The hypothesis guiding this study is that microvascular endothelial cell (MVEC) apoptosis plays a key role in the pathophysiology of idiopathic and HIV-associated thrombotic thrombocytopenic purpura (TTP). It is also proposed that apoptosis is initiated by plasma factors up regulated in HIV and certain other infections, particularly soluble tumor necrosis factor-related ligand (TRAIL). It is furthermore proposed that these factors lead to alterations in MVEC-extracellular matrix (ECM) interactions and production of cytokines and vasoactive substances such as nitric oxide, all critical to MVEC survival. These concepts are supported by observations that: plasmas from HIV+ and HIV- patients with idiopathic and ticlopidine-linked TTP induce apoptosis in restricted lineages of MVEC, paralleling the EC tissue restriction of TTP lesions in vivo; plasma from patients with TTP or hemolytic-uremic syndromes related to cancer, marrow transplantation or other drugs, diseases distinct pathologically from idiopathic TTP, do not have these effects in vitro; apoptotic MVEC are present in splenic and marrow biopsies of idiopathic, HIV, and ticlopidine-linked TTP, accompanied by down regulation of ECM; and ticlopidine and HIV can directly affect ECM deposition and/or production. An additional recent finding is that MVEC-soluble HIV gp120-monocyte interactions up regulate TRAIL, TRAIL receptors, capsases 1 and 3, and suppress bcl-2-related molecules. Up regulation of bcl-2, anti-TRAIL antibody, or over expression of TRAIL decoys blocked TTP plasma-mediated apoptosis. The underlying hypothesis provides a basis for the clinical efficacy of anti-apoptotic agents and the nitric oxide precursor L-arginine in pilot trials for refractory TTP. The model presented could also enable exploration of new therapeutic modalities for TTP, based upon modulation of specific apoptotic pathways.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055646-06
Application #
6389542
Study Section
Pathology A Study Section (PTHA)
Program Officer
Ganguly, Pankaj
Project Start
1995-08-01
Project End
2005-07-31
Budget Start
2001-08-16
Budget End
2002-07-31
Support Year
6
Fiscal Year
2001
Total Cost
$339,000
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Yin, M T; Modarresi, R; Shane, E et al. (2011) Effects of HIV infection and antiretroviral therapy with ritonavir on induction of osteoclast-like cells in postmenopausal women. Osteoporos Int 22:1459-68
Modarresi, Rozbeh; Xiang, Zhaoying; Yin, Michael et al. (2009) WNT/beta-catenin signaling is involved in regulation of osteoclast differentiation by human immunodeficiency virus protease inhibitor ritonavir: relationship to human immunodeficiency virus-linked bone mineral loss. Am J Pathol 174:123-35
Saxena, Brij B; Han, Young A; Fu, Dingyi et al. (2009) Sustained release of microbicides by newly engineered vaginal rings. AIDS 23:917-22
Stefanescu, Radu; Bassett, Dustin; Modarresi, Rozbeh et al. (2008) Synergistic interactions between interferon-gamma and TRAIL modulate c-FLIP in endothelial cells, mediating their lineage-specific sensitivity to thrombotic thrombocytopenic purpura plasma-associated apoptosis. Blood 112:340-9
Fakruddin, J M; Laurence, J (2005) HIV-1 Vpr enhances production of receptor of activated NF-kappaB ligand (RANKL) via potentiation of glucocorticoid receptor activity. Arch Virol 150:67-78
Fakruddin, J M; Laurence, J (2004) Interactions among human immunodeficiency virus (HIV)-1, interferon-gamma and receptor of activated NF-kappa B ligand (RANKL): implications for HIV pathogenesis. Clin Exp Immunol 137:538-45
Mauro, Michael; Zlatopolskiy, Andrey; Raife, Thomas J et al. (2004) Thienopyridine-linked thrombotic microangiopathy: association with endothelial cell apoptosis and activation of MAP kinase signalling cascades. Br J Haematol 124:200-10
Laurence, Jeffrey (2003) Repetitive and consistent cervicovaginal exposure to certain viral pathogens appears to protect against their sexual acquisition in some women: potential mechanisms. J Reprod Immunol 58:79-91
Kim, J; Wu, H; Hawthorne, L et al. (2001) Endothelial cell apoptotic genes associated with the pathogenesis of thrombotic microangiopathies: an application of oligonucleotide genechip technology. Microvasc Res 62:83-93
Mauro, M; Kim, J; Costello, C et al. (2001) Role of transforming growth factor beta1 in microvascular endothelial cell apoptosis associated with thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. Am J Hematol 66:12-22

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