Resolution of inflammatory lesions involves removal of apoptotic inflammatory cells by uptake into macrophages and surrounding tissue cells, such as epithelial cells and fibroblasts. We suggest that the engulfment of apoptotic cells is driven by a variety of adhesion ligands acting in conjunction with a critical receptor for phosphatidylserine (the PS receptor or PSR) that actually mediates the signaling for phagocytosis. Ingestion via this receptor also initiates the production of active TGFB1. This mediator then has important effects in limiting further generation of inflammatory mediators and the potential to initiate fibroblast to myofibroblast phenotypic conversion and the process of fibrosis. It is further suggested that cell debris and membrane fragments are removed by similar mechanisms with similar consequences. To explore these suggestions, the clearance of apoptotic cells will be examined for 1) its dependency in PSR upregulation in cells in the inflammatory foci with resultant ingestion of damaged cells and fragments as well as local generation of active TGFB1; 2)its role in TGFB1 synthesis, secretion, and activation; 3) the mechanisms by which it mediates the resolution of inflammation; and 4) for its potential role in mediating progression to fibrosis and initiate myofibroblast conversion via TGFB1 induction. The experiments will be performed in vivo using a murine model of inflammation and fibrosis and will make use of several knock out strains, and whenever possible, in primary macrophages and epithelial cells. The overall objective is to examine in detail one potentially important mechanism for the resolution of pulmonary inflammation and generation of fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL069920-01
Application #
6460305
Study Section
Special Emphasis Panel (ZHL1-CSR-M (F2))
Program Officer
Colombini-Hatch, Sandra
Project Start
2002-07-15
Project End
2007-06-30
Budget Start
2002-07-15
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$131,490
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045