TY - JOUR
T1 - Apoptosis in lymphoid and parenchymal cells during sepsis
T2 - Findings in normal and T- and B-celldeficient mice
AU - Hotchkiss, Richard S.
AU - Swanson, Paul E.
AU - Cobb, J. Perren
AU - Jacobson, Allyson
AU - Buchman, Timothy G.
AU - Karl, Irene E.
PY - 1997/8
Y1 - 1997/8
N2 - Objectives: To determine if apoptosis (programmed cell death) occurs systemically in lymphoid and parenchymal cells during sepsis. To examine the potential role of T and B cells in the apoptotic process using knockout mice deficient in mature T and B lymphocytes. Design: Prospective, randomized, controlled trial. Setting: Animal laboratory in a university medical setting. Interventions: Cecal ligation and puncture (CLP) (n = 34) or sham surgery (n = 13) was performed in female ND4 mice and, 15 to 22 hrs postoperatively, thymus, lung, heart, spleen, ileum, colon, liver, kidney, brain, and muscle were obtained and examined for apoptosis. A second group of mice (Rag-1) which are totally deficient in mature T and B cells also underwent CLP (n = 14) or sham surgery (n= 14) and had examination of tissues for apoptosis. Measurements and Main Results: Four methods with varying sensitivities and specificities were used to detect apoptosis, including: a) DNA agarose gel electrophoresis; b) terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL); c) electron microscopy; and d) light microscopy. In CLP mice, multiple methods demonstrated apoptosis in lymphocytes in thymus, spleen, ileum, colon, lung, and skeletal muscle. In addition to lymphocytes, parenchymal cells in ileum, colon, lung, and to a lesser extent, in skeletal muscle and kidney were apoptotic in CLP mice. There was no evidence of apoptosis by any method of detection in liver, brain, or heart. Results in Rag-1 mice which aredeficient in T and B cells demonstrated extensive apoptosis in thymus, spleen, and ileum with less degrees of apoptosis in colon and lung. Both lymphoid cells and parenchymal cells were apoptotic. Rag-1 mice which underwent CLP did not die prematurely and there were no apparent observable differences in the physical response (tachypnea, piloerection, lethargy, etc), or intra-abdominal bowel inflammtion/adhesions compared with CLP mice with normal T and S cells. Conclusions: Apoptosis is an important mechanism of cell death in lymphocytes and parenchymal cells in sepsis and occurs systemically in many organs. Apoptosis may be an important cause of immunologic suppression in sepsis by inducing widespread lympbocyte depletion. Alternately, apoptosis may be beneficial to host survival by down- regulating the inflammatory response which accompanies sepsis. The degree to which parenchymal cell apoptosis is contributing to multiple organ failure cannot be determined from the present study. Findings in Rag-1 mice demonstrate that mature T and B cells and their secretory products are not necessary for apoptosis to occur during sepsis and that apoptotic cell death is not restricted to T or B cells. Apoptosis may be a key regulator of the balance between the pro-and anti-inflammatory process.
AB - Objectives: To determine if apoptosis (programmed cell death) occurs systemically in lymphoid and parenchymal cells during sepsis. To examine the potential role of T and B cells in the apoptotic process using knockout mice deficient in mature T and B lymphocytes. Design: Prospective, randomized, controlled trial. Setting: Animal laboratory in a university medical setting. Interventions: Cecal ligation and puncture (CLP) (n = 34) or sham surgery (n = 13) was performed in female ND4 mice and, 15 to 22 hrs postoperatively, thymus, lung, heart, spleen, ileum, colon, liver, kidney, brain, and muscle were obtained and examined for apoptosis. A second group of mice (Rag-1) which are totally deficient in mature T and B cells also underwent CLP (n = 14) or sham surgery (n= 14) and had examination of tissues for apoptosis. Measurements and Main Results: Four methods with varying sensitivities and specificities were used to detect apoptosis, including: a) DNA agarose gel electrophoresis; b) terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL); c) electron microscopy; and d) light microscopy. In CLP mice, multiple methods demonstrated apoptosis in lymphocytes in thymus, spleen, ileum, colon, lung, and skeletal muscle. In addition to lymphocytes, parenchymal cells in ileum, colon, lung, and to a lesser extent, in skeletal muscle and kidney were apoptotic in CLP mice. There was no evidence of apoptosis by any method of detection in liver, brain, or heart. Results in Rag-1 mice which aredeficient in T and B cells demonstrated extensive apoptosis in thymus, spleen, and ileum with less degrees of apoptosis in colon and lung. Both lymphoid cells and parenchymal cells were apoptotic. Rag-1 mice which underwent CLP did not die prematurely and there were no apparent observable differences in the physical response (tachypnea, piloerection, lethargy, etc), or intra-abdominal bowel inflammtion/adhesions compared with CLP mice with normal T and S cells. Conclusions: Apoptosis is an important mechanism of cell death in lymphocytes and parenchymal cells in sepsis and occurs systemically in many organs. Apoptosis may be an important cause of immunologic suppression in sepsis by inducing widespread lympbocyte depletion. Alternately, apoptosis may be beneficial to host survival by down- regulating the inflammatory response which accompanies sepsis. The degree to which parenchymal cell apoptosis is contributing to multiple organ failure cannot be determined from the present study. Findings in Rag-1 mice demonstrate that mature T and B cells and their secretory products are not necessary for apoptosis to occur during sepsis and that apoptotic cell death is not restricted to T or B cells. Apoptosis may be a key regulator of the balance between the pro-and anti-inflammatory process.
KW - Cytokines
KW - Endotoxin
KW - Immune deficiency
KW - Immunosuppression
KW - Lymphocytes
KW - Multiple organ failure
KW - Rag- 1
KW - Septic shock
KW - Systemic inflammatory response syndrome
UR - http://www.scopus.com/inward/record.url?scp=0030739250&partnerID=8YFLogxK
U2 - 10.1097/00003246-199708000-00015
DO - 10.1097/00003246-199708000-00015
M3 - Review article
C2 - 9267941
AN - SCOPUS:0030739250
SN - 0090-3493
VL - 25
SP - 1298
EP - 1307
JO - Critical Care Medicine
JF - Critical Care Medicine
IS - 8
ER -