Sepsis induced immunosuppression: Implications for secondary infections and complications

Sundar, Krishna M.; Sires, Mazen

doi:10.4103/0972-5229.117054

Cited by 50 publications

(36 citation statements)

References 72 publications

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“…In brief, the role of peptic ulcer disease with hemorrhage might be more prominent in patients recovering from advanced AKI. Although AKI involves some degree of inflammation (31)(32)(33), an "immunoparalysis" state, similar to that ensuing from sepsis and critical illness (34,35), may coexist and make the effects of H. pylori more pernicious. Our study showed, however, that a small portion of patients received H. pylori eradication therapy.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Risk of Upper Gastrointestinal Hemorrhage after Advanced AKI

Lin

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives There are few reports on temporary dialysis-requiring AKI as a risk factor for future upper gastrointestinal bleeding (UGIB). This study sought to explore the long-term association between dialysisrequiring AKI and UGIB.Design, setting, participants, & measurements This nationwide cohort study used data from the Taiwan National Health Insurance Research Database. Patients who recovered from dialysis-requiring AKI and matched controls were selected from hospitalized patients age $18 years between 1998 and 2006. The cumulative incidences of long-term de novo UGIB were calculated, and the risk factors of UGIB and mortality were identified using timevarying Cox proportional hazard models adjusted for subsequent CKD and ESRD after AKI.Results A total of 4565 AKI-recovery patients and the same number of matched patients without AKI were analyzed. After a median follow-up time of 2.33 years (interquartile range, 0.97-4.81 years), the incidence rates of UGIB were 50 (by stringent criterion) and 69 (by lenient criterion) per 1000 patient-years in the AKI-recovery group and 31 (by stringent criterion) and 48 (by lenient criterion) per 1000 patient-years in the non-AKI group (both P,0.001). When compared with patients in the non-AKI group, the multivariate hazard ratio (HR) for UGIB was 1.30 (95% confidence interval [95% CI], 1.14 to 1.48) for dialysis-requiring AKI, 1.83 (95% CI, 1.53 to 2.20) for time-varying CKD, and 2.31 (95% CI, 1.92 to 2.79) for time-varying ESRD (all P,0.001). Finally, the risk for long-term mortality increased after UGIB (HR, 1.24; 95% CI, 1.12 to 1.38) and dialysis-requiring AKI (HR, 1.66; 95% CI, 1.54 to 1.78).Conclusions Recovery from dialysis-requiring AKI was associated with future UGIB and mortality.

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Section: Discussionmentioning

confidence: 99%

Long-Term Risk of Upper Gastrointestinal Hemorrhage after Advanced AKI

Lin

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…As the most frequent cause of mortality in intensive care unit (ICU), sepsis is responsible for over 250,000 deaths each year in the United States (Martin, Mannino & Moss, 2006). Numerous studies have shown that the predominant driving force for morbidity and mortality of sepsis is immunosuppression (Hotchkiss, Monneret & Payen, 2013a; Hotchkiss & Nicholson, 2006; Hotchkiss & Opal, 2010; Hotchkiss et al, 2005; Sundar & Sires, 2013). Apoptosis of various immune cells has been proposed as a critical mediator of this sepsis-induced immunosuppression (Hotchkiss, Monneret & Payen, 2013b; Hotchkiss & Nicholson, 2006).…”

Section: Introductionmentioning

confidence: 99%

Grape seed proanthocyanidin extract protects lymphocytes against histone-induced apoptosis

Chang

Cauvi

et al. 2017

PeerJ

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Apoptosis of lymphocytes is associated with immunosuppression and poor prognosis in sepsis. Our previous report showed that histones, nuclear proteins released from damaged or dying cells in sepsis, can mediate lymphocyte apoptosis via mitochondria damage. Grape seed proanthocyanidin extract (GSPE), a natural substance with protective properties against oxidative stress, plays a vital role in cell and mitochondria protection. We thus hypothesized that GSPE may play a protective role in histone-induced lymphocyte apoptosis through its anti-oxidative properties. In this study, we investigated the protective efficacy of GSPE on lymphocyte apoptosis induced by extracellular histones, a main contributor of death in sepsis. Human blood lymphocytes were treated with 50 μg/ml histones, 2 μg/ml GSPE, or a combination of both. A total of 100 μM N-acetylcysteine (NAC), a reactive oxygen species (ROS) inhibitor, was used as a positive control for GSPE. Apoptosis, intracellular ROS levels, mitochondrial membrane potential, Bcl-2 expression, and caspase-3 cleavage were measured. Our data clearly indicate that GSPE significantly inhibited lymphocyte apoptosis, generation of ROS, the loss of mitochondrial membrane potential, the decrease in Bcl-2 expression, and caspase-3 activation induced by extracellular histones. In conclusion, we show that GSPE has a protective effect on lymphocyte apoptosis induced by extracellular histones. This study suggests GSPE as a potential therapeutic agent that could help reduce lymphocyte apoptosis, and thus the state of immunosuppression was observed in septic patients.

