Prevention of lymphocyte cell death in sepsis improves survival in mice.

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.

[1]  R. Hotchkiss,et al.  Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. , 1999, Critical care medicine.

[2]  S. Korsmeyer,et al.  Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. , 1999, Journal of immunology.

[3]  J. Lederer,et al.  The effects of injury on the adaptive immune response. , 1999, Shock.

[4]  J. Cleveland,et al.  Neuroprotection by a caspase inhibitor in acute bacterial meningitis , 1999, Nature Medicine.

[5]  G. Bernard Research in sepsis and acute respiratory distress syndrome: are we changing course? , 1999, Critical Care Medicine.

[6]  S. Nasraway Sepsis research: we must change course. , 1999, Critical care medicine.

[7]  P. Auberger,et al.  A caspase inhibitor fully protects rats against lethal normothermic liver ischemia by inhibition of liver apoptosis , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  N. Thornberry,et al.  Inhibition of Human Caspases by Peptide-based and Macromolecular Inhibitors* , 1998, The Journal of Biological Chemistry.

[9]  Y. Lazebnik,et al.  Caspases: enemies within. , 1998, Science.

[10]  Z. Wang,et al.  Autocrine and paracrine apoptosis are mediated by differential regulation of Fas ligand activity in two distinct Jurkat T cell populations. , 1998, Journal of immunology.

[11]  S. Garg,et al.  Exogenous interleukin-10 fails to decrease the mortality or morbidity of sepsis. , 1998, Critical care medicine.

[12]  Huiling He,et al.  Apoptosis induction by the glucocorticoid hormone dexamethasone and the calcium-ATPase inhibitor thapsigargin involves Bc1-2 regulated caspase activation , 1998, Molecular and Cellular Endocrinology.

[13]  M. Moskowitz,et al.  Attenuation of Delayed Neuronal Death after Mild Focal Ischemia in Mice by Inhibition of the Caspase Family , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[14]  E. Deitch ANIMAL MODELS OF SEPSIS AND SHOCK: A REVIEW AND LESSONS LEARNED , 1998, Shock.

[15]  R. Hotchkiss,et al.  Apoptosis in lymphoid and parenchymal cells during sepsis: findings in normal and T- and B-cell-deficient mice. , 1997, Critical care medicine.

[16]  John Calvin Reed Double identity for proteins of the Bcl-2 family , 1997, Nature.

[17]  K. Asadullah,et al.  Monocyte deactivation in septic patients: Restoration by IFN-γ treatment , 1997, Nature Medicine.

[18]  Guido Kroemer,et al.  The proto-oncogene Bcl-2 and its role in regulating apoptosis , 1997, Nature Medicine.

[19]  T. Kay,et al.  Lymphocytopenia in a hospital population--what does it signify? , 1997, Australian and New Zealand journal of medicine.

[20]  G. Evan,et al.  15 Methods for Detecting and Quantifying Apoptosis , 1997 .

[21]  P. Henkart,et al.  Different Interleukin-1β Converting Enzyme (ICE) Family Protease Requirements for the Apoptotic Death of T Lymphocytes Triggered by Diverse Stimuli , 1996, The Journal of experimental medicine.

[22]  S. Nagata,et al.  Systemic injection of a tripeptide inhibits the intracellular activation of CPP32-like proteases in vivo and fully protects mice against Fas-mediated fulminant liver destruction and death , 1996, The Journal of experimental medicine.

[23]  R. Bone,et al.  Sir Isaac Newton, sepsis, SIRS, and CARS. , 1996, Critical care medicine.

[24]  I. Chaudry,et al.  Differential induction of apoptosis in lymphoid tissues during sepsis: variation in onset, frequency, and the nature of the mediators. , 1996, Blood.

[25]  P. Amiri,et al.  Requirement of an ICE-Like Protease for Induction of Apoptosis and Ceramide Generation by REAPER , 1996, Science.

[26]  Patrick R. Griffin,et al.  Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis , 1995, Nature.

[27]  I. Chaudry,et al.  THE INDUCTION OF ACCELERATED THYMIC PROGRAMMED CELL DEATH DURING POLYMICROBIAL SEPSIS: CONTROL BY CORTICOSTEROIDS BUT NOT TUMOR NECROSIS FACTOR , 1995, Shock.

[28]  Y. S. Lin,et al.  Sepsis-induced apoptosis of the thymocytes in mice. , 1994, Journal of immunology.

[29]  R. Stone Search for sepsis drugs goes on despite past failures. , 1994, Science.

[30]  J. L. Rodriguez,et al.  Lymphocyte subset responses to trauma and sepsis. , 1993, The Journal of trauma.

[31]  J. Palmer,et al.  The effects of fluoromethyl ketone inhibitors of cathepsin B on adjuvant induced arthritis. , 1993, The Journal of rheumatology.

[32]  Suzanne Cory,et al.  bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship , 1991, Cell.

[33]  S. Korsmeyer,et al.  bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes , 1991, Cell.

[34]  S. Korsmeyer,et al.  bcl-2-Immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation , 1989, Cell.

[35]  C. Fathman,et al.  Enhanced cell-mediated protection against fatal Escherichia coli septicemia induced by treatment with recombinant IL-2. , 1989, Journal of immunology.