The Induction of Accelerated Thymic Programmed Cell Death During Polymicrobial Sepsis

Ayala, Alfred; Herdon, Crystal D.; Lehman, Donna L.; DeMaso, Catherine M.; Ayala, Carol A.; Chaudry, Irshad H.

doi:10.1097/00024382-199504000-00003

Cited by 129 publications

(91 citation statements)

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“…Previous studies have shown that sepsis induces extensive lymphocyte apoptosis in diverse organs, including spleen and intestine (8,17,20,29). Although most studies focused on lymphocyte apoptosis in tissues, few studies have examined the effects of sepsis on circulating lymphocytes (18).…”

Section: Discussionmentioning

confidence: 99%

Accelerated Lymphocyte Death in Sepsis Occurs by both the Death Receptor and Mitochondrial Pathways

Hotchkiss

Osmon

Chang³

et al. 2005

The Journal of Immunology

306

280

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Patients with sepsis are immune compromised, as evidenced by their failure to clear their primary infection and their propensity to develop secondary infections with pathogens that are often not particularly virulent in normal healthy individuals. A potential mechanism for immunosuppression in sepsis is lymphocyte apoptosis, which may occur by either a death receptor or a mitochondrial-mediated pathway. A prospective study of blood samples from 71 patients with sepsis, 55 nonseptic patients, and 6 healthy volunteers was undertaken to quantitate lymphocyte apoptosis and determine cell death pathways and mechanisms of apoptosis. Apoptosis was evaluated by flow cytometry and Western blotting. Lymphocyte apoptosis was increased in CD4 and CD8 T cells, B cells (CD20), and NK cells (CD56) in septic vs nonseptic patients. Samples taken sequentially from 10 patients with sepsis showed that the degree of CD3 T cell apoptosis correlated with the activity of his/her sepsis. In septic patients, apoptotic lymphocytes were positive for active caspases 8 and 9, consistent with death occurring by both mitochondrial-mediated and receptor-mediated pathways. In support of the concept that both death pathways were operative, lymphocyte apoptosis occurred in cells with markedly decreased Bcl-2 (an inhibitor of mitochondrial-mediated apoptosis) as well as cells with normal concentrations of Bcl-2. In conclusion, apoptosis occurs in a broad range of lymphocyte subsets in patients with sepsis and correlates with the activity of the disease. Lymphocyte loss occurs by both death receptor and mitochondrial-mediated apoptosis, suggesting that there may be multiple triggers for lymphocyte apoptosis.

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Section: Discussionmentioning

confidence: 99%

Accelerated Lymphocyte Death in Sepsis Occurs by both the Death Receptor and Mitochondrial Pathways

Hotchkiss

Osmon

Chang³

et al. 2005

The Journal of Immunology

306

280

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“…The absence of prolactin, which is a necessary cofactor for IL-2-mediated lymphocyte proliferation, may have a similar effect (28). Prolactin is known to protect against glucocorticoid-induced lymphocyte apoptosis in vitro and in animal models (29,30), and levels of glucocorticoids commonly seen in stressed patients have been shown to cause lymphocyte apoptosis (31,32). Because prolactin release occurs simultaneously with stress-induced hypothalamic/pituitary/adrenal axis activation, it may protect the organism from the immune-suppressive effects of stress cortisol.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Lymphopenia, Lymphoid Depletion, and Hypoprolactinemia in Children with Nosocomial Sepsis and Multiple Organ Failure

Felmet¹,

Hall

Clark³

et al. 2005

The Journal of Immunology

235

200

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Lymphopenia and lymphoid depletion occur in adults dying of sepsis. Prolactin increases Bcl-2 expression, suppresses stress-induced lymphocyte apoptosis, and improves survival from experimental sepsis. We hypothesized that prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia occur in children dying with sepsis and multiple organ failure (MOF). Fifty-eight critically ill children with and 55 without MOF admitted to a university hospital pediatric intensive care unit were enrolled in a prospective, longitudinal, observational clinical study. Prolactin levels and absolute lymphocyte count were measured on days 1, 3, 7, 14, and 21. Lymph node, thymus, and spleen autopsy specimens were examined for lymphoid depletion, with immunohistochemical staining for CD4, CD20, and CD21 and for lymphoid apoptosis. Prolonged lymphopenia (absolute lymphocyte count < 1000 for >7 days) occurred only in children with MOF (29 vs 0%, p < 0.05) and was associated independently with nosocomial infection (odds ratio (OR), 5.5, 95% confidence interval (CI), 1.7–17, p < 0.05), death (OR, 6.8, 95% CI, 1.3–34, p < 0.05), and splenic and lymph node hypocellularity (OR, 42, 95% CI, 3.7–473, p < 0.05). Lymphocyte apoptosis and ante/postmortem infection were observed only in children with lymphoid depletion. Prolonged hypoprolactinemia (>7 days) was more common in children with MOF (17 vs 2%, p < 0.05) and was associated independently with prolonged lymphopenia (OR, 8.3, 95% CI, 2.1–33, p < 0.05) and lymphoid depletion (OR, 12.2, 95% CI, 2.2–65, p < 0.05). Prolonged lymphopenia and apoptosis-associated depletion of lymphoid organs play a role in nosocomial sepsis-related death in critically ill children. Prolonged hypoprolactinemia is a previously unrecognized risk factor for this syndrome.

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“…Apoptosis was not only seen in the thymus [16;17] but also in the bone marrow [18] and in mucosal lymphocytes [19] and appeared to involve T- [20] as well as B-lymphocytes [21], though with different kinetics. Thymocyte apoptosis during polymicrobial sepsis was independent from the early pro-inflammatory response mediated by TNF-α [16] and was neither mediated through FasL nor through endotoxin, but through corticosteroids acting on Bcl-2 [20;22] whereas mucosal lymphocyte [19] and CD4 + -Tlymphocyte deaths [20] were mediated by FasL. In addition, complement C5a has been reported to contribute to thymocyte apoptosis in early sepsis [23].…”

Section: Lymphocyte Apoptosis Suppresses the Immune Systemmentioning

confidence: 99%

Role of programmed cell death in the immunopathogenesis of sepsis

Perl

Chung

Swan

et al. 2007

Drug Discovery Today: Disease Mechanisms

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Apoptosis is an important mechanism during the immunopathogenesis of sepsis. Early programmed cell death of lymphocytes substantially impairs innate and adaptive immunity reducing the capacity to ward off the invading pathogen. Apoptosis of parenchymal cells (e.g. in the lung, liver and gut) may also promote organ failure and death. Several experimental therapeutic strategies have now been developed to beneficially influence these mechanisms; however, their potential clinical benefit is yet to be evaluated.

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The Induction of Accelerated Thymic Programmed Cell Death During Polymicrobial Sepsis

Cited by 129 publications

References 0 publications

Accelerated Lymphocyte Death in Sepsis Occurs by both the Death Receptor and Mitochondrial Pathways

Accelerated Lymphocyte Death in Sepsis Occurs by both the Death Receptor and Mitochondrial Pathways

Prolonged Lymphopenia, Lymphoid Depletion, and Hypoprolactinemia in Children with Nosocomial Sepsis and Multiple Organ Failure

Role of programmed cell death in the immunopathogenesis of sepsis

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