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Departments of
*
Anesthesiology,
Pathology,
Laboratory Medicine,
§
Surgery, and
¶
Medicine, and the Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110
In sepsis there is extensive apoptosis of lymphocytes, which may be
beneficial by down-regulating the accompanying inflammation.
Alternatively, apoptosis may be detrimental by impairing host defense.
We studied whether Bcl-2, a potent antiapoptotic protein, could prevent
lymphocyte apoptosis in a clinically relevant model of sepsis.
Transgenic mice in which Bcl-2 was overexpressed in T cells had
complete protection against sepsis-induced T lymphocyte apoptosis in
thymus and spleen. Surprisingly, there was also a decrease in splenic B
cell apoptosis in septic Bcl-2 overexpressors compared with septic HeJ
and HeOuJ mice. There were marked increases in TNF-
, IL-1ß, and
IL-10 in thymic tissue in sepsis in the three species of mice, and the
increase in TNF-
and IL-10 in HeOuJ mice was greater than that in
Bcl-2 mice. Mitotracker, a mitochondrial membrane potential indicator,
demonstrated a sepsis-induced loss of membrane potential in T cells in
HeJ and HeOuJ mice but not in Bcl-2 mice. Importantly, Bcl-2
overexpressors also had improved survival in sepsis. To investigate the
potential impact of loss of lymphocytes on survival in sepsis,
Rag-1-/- mice, which are totally deficient in mature T
and B cells, were also studied. Rag-1-/- mice had
decreased survival compared with immunologically normal mice with
sepsis. We conclude that overexpression of Bcl-2 provides protection
against cell death in sepsis. Lymphocyte death may be detrimental in
sepsis by compromising host defense.
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K. Kurosaka, N. Watanabe, and Y. Kobayashi Potentiation by human serum of anti-inflammatory cytokine production by human macrophages in response to apoptotic cells J. Leukoc. Biol., June 1, 2002; 71(6): 950 - 956. [Abstract] [Full Text] [PDF] |
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R. S. Hotchkiss, K. W. Tinsley, P. E. Swanson, M. H. Grayson, D. F. Osborne, T. H. Wagner, J. P. Cobb, C. Coopersmith, and I. E. Karl Depletion of Dendritic Cells, But Not Macrophages, in Patients with Sepsis J. Immunol., March 1, 2002; 168(5): 2493 - 2500. [Abstract] [Full Text] [PDF] |
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R. S. Hotchkiss, W. M. Dunne, P. E. Swanson, C. G. Davis, K. W. Tinsley, K. C. Chang, T. G. Buchman, I. E. Karl, H. Grassme, S. Kirschnek, et al. Role of Apoptosis in Pseudomonas aeruginosa Pneumonia Science, November 30, 2001; 294(5548): 1783a - 1783. [Full Text] [PDF] |
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D. G. Mordue, F. Monroy, M. La Regina, C. A. Dinarello, and L. D. Sibley Acute Toxoplasmosis Leads to Lethal Overproduction of Th1 Cytokines J. Immunol., October 15, 2001; 167(8): 4574 - 4584. [Abstract] [Full Text] [PDF] |
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C. Oberholzer, A. Oberholzer, F. R. Bahjat, R. M. Minter, C. L. Tannahill, A. Abouhamze, D. LaFace, B. Hutchins, M. J. Clare-Salzler, and L. L. Moldawer Targeted adenovirus-induced expression of IL-10 decreases thymic apoptosis and improves survival in murine sepsis PNAS, September 5, 2001; (2001) 181338198. [Abstract] [Full Text] [PDF] |
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C. ADRIE, M. BACHELET, M. VAYSSIER-TAUSSAT, F. RUSSO-MARIE, I. BOUCHAERT, M. ADIB-CONQUY, J.-M. CAVAILLON, M. R. PINSKY, J.-F. DHAINAUT, and B. S. POLLA Mitochondrial Membrane Potential and Apoptosis Peripheral Blood Monocytes in Severe Human Sepsis Am. J. Respir. Crit. Care Med., August 1, 2001; 164(3): 389 - 395. [Abstract] [Full Text] [PDF] |
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R. S. Hotchkiss, K. W. Tinsley, P. E. Swanson, R. E. Schmieg Jr., J. J. Hui, K. C. Chang, D. F. Osborne, B. D. Freeman, J. P. Cobb, T. G. Buchman, et al. Sepsis-Induced Apoptosis Causes Progressive Profound Depletion of B and CD4+ T Lymphocytes in Humans J. Immunol., June 1, 2001; 166(11): 6952 - 6963. [Abstract] [Full Text] [PDF] |
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C.-S. Chung, W. Wang, I. H. Chaudry, and A. Ayala Increased apoptosis in lamina propria B cells during polymicrobial sepsis is FasL but not endotoxin mediated Am J Physiol Gastrointest Liver Physiol, May 1, 2001; 280(5): G812 - G818. [Abstract] [Full Text] [PDF] |
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S. J. Ebong, S. M. Goyert, J. A. Nemzek, J. Kim, G. L. Bolgos, and D. G. Remick Critical Role of CD14 for Production of Proinflammatory Cytokines and Cytokine Inhibitors during Sepsis with Failure To Alter Morbidity or Mortality Infect. Immun., April 1, 2001; 69(4): 2099 - 2106. [Abstract] [Full Text] [PDF] |
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C. OBERHOLZER, A. OBERHOLZER, M. CLARE-SALZLER, and L. L. MOLDAWER Apoptosis in sepsis: a new target for therapeutic exploration FASEB J, April 1, 2001; 15(6): 879 - 892. [Abstract] [Full Text] [PDF] |
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A. O. Tzianabos Polysaccharide Immunomodulators as Therapeutic Agents: Structural Aspects and Biologic Function Clin. Microbiol. Rev., October 1, 2000; 13(4): 523 - 533. [Abstract] [Full Text] [PDF] |
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R. S. Hotchkiss, K. W. Tinsley, J.-J. Hui, K. C. Chang, P. E. Swanson, A. M. Drewry, T. G. Buchman, and I. E. Karl p53-Dependent and -Independent Pathways of Apoptotic Cell Death in Sepsis J. Immunol., April 1, 2000; 164(7): 3675 - 3680. [Abstract] [Full Text] [PDF] |
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R. S. Hotchkiss, K. W. Tinsley, P. E. Swanson, K. C. Chang, J. P. Cobb, T. G. Buchman, S. J. Korsmeyer, and I. E. Karl Prevention of lymphocyte cell death in sepsis improves survival in mice PNAS, December 7, 1999; 96(25): 14541 - 14546. [Abstract] [Full Text] [PDF] |
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G. Bilbao, J. L. Contreras, H.-G. Zhang, M. J. Pike, K. Overturf, G. Mikheeva, V. Krasnykh, and D. T. Curiel Adenovirus-Mediated Gene Expression In Vivo Is Enhanced by the Antiapoptotic Bcl-2 Gene J. Virol., August 1, 1999; 73(8): 6992 - 7000. [Abstract] [Full Text] |
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C. Oberholzer, A. Oberholzer, F. R. Bahjat, R. M. Minter, C. L. Tannahill, A. Abouhamze, D. LaFace, B. Hutchins, M. J. Clare-Salzler, and L. L. Moldawer Targeted adenovirus-induced expression of IL-10 decreases thymic apoptosis and improves survival in murine sepsis PNAS, September 25, 2001; 98(20): 11503 - 11508. [Abstract] [Full Text] [PDF] |
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