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“…Sepsis can be potentially life threatening; of more than 1 million Americans who are diagnosed with severe sepsis every year, between 28 and 50% will die from this disease (1,2). It is well-recognized that patients with sepsis are often immune suppressed, a state of reduced responsiveness to endotoxin known as endotoxin tolerance, deaths in this immunosuppressive phase are typically due to failure to control the secondary infections (3)(4)(5). The molecular mechanisms underlying this endotoxin tolerance phenomenon is poorly understood.…”

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Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Lan

Ren

et al. 2016

Journal of Biological Chemistry

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Sepsis is one of the leading causes of death worldwide. Although the prevailing theory for the sepsis syndrome is a condition of uncontrolled inflammation in response to infection, sepsis is increasingly being recognized as an immunosuppressive state known as endotoxin tolerance. We found sialylation of cell surface was significantly increased on LPS-induced tolerant cells; knockdown of Neu1 in macrophage cell line RAW 264.7 cells resulted in enhanced LPS-induced tolerance, whereas overexpression of Neu1 or treatment with sialidase abrogated LPS-induced tolerance, as defined by measuring TNF-␣ levels in the culture supernatants. We also found that the expression of Siglec-1 (a member of sialic acid-binding Ig (I)-like lectin family members, the predominant sialic acid-binding proteins on cell surface) was specifically up-regulated in endotoxin tolerant cells and the induction of Siglec-1 suppresses the innate immune response by promoting TGF-␤1 production. The enhanced TGF-␤1 production by Siglec-1 was significantly attenuated by spleen tyrosine kinase (Syk) inhibitor. Knockdown of siglec-1 in RAW 264.7 cells resulted in inhibiting the production of TGF-␤1 by ubiquitin-dependent degradation of Syk. Mechanistically, Siglec-1 associates with adaptor protein DNAX-activation protein of 12 kDa (DAP12) and transduces a signal to Syk to control the production of TGF-␤1 in endotoxin tolerance. Thus, Siglec-1 plays an important role in the development of endotoxin tolerance and targeted manipulation of this process could lead to a new therapeutic opportunity for patients with sepsis.Sepsis is generally defined as a systemic inflammatory response syndrome in response to infection. Sepsis can be potentially life threatening; of more than 1 million Americans who are diagnosed with severe sepsis every year, between 28 and 50% will die from this disease (1, 2). It is well-recognized that patients with sepsis are often immune suppressed, a state of reduced responsiveness to endotoxin known as endotoxin tolerance, deaths in this immunosuppressive phase are typically due to failure to control the secondary infections (3-5). The molecular mechanisms underlying this endotoxin tolerance phenomenon is poorly understood.Sialic acids are a family of nine-carbon acidic monosaccharides and are involved in immune response, such as host-pathogen recognition, migration, and antigen presentation. Mounting experimental evidence suggests that the presence of sialic acid residue act as a marker of self in the immune system, as such residues are absent from most microbes (6). Indeed, host cells can be lysed by immune cytotoxic effector mechanisms after extensive desialylation, an observation that demonstrates the significant role played by cell surface sialic acids in the selfrecognition process (7). In addition, normal human serum contains natural antibodies to sialidase-treated red blood cells (7-9), lymphocytes (10), and thymocytes (7). Recently, Meesmann et al. showed that desialylation acted as an "eat me" signal and caused an enhanced upt...

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Sepsis induced immunosuppression: Implications for secondary infections and complications

Cited by 50 publications

References 72 publications

Long-Term Risk of Upper Gastrointestinal Hemorrhage after Advanced AKI

Long-Term Risk of Upper Gastrointestinal Hemorrhage after Advanced AKI

Grape seed proanthocyanidin extract protects lymphocytes against histone-induced apoptosis

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

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