Evaluation of protein C and other biomarkers as predictors of mortality in a rat cecal ligation and puncture model of sepsis*

Heuer, Josef G.; Sharma, Ganesh R.; Gerlitz, Bruce; Zhang, Tonghai; Bailey, Dianna L.; Ding, Chunjin; Berg, David T.; Perkins, Douglas J; Stephens, Eddie J.; Holmes, Kimberly; Grubbs, Renee L.; Fynboe, Kelly A.; Chen, Yunfei; Grinnell, Brian W.; Jakubowski, Joseph A.

doi:10.1097/01.ccm.0000129488.54282.1a

Cited by 61 publications

(53 citation statements)

References 47 publications

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“…25,26 Increased plasma levels of MIP-2 and KC also correlate with poor outcome in rodent CLP models. 9 Our studies support the use of these cytokines as markers of lethality following CLP. Interestingly, concentrations of the type 1 cytokines IFN-g and IL-12 were very low in both wild type and CD8KO/aAsGM1 mice.…”

Section: Discussionsupporting

confidence: 54%

“…It is likely that CLP represents a model of both infection and intestinal ischemia. The high bacterial counts in blood, peritoneal fluid and lung observed in this report and others 8,9 clearly demonstrates the functional importance of bacterial dissemination for CLP-induced mortality. We demonstrate significantly lower bacterial counts in blood at 16 h after CLP in CD8KO/aAsGM1 mice compared to wild-type controls.…”

Section: Discussionmentioning

confidence: 60%

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Mice depleted of CD8+ T and NK cells are resistant to injury caused by cecal ligation and puncture

Sherwood

Enoh

Murphey

et al. 2004

Laboratory Investigation

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We previously showed that beta 2 microglobulin knockout mice depleted of NK cells by treatment with antiasialoGM1 (b2MKO/aAsGM1 mice) are resistant to sepsis caused by cecal ligation and puncture (CLP). b2MKO mice possess multiple immunological defects including depletion of CD8 þ T cells. This study was designed to determine the contribution of CD8 þ T and NK cell deficiency to the resistance of b2MKO/aAsGM1 mice to CLPinduced injury. b2MKO/aAsGM1 mice and CD8 knockout mice treated with anti-asialoGM1 (CD8KO/aAsGM1 mice) survived significantly longer than wild-type mice following CLP. Improved long-term survival was also observed in wild-type mice rendered CD8 þ T/NK cell-deficient by treatment with both anti-CD8a and antiasialoGM1. Blood gas analysis and body temperature measurements showed that CD8 þ T and NK cell-deficient mice have significantly reduced metabolic acidosis and less hypothermia compared to control mice at 18 h after CLP. CD8 þ T/NK cell-deficient mice also showed an attenuated proinflammatory response as indicated by decreased expression of mRNAs for IL-1, IL-6 and MIP-2 in spleen and heart. IL-6, KC and MIP-2 levels in blood and peritoneal fluid were also significantly decreased CD8 þ T/NK cell-deficient mice compared to controls. CD8 þ T/NK cell-deficient mice exhibited decreased bacterial concentrations in blood, but not in peritoneal fluid or lung, compared to wild-type controls. These data show that mice depleted of CD8 þ T and NK cells exhibit survival benefit, improved physiologic function and an attenuated proinflammatory response following CLP that is comparable to b2M/aAsGM1 mice. We previously demonstrated that b2 microglobulin knockout mice that were depleted of natural killer (NK) cells by treatment with anti-asialoGM1 (b2MKO/aAsGM1 mice) are resistant to systemic injury caused by cecal ligation and puncture (CLP). 1 Specifically, b2MKO/aAsGM1 mice exhibit improved survival, less metabolic acidosis, reduced hypothermia and better hemodynamic function compared to control mice following CLP. 1,2 These improvements in physiological function are associated with attenuation of the CLP-induced proinflammatory response.b2MKO/aAsGM1 mice have multiple immunological defects including an absence of CD8 þ T, natural killer (NK) and natural killer T (NKT) cells as well as deficient expression of the class I major histocompatability complex (MHC-I) and CD1 molecules. 1,3-5 One of our goals is to determine which of these immunological alterations confers resistance to the CLP-induced sepsis syndrome. We previously showed that adoptive transfer of CD8 þ T and NK cells into b2MKO/aAsGM1 mice will re-establish CLP-induced mortality. 1 In addition, we showed improved post-CLP survival in mice that are deficient of both CD8 þ T and NK cells. Based on this observation, we hypothesize that CD8 þ T and NK cell depletion contributes to the resistance of b2MKO/aAsGM1 mice to CLP-induced injury. To test this hypothesis, we directly compared CLP-induced mortality in b2MKO/aAsGM1 mice and CD8 þ T/NK cell-d...

