Abstract

and specific aims): Apoptosis is a process that is widespread in nature and leads to non-necrotic cell removal during tissue remodeling. It involves a number of active cell processes including characteristic DNA fragmentation, morphologic alterations and surface changes that can be recognized by phagocytic cell, especially macrophages, leading to engulfment. Uptake and removal of apoptotic cells has been suggested to be involved in resolution of inflammation: the engulfment occurs prior to inflammatory cell lysis and is postulated not to lead to the normal pro-inflammatory sequelae of macrophage phagocytosis. Three main areas will be investigated: 1) The utilization by macrophages of different receptors for apoptotic cells will be examined in vitro and in pulmonary inflammation, as well as the outcome of inflammatory lesions in which such recognition and removal is inhibited. 2) The selective inability of macrophages to respond to uptake of apoptotic cells by elaboration of cytokines and other mediators of inflammation will be examined, testing the hypothesis that TGFb production actively inhibits the generation of other mediators and manifestations of macrophage activation. 3) The mechanisms by which the phospholipid membrane asymmetry is lost and PS is expressed during apoptosis will be explored.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM048211-06
Application #
2701576
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1993-05-01
Project End
2001-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206

  Publications

Gardai, Shyra J; McPhillips, Kathleen A; Frasch, S Courtney et al. (2005) Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:321-34
Gardai, Shyra J; Xiao, Yi-Qun; Dickinson, Matthew et al. (2003) By binding SIRPalpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Cell 115:13-23
Vandivier, R William; Fadok, Valerie A; Hoffmann, Peter R et al. (2002) Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. J Clin Invest 109:661-70
Vandivier, R William; Ogden, Carol Anne; Fadok, Valerie A et al. (2002) Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex. J Immunol 169:3978-86
Fadok, V A; de Cathelineau A; Daleke, D L et al. (2001) Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibroblasts. J Biol Chem 276:1071-7
Fadok, V A; Bratton, D L; Guthrie, L et al. (2001) Differential effects of apoptotic versus lysed cells on macrophage production of cytokines: role of proteases. J Immunol 166:6847-54
Ogden, C A; deCathelineau, A; Hoffmann, P R et al. (2001) C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med 194:781-95
Frasch, S C; Henson, P M; Kailey, J M et al. (2000) Regulation of phospholipid scramblase activity during apoptosis and cell activation by protein kinase Cdelta. J Biol Chem 275:23065-73
Whitlock, B B; Gardai, S; Fadok, V et al. (2000) Differential roles for alpha(M)beta(2) integrin clustering or activation in the control of apoptosis via regulation of akt and ERK survival mechanisms. J Cell Biol 151:1305-20
McDonald, P P; Fadok, V A; Bratton, D et al. (1999) Transcriptional and translational regulation of inflammatory mediator production by endogenous TGF-beta in macrophages that have ingested apoptotic cells. J Immunol 163:6164-72

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