD responsible for inhibition by PSDP. 2. determine the relationship between PIPP and phosphoinositide turnover during human PMN stimulation, and 3. elucidate a novel phosphatase responsible for PIPP remodeling during PMN stimulation. From my clinical training as a pulmonologist, I became acutely aware of our incomplete understanding of the pathobiology of pulmonary inflammation. As a new investigator, I am firmly committed to the pursuit of pivotal regulatory mechanisms for pulmonary inflammation. The long-term objectives are two-fold: (i) identify a basis for new interventional strategies that promote resolution of inflammatory responses and (ii) elucidate the role of lipid mediators in respiratory diseases of elderly individuals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068669-03
Application #
6682329
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Croxton, Thomas
Project Start
2001-12-10
Project End
2006-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
3
Fiscal Year
2004
Total Cost
$302,750
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Abdulnour, R E; Sham, H P; Douda, D N et al. (2016) Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation. Mucosal Immunol 9:1278-87
Awji, Elias G; Chand, Hitendra; Bruse, Shannon et al. (2015) Wood smoke enhances cigarette smoke-induced inflammation by inducing the aryl hydrocarbon receptor repressor in airway epithelial cells. Am J Respir Cell Mol Biol 52:377-86
Karra, L; Haworth, O; Priluck, R et al. (2015) Lipoxin B? promotes the resolution of allergic inflammation in the upper and lower airways of mice. Mucosal Immunol 8:852-62
Doyle, Jamie R; Krishnaji, Subrahmanian T; Zhu, Guangli et al. (2014) Development of a membrane-anchored chemerin receptor agonist as a novel modulator of allergic airway inflammation and neuropathic pain. J Biol Chem 289:13385-96
Levy, Bruce D; Serhan, Charles N (2014) Resolution of acute inflammation in the lung. Annu Rev Physiol 76:467-92
Abdulnour, Raja-Elie E; Dalli, Jesmond; Colby, Jennifer K et al. (2014) Maresin 1 biosynthesis during platelet-neutrophil interactions is organ-protective. Proc Natl Acad Sci U S A 111:16526-31
Serhan, Charles N; Chiang, Nan; Dalli, Jesmond et al. (2014) Lipid mediators in the resolution of inflammation. Cold Spring Harb Perspect Biol 7:a016311
Li, Chenggang; Lee, Po-Shun; Sun, Yang et al. (2014) Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. J Exp Med 211:15-28
Sagliani, Kristen D; Dolnikowski, Gregory G; Hill, Nicholas S et al. (2013) Differences between basal lung levels of select eicosanoids in rat and mouse. Pulm Circ 3:82-8
Eickmeier, O; Seki, H; Haworth, O et al. (2013) Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury. Mucosal Immunol 6:256-66

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