Acute Inflammation and Microthrombosis Induced by Endotoxin, Interleukin-1, and Tumor Necrosis Factor and their Implication in Gram-Negative Infection

Cybulsky, Myron I.; Chan, Man Khun; Movat, Henry Z.

doi:10.1007/978-1-4612-4502-5_6

Cited by 105 publications

(86 citation statements)

References 72 publications

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“…Death in sepsis is due to circulatory collapse and multiple organ failure (1,48). The integrity of the endothelium is crucial during sepsis, and endothelial death and loss of its barrier function may play a key role in the pathogenesis of septic shock (49). LPS induces endothelial damage in vivo, and microvascular injury occurs in numerous tissues during sepsis (2, 50 -52).…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Signals an Endothelial Apoptosis Pathway Through TNF Receptor-Associated Factor 6-Mediated Activation of c-Jun NH2-Terminal Kinase

Hull

McLean

Wong

et al. 2002

The Journal of Immunology

101

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Inflammatory mediators such as TNF and bacterial LPS do not cause significant apoptosis of endothelial cells unless the expression of cytoprotective genes is blocked. In the case of TNF, the transcription factor NF-κB conveys an important survival signal. In contrast, even though LPS can also activate NF-κB, this signal is dispensable for LPS-inducible cytoprotective activity. LPS intracellular signals are transmitted through a member of the Toll-like receptor family, TLR4. This family of receptors transduces signals through a downstream molecule, TNFR-associated factor 6 (TRAF6). In this study, we demonstrate that the C-terminal fragment of TRAF6 (TRAF6-C) inhibits LPS-induced NF-κB nuclear translocation and c-Jun NH2-terminal kinase (JNK) activation in endothelial cells. In contrast, LPS activation of p38 kinase is not inhibited by TRAF6-C. TRAF6-C also inhibits LPS-initiated endothelial apoptosis, but potentiates TNF-induced apoptosis. LPS-induced loss of mitochondrial transmembrane potential, cytochrome c release, and caspase activation are all blocked by TRAF6-C. We demonstrate that TRAF6 signals apoptosis via JNK activation, since inhibition of JNK activation using a dominant-negative mutant also inhibits apoptosis. JNK inhibition blocks caspase activation, but the reverse is not true. Hence, JNK activation lies upstream of caspase activation in response to LPS stimulation.

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Signals an Endothelial Apoptosis Pathway Through TNF Receptor-Associated Factor 6-Mediated Activation of c-Jun NH2-Terminal Kinase

Hull

McLean

Wong

et al. 2002

The Journal of Immunology

101

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“…Endothelial cell injury and detachment from the vascular wall have been demonstrated when LPS was injected into mice (Koshi et al, 1993), rats (Reidy and Schwartz, 1983;Sutton et al, 1993), rabbits (Cybulsky et al, 1988;McCuskey et al, 1996), and sheep (Meyrick, 1986b). In a mouse model of endotoxemia, intraperitoneal delivery of LPS from Salmonella typhimurium could result in widespread apoptosis of the endothelium in a process mediated via ceramide generation (Haimovitz-Friedman et al, 1997).…”

Section: Endothelial Cell Apoptosismentioning

confidence: 99%

Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction

Matsuda

Hattori

2007

J Smooth Muscle Res

116

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Sepsis is the leading cause of mortality in critically ill patients. In this pathological syndrome, septic shock and sequential multiple organ failure correlate with poor outcome. The pathophysiology of sepsis with acute organ dysfunction involves a highly complex, integrated response that includes activation of number of cell types, inflammatory mediators, and the hemostatic system. Central to this process may be alterations in vascular functions. This review article provides a growing body of evidence for the potential impact of vascular dysfunction on sepsis pathophysiology with a major emphasis on the endothelium. Furthermore, the role of apoptotic signaling molecules in the mechanisms underlying endothelial cell injury and death during sepsis and its potential value as a target for sepsis therapy will be discussed, which may help in the assessment of ongoing therapeutic strategies.

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“…A correlation between clotting and cancer is supported by histologic studies using immunochemical or electron microscopic techniques which demonstrate the presence of fibrin within and around primary and metastatic tumors, final product of the coagulation cascade, 19 as well as platelet microthrombi associated with growing tumor cells. 24 Multiple mechanisms, direct and indirect, are implicated in the pathophysiology of coagulation disorders which occur in the neoplastic patient.…”

Section: Pathophysiologymentioning

confidence: 99%

Coagulation and cancer: Implications for diagnosis and management

Loreto

Martinis

Corsi

et al. 2000

Pathol. Oncol. Res.

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Acute Inflammation and Microthrombosis Induced by Endotoxin, Interleukin-1, and Tumor Necrosis Factor and their Implication in Gram-Negative Infection

Cited by 105 publications

References 72 publications

Lipopolysaccharide Signals an Endothelial Apoptosis Pathway Through TNF Receptor-Associated Factor 6-Mediated Activation of c-Jun NH2-Terminal Kinase

Lipopolysaccharide Signals an Endothelial Apoptosis Pathway Through TNF Receptor-Associated Factor 6-Mediated Activation of c-Jun NH2-Terminal Kinase

Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction

Coagulation and cancer: Implications for diagnosis and management

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