While neutrophil (PMN) recruitment and activation are crucial for lung host defense against microbes (e.g. fungi. Project 1) they also contribute to potential injury (e.g. ozone, Project 3). Once infection is contained or sterilized, signals to both suppress PMN recruitment and enhance removal are essential for proper resolution of inflammation and restoration of tissue function. Loss of such controls likely contributes to chronic lung inflammation, permanent damage (e.g. emphysema) and/or abnormal tissue repair (e.g. fibrosis). Evidence suggests that recruited PMNs usually die by apoptosis, and are removed by macrophage (MO) in situ. PMN removal, before disintegration, prevents release of phlogistic intracellular constituents. Ordinarily, few apoptotic PMNs are evident suggesting that removal is highly efficient, however, defects in PMN clearance are described in chronic lung disease (e.g. COPD, CF and severe asthma). The """"""""turn off'of PMN recruitment and the """"""""turn on"""""""" of PMN removal normally occur in a highly orchestrated manner though the signals are not well understood. It is hypothesized that the novel phospholipid lysophosphatidylserine (lyso-PS) signals for both enhanced PMN removal and suppression of production of mediators for PMN recruitment. Mechanistically, it is hypothesized that activation of the NADPH oxidase in recruited PMNs results in robust production of lyso-PS detected by innovative mass spectrometry techniques. Lyso-PS displayed on the activated PMN surface signals to MO via the G-protein coupled receptor G2A for the activation of cPL{A}2 and prostanoid production. In turn, adenyl cyclase, PKA and Raci are activated resulting in high capacity engulfment of activated and dying PMNs and suppression of pro-inflammatory mediator production. Additionally, MO produce lyso-PS by alternative mechanisms amplifying the signal in an autocrine/paracrine manner.
The specific aims are to 1) determine the pathways of production of lyso-PS in human and murine PMNs and MO during acute inflammation, 2) define the mechanisms and consequences of lyso-PS signaling in the resolution of neutrophilia, and 3) to enhance resolution of inflammation by deliberately supplying lyso-PS in a murine model of acute lung inflammation. Investigation of lyso-PS production, signaling and biological consequences in vitro and in vivo under normal conditions and during disrupted or deficient signaling will define the role of this novel lipid in the fundamental control of neutrophilia. As such, these studies will contribute significantly to the definition of strategies applicable to disease states where PMNs and impaired removal of apoptotic cells are implicated in dysregulated lung inflammation.

Public Health Relevance

While activated neutrophils are crucial to lung defense against microbes, they also damage tissues. It is hypothesized that the novel lipid, lyso-PS, made in activated neutrophils signals to lung macrophage in an orchestrated fashion for efficient neutrophil removal and suppression of recruitment mediators. Investigation of lyso-PS production and signaling will help to define strategies applicable to chronic inflammation where uncontrolled neutrophil activation and impaired removal are implicated (e.g. COPD, CF and severe asthma).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL034303-27
Application #
8374545
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
27
Fiscal Year
2012
Total Cost
$289,385
Indirect Cost
$69,868
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
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