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Prevention of lymphocyte cell death in sepsis improves survival in mice.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 1999 Dec 07; Vol. 96 (25), pp. 14541-6. - Publication Year :
- 1999
-
Abstract
- Sepsis induces extensive lymphocyte apoptosis, a process which may be beneficial to host survival by down-regulating the inflammatory response or, alternatively, harmful by impairing host defenses. To determine the beneficial vs. adverse effects of lymphocyte apoptosis in sepsis, we blocked lymphocyte apoptosis either by N-benzyloxycarbonyl-Val-Ala-Asp(O-methyl) fluoromethyl ketone (z-VAD), a broad-spectrum caspase inhibitor, or by use of Bcl-2 Ig transgenic mice that selectively overexpress the antiapoptotic protein Bcl-2 in a lymphoid pattern. Both z-VAD and Bcl-2 prevented lymphocyte apoptosis and resulted in a marked improvement in survival. z-VAD did not decrease lymphocyte tumor necrosis factor-alpha production. Considered together, these two studies employing different methods of blocking lymphocyte apoptosis provide compelling evidence that immunodepression resulting from the loss of lymphocytes is a central pathogenic event in sepsis, and they challenge the current paradigm that regards sepsis as a disorder resulting from an uncontrolled inflammatory response. Caspase inhibitors may represent a treatment strategy in this highly lethal disorder.
- Subjects :
- Animals
Base Sequence
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Transgenic
Molecular Sequence Data
Proto-Oncogene Proteins c-bcl-2 analysis
Sepsis immunology
Tumor Necrosis Factor-alpha biosynthesis
Apoptosis drug effects
Caspase Inhibitors
Cysteine Proteinase Inhibitors pharmacology
Lymphocytes physiology
Proto-Oncogene Proteins c-bcl-2 physiology
Sepsis mortality
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 96
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 10588741
- Full Text :
- https://doi.org/10.1073/pnas.96.25.14541