Rapid onset of intestinal epithelial and lymphocyte apoptotic cell death in patients with trauma and shock

Hotchkiss, Richard S.; Schmieg, Robert E.; Swanson, Paul E.; Freeman, Bradley D.; Tinsley, Kevin W.; Cobb, J. Perren; Karl, Irene E.; Buchman, Timothy G.

doi:10.1097/00003246-200009000-00016

Cited by 180 publications

(121 citation statements)

References 30 publications

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“…This effect of adoptive transfer of apoptotic cells to decrease sepsis survival is particularly striking considering that mice that had adoptive transfer of necrotic cells had a significant improvement in survival compared with salinetreated mice. Apoptosis is a major cause of death in lymphocytes and gastrointestinal epithelial cells in patients with sepsis and trauma (14,(32)(33)(34). Immunohistochemical studies of spleens from patients dying of sepsis demonstrated focal regions in which 25-50% of cells were positive for markers of apoptosis (14,34).…”

Section: Discussionmentioning

confidence: 99%

“…Apoptosis is a major cause of death in lymphocytes and gastrointestinal epithelial cells in patients with sepsis and trauma (14,(32)(33)(34). Immunohistochemical studies of spleens from patients dying of sepsis demonstrated focal regions in which 25-50% of cells were positive for markers of apoptosis (14,34). A recent study of circulating white blood cells from patients with sepsis showed that 15-20% of circulating T and B cells were undergoing apoptosis (32).…”

Section: Discussionmentioning

confidence: 99%

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Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis

Hotchkiss

Chang

Grayson

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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In sepsis, both necrotic and apoptotic cell death can occur. Apoptotic cells induce anergy that could impair the host response, whereas necrotic cells cause immune activation that might result in enhanced antimicrobial defenses. We determined whether adoptive transfer of apoptotic or necrotic cells impacted survival in a clinically relevant sepsis model. We also evaluated the effects of adoptive transfer of apoptotic or necrotic cells on the prototypical TH1 and TH2 cytokines IFN-␥ and IL-4, respectively. C57BL6͞J mice had adoptive transfer of apoptotic (irradiated) or necrotic (freeze thaw) splenocytes. Controls received saline. Apoptotic cells greatly increased mortality, whereas necrotic splenocytes markedly improved survival, P < 0.05. The contrasting effects that apoptotic or necrotic cells exerted on survival were mirrored by opposite effects on splenocyte IFN-␥ production with greatly decreased and increased production, respectively. Importantly, either administration of anti-IFN-␥ antibodies or use of IFN-␥ knockout mice prevented the survival benefit occurring with necrotic cells. This study demonstrates that the type of cell death impacts survival in a clinically relevant model and identifies a mechanism for the immune suppression that is a hallmark of sepsis. Necrotic cells (and likely apoptotic cells) exert their effects via modulation of IFN-␥. Sepsis is the leading cause of death in many intensive-care units and currently ranks as the 12th most common cause of death in America (1). Septic patients are severely immune suppressed as typified by their loss of delayed type hypersensitivity, inability to eradicate their primary infection, and a predisposition to develop secondary nosocomial infections (2-6). A feature illustrative of the immune suppression in septic patients is their failure to respond to skin testing with antigens derived from microbes to which previous exposure occurred (positive controls) (2, 7). Animal studies indicate that the immune defect in sepsis may be critical to the pathogenesis and resultant mortality (8-10). Evidence to support this contention is also provided by a recent clinical trial using IFN-␥. Administration of this cytokine, which is a potent macrophage activator and an inducer of the TH1 response, improved survival in patients with sepsis (11).A number of defects in the immune system have been reported in sepsis. These abnormalities include a shift from a proinflammatory TH1 to an antiinflammatory TH2 lymphocyte profile, a loss in cellular MHC II expression, and a profound apoptosisinduced depletion of CD4 T and B cells (5,(11)(12)(13)(14)(15). The sepsis-induced apoptosis of lymphocytes may be particularly important not only because of the extensive lymphocyte loss but also because of a potential immunosuppressive effect of apoptotic cells on the immune system. Recent work has demonstrated that uptake of apoptotic cells by phagocytic cells stimulates immune tolerance by the release of antiinflammatory cytokines and suppression of release of proinflammatory cytokin...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis