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 60%

Mice depleted of CD8+ T and NK cells are resistant to injury caused by cecal ligation and puncture

Sherwood

Enoh

Murphey

et al. 2004

Laboratory Investigation

View full text Add to dashboard Cite

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“…The rat CLP model of polymicrobial sepsis was described in detail previously (20). Briefly, Sprague-Dawley rats (245 to 265 g) were purchased from Harlan (Indianapolis, IN) and allowed to acclimate for a minimum of 6 d before surgery.…”

Section: Anesthesia and Clp Surgerymentioning

confidence: 99%

“…The ELISA for measurement of PC levels was performed as described previously (20), and purified recombinant rat PC was used as a reference standard. Measurements of CXCL1 and CXCL2 were by immunoassay using the Rodent Multi-Analyte Profile (Rules Based Medicine, Austin, TX).…”

Section: Plasma and Tissue Measurementsmentioning

confidence: 99%

“…Studies have also suggested that PC deficiency may appear before the onset of defined clinical parameters of severe sepsis or septic shock (19). Moreover, low PC levels are predictive of early death in a rat model of polymicrobial sepsis (20) and clinically have been associated with early death resulting from refractory shock and multiple-organ failure in severe sepsis (21). These studies support the important role of the PC pathway in response to infection, which is further exemplified by the efficacy of recombinant human activated PC in the treatment of severe sepsis (22).…”

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confidence: 99%

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Role of Protein C in Renal Dysfunction after Polymicrobial Sepsis

Gupta

Berg²,

Gerlitz³

et al. 2007

Journal of the American Society of Nephrology

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Protein C (PC) plays an important role in vascular function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. This study explored the consequences of PC suppression on the kidney in a cecal ligation and puncture model of polymicrobial sepsis. This study shows that a rapid drop in PC after sepsis is strongly associated with an increase in blood urea nitrogen, renal pathology, and expression of known markers of renal injury, including neutrophil gelatinase-associated lipocalin, CXCL1, and CXCL2. The endothelial PC receptor, which is required for the anti-inflammatory and antiapoptotic activity of activated PC (APC), was significantly increased after cecal ligation and puncture as well as in the microvasculature of human kidneys after injury. Treatment of septic animals with APC reduced blood urea nitrogen, renal pathology, and chemokine expression and dramatically reduced the induction of inducible nitric oxide synthase and caspase-3 activation in the kidney. The data demonstrate a clear link between acquired PC deficiency and renal dysfunction in sepsis and suggest a compensatory upregulation of the signaling receptor. Moreover, these data suggest that APC treatment may be effective in reducing inflammatory and apoptotic insult during sepsis-induced acute renal failure.

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Multiplex microsphere‐based flow cytometric platforms for protein analysis and their application in clinical proteomics – from assays to results

2009

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Advances in high-throughput screening, together with rapid progress in genomic and proteomic sciences, have considerably stimulated the development of a variety of biomarker discovery tools and have contributed to the improvement of clinical diagnosis. Major challenges include the obtaining of high-quality data sets based on assays that are rapid, reliable, and inexpensive, but still highly sensitive and easy to perform. The microsphere-based flow cytometric technology is a platform that is currently entering the diagnostic market. This article reviews the development and the applications of microsphere-based flow cytometric platforms in basic and applied proteomic research, and discusses bead-based assays used in clinical applications.

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Evaluation of protein C and other biomarkers as predictors of mortality in a rat cecal ligation and puncture model of sepsis*

Abstract: The data from this study indicate that an early decrease in protein C concentration predicts poor outcome in a rat sepsis model. The data further indicate that increases in the CXC chemokines macrophage inflammatory protein-2 and KC precede poor outcome.

Cited by 61 publications

References 47 publications

Mice depleted of CD8+ T and NK cells are resistant to injury caused by cecal ligation and puncture

Mice depleted of CD8+ T and NK cells are resistant to injury caused by cecal ligation and puncture

Role of Protein C in Renal Dysfunction after Polymicrobial Sepsis

Multiplex microsphere‐based flow cytometric platforms for protein analysis and their application in clinical proteomics – from assays to results

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