The enigma of sepsis

Riedemann, Niels C.; Guo, Ruocheng; Ward, Peter A.

doi:10.1172/jci19523

Cited by 396 publications

(457 citation statements)

References 77 publications

(14 reference statements)

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“…3,45 As examples, serum TNF-␣ 37,46,47 and LPS levels 48 were not elevated in the same kinetic manners in septic patients or CLP-treated mice, as was found in LPS-injected mice. Moreover, the kinetics and magnitude of cytokine expression described by the LPS models do not reproduce appropriately the cytokine profile of sepsis.…”

Section: Discussionmentioning

confidence: 67%

“…In the systemic inflammatory state characteristic of sepsis, both the endothelium and leukocytes are activated by proinflammatory cytokines, 3 with a consequent up-regulation of coagulation. As a result, vascular permeability is increased and activated leukocytes adhere to the endothelium and extravasate into organs.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 This disease is associated with a response to infection causing systemic inflammatory response syndrome, which involves a variety of symptoms including hypothermia and hyperthermia, tachycardia and tachypnea, and anomalous white blood cell counts. 3 As a consequence, the inflammatory system is hyperactive and evokes both cellular and humoral responses, such as the release of cytokines and chemokines that serve as mediators for crosstalk between endothelial cells (ECs) and epithelial cells on one hand, and neutrophils and macrophages on the other. 4,5 The inflammatory state is closely related to coagulation through several connecting elements, which include: 1) receptors and membrane proteins, eg, endothelial protein C receptor (EPCR), thrombomodulin (Tm), and protease-activated receptors (PAR); 2) hemostasis-related proteins, eg, tissue factor (TF), factor (F) VII, FXI, and FXII; 3) systems that regulate thrombin formation, such as protein C (PC) system components, tissue factor pathway inhibitor, and anti-thrombin-III; 4) inflammatory mediators, eg, tumor necrosis factor (TNF)-␣, interleukin (IL)-1, IL-6, and inducible nitric oxide synthase; and 5) cell adhesion mediators for extravasation of inflammatory cells, such as E-selectin, Pselectin, and integrins.…”

mentioning

confidence: 99%

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A Protein C Deficiency Exacerbates Inflammatory and Hypotensive Responses in Mice During Polymicrobial Sepsis in a Cecal Ligation and Puncture Model

Ganopolsky

Castellino

2004

The American Journal of Pathology

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During the systemic inflammatory state induced by sepsis, the potential for coagulopathy exists because of up-regulation of natural procoagulants and antifibrinolytics, and down-regulation of natural anti-coagulants, with protein C (PC) being a critical example of the latter case. PC functions as an anti-coagulant, profibrinolytic, and anti-inflammatory agent, and, thus, its administration or deficiency may affect the course and outcome of sepsis in patients. In this study, a cecal ligation and puncture model of septic peritonitis was applied to wild-type mice and littermates with a targeted heterozygous deficiency of PC (PC ؉/؊ ) to characterize the importance of a PC-deficiency on polymicrobial sepsis. An enhanced mortality rate was found to accompany a PC deficiency. Plasma cytokines, as well as organ-specific expression of cytokine transcripts, were elevated in PC ؉/؊ mice. No signs of severe disseminated intravascular coagulation (DIC) were observed in wild-type or PC ؉/؊ mice, as indicated by an increase in fibrinogen levels and the invariability of platelet counts after cecal ligation and puncture. Consumption of coagulation factors was similar in both genotypes and a decrease in the PC mRNA and protein levels was more prominent in PC ؉/؊ mice. Renal and organ muscle damage was enhanced in PC ؉/؊ mice, as shown by increases in plasma blood urea nitrogen, creatinine, and creatinine kinase. Hypotension and bradycardia were more enhanced in PC ؉/؊ mice than in wild-type mice, thus provoking a more severe septic shock response. Thus, the hemodynamic role of PC during sepsis is of critical importance to the outcome of the

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A Protein C Deficiency Exacerbates Inflammatory and Hypotensive Responses in Mice During Polymicrobial Sepsis in a Cecal Ligation and Puncture Model

Ganopolsky

Castellino

2004

The American Journal of Pathology

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“…S eptic shock is a common cause of mortality in intensive care units despite the availability of antibiotics to treat infection and vasopressors to support tissue perfusion (1,2). Bacterial LPS has been identified as a major cause of septic shock (3).…”

mentioning

confidence: 99%

Suppressive Oligodeoxynucleotides Protect Mice from Lethal Endotoxic Shock

Shirota

Gürsel

et al. 2005

The Journal of Immunology

122

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Endotoxic shock is a life-threatening condition caused by exposure to bacterial LPS. LPS triggers the release of acute phase, proinflammatory, and Th1 cytokines that facilitate the development of endotoxic shock. Synthetic oligodeoxynucleotides (ODN) expressing suppressive TTAGGG motifs effectively down-regulate the production of proinflammatory and Th1 cytokines elicited by a variety of immune stimuli. The current results demonstrate that suppressive ODN protect mice from LPS-induced endotoxic shock. Underlying this protective effect is the ability of suppressive ODN to bind to and prevent the phosphorylation of STAT1 and STAT4, thereby blocking the signaling cascade mediated by LPS-induced IFN-β and IL-12. These findings suggest that suppressive ODN might be of use in the treatment of endotoxic shock.

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“…In addition, inflammatory mediators and pathogen components will also activate the coagulation system causing disseminated intravascular coagulation. Together, those effects will lead to hypoperfusion and tissue hypoxia that apparently are the main cause of organ dysfunction, which represents the often-lethal stage of sepsis (Riedemann et al 2003, Van Amersfoort et al 2003.…”

Section: Paf-ah In Diseases and Disease Modelsmentioning

confidence: 99%