Hotchkiss

Chang

Grayson

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

172

132

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“…Apoptosis causes the marked deletion of immune cells, including natural killer (NK) cells, CD4 + and CD8 + T cells, B cells, and dendritic cells (DC), in various organs of patients dying of sepsis, leading to immunosuppression (Figure 2). Apoptosis of immune cells occurs in lymphoid tissues and gut‐associated lymphoid tissues 15. The loss of intestinal intraepithelial and lamina propria lymphocytes might facilitate bacterial translocation into the systemic circulation, thereby perpetuating the systemic inflammatory response and predisposing to secondary infections.…”

Section: Mechanism Of Sepsis‐induced Immunosuppressionmentioning

confidence: 99%

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

Ono

Tsujimoto

Hiraki

et al. 2018

Annals of Gastroent Surgery

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Surgical injury can be a life‐threatening complication, not only due to the injury itself, but also due to immune responses to the injury and subsequent development of infections, which readily result in sepsis. Sepsis remains the leading cause of death in most intensive care units. Unfavorable outcomes of several high‐profile trials in the treatment of sepsis have led researchers to state that sepsis studies need a new direction. The immune response that occurs during sepsis is characterized by a cytokine‐mediated hyper‐inflammatory phase, which most patients survive, and a subsequent immunosuppressive phase. Therefore, therapies that improve host immunity might increase the survival of patients with sepsis. Many mechanisms are responsible for sepsis‐induced immunosuppression, including apoptosis of immune cells, increased regulatory T cells and expression of programmed cell death 1 on CD4+ T cells, and cellular exhaustion. Immunomodulatory molecules that were recently identified include interleukin‐7, interleukin‐15, and anti‐programmed cell death 1. Recent studies suggest that immunoadjuvant therapy is the next major advance in sepsis treatment.

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“…Previous studies have also indicated that stress could damage the function of intestinal mucosal barrier (Hotchkiss et al, 2000;Grogan et al, 2004). The gastrointestinal tract bears the stressful events such as the severe brain injury, trauma, burn, infection, and hemorrhagic shock.…”

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confidence: 99%

Changes in Serum Ghrelin and Small Intestinal Motility in Rats with Ischemic Stroke

Zhu

Chuai

2011

The Anatomical Record

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Ischemic stroke occurs as a result of an obstruction within a blood vessel supplying blood to the brain. Gastrointestinal mucosal damage not only induces local and systemic inflammatory reactions but may also result in multiple organ dysfunction syndrome. We studied whether the changes in serum ghrelin and small intestinal motility occur in cerebral ischemia. The focal cerebral ischemia rat models were produced by the middle cerebral artery occlusion (MCAO) method. The MCAO group was further equally divided into five subgroups at 3, 6, 12, 24, and 48 hr, and the sham operated rats were used as controls. Serum ghrelin level was analyzed using enzyme-linked immunosorbent assay, and small intestinal motility was measured by methylene blue staining. The ileum tissue was examined by light and electron microscopy. The neurologic scores were 0 for all the rats in the control group and 2-3 for those in the MCAO group, suggesting that rat models were established successfully. The serum ghrelin level was higher in the MCAO group when compared with the control group (P < 0.05). However, the impelling force in MCAO rats was significantly lower than that of the control group (P < 0.05), reaching the lowest level at 24 hr. Damage to the intestinal mucosa, including villus intestinalis, vacuolar degeneration of organelles, widened cell-cell junctions, and apoptotic cells could be found under the light and electron microscopy. Our results showed that higher level of serum ghrelin decreased gastrointestinal motility and damage to the intestinal mucosa existed in rats with MCAO. Anat Rec, 295:307-312, 2012. V V C 2011 Wiley Periodicals, Inc.

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Rapid onset of intestinal epithelial and lymphocyte apoptotic cell death in patients with trauma and shock

Cited by 180 publications

References 30 publications

Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis

Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

Changes in Serum Ghrelin and Small Intestinal Motility in Rats with Ischemic Stroke

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