Vascular Lesions: Possible Pathogenetic Basis of the Generalized Shwartzman Reaction

Gaynor, Evelyn; Bouvier, C A; Spaet, Theodore H.

doi:10.1126/science.170.3961.986

Cited by 143 publications

(40 citation statements)

References 13 publications

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“…Furthermore, the plasma levels of PA-inhibitor were unchanged (5). Moreover, the minimum dose of endotoxin capable of inducing a marked inhibitor response in vivo (10 ng/kg body wt) is at least two orders of magnitude lower than the dose shown to produce vascular lesions in rabbits (4,30).…”

Section: Discussionmentioning

confidence: 90%

“…Endotoxin-induced DIC is a multifactorial process that involves both cellular and humoral pathways (3). Endothelial cell damage with exposure of the subendothelial structures has been proposed as one of the main pathogenetic mechanisms (3,4). In addition, endotoxin-stimulated endothelial cells may trigger blood coagulation by producing procoagulant (thromboplastin-like) activity (5).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation.

Colucci¹,

Paramo²,

Collen³

1985

J. Clin. Invest.

414

159

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Endotoxin producing bacteria cause disseminated intravascular coagulation (DIC); however, the mechanism of endotoxin action in man is still unclear. Impairment of the fibrinolytic system has been suggested as a contributing mechanism.A single injection of Escherichia coli lipopojysaccharide in rabbits resulted in a marked and prolonged increase of the levels of a fast-acting inhibitor of plasminogen activator (PAinhibitor) in plasma (from 3.9±0.7 to 41±13.2 U/ml after 3 h). Gel filtration studies indicated that inhibition of human tissue-type plasminogen activator (t-PA) by rabbit plasma is accompanied by a change in the elution profile of the activator compatible with the formation of an enzyme-inhibitor complex with an apparent molecular weight of 100,000. Injection of human t-PA (1,500 IU/kg body wt) in endotoxin treated animals resulted in very fast inhibition of t-PA and formation of a similar complex.The half-life of circulating PA-inhibitor activity in rabbits was about 7 min as estimated by donor receiver plasma transfusion experiments.Stimulation of cultured human endothelial cells with endotoxin resulted in enhanced rate of accumulation of PAinhibitor activity in the culture medium (two-to sevenfold increase). In five patients with septicemia, markedly increased levels of PA-inhibitor (14.3±15.5 U/ml) as compared with control subjects (13±0.7 U/ml) were observed in plasma.A very strong correlation (r = 0.98) was found between inhibition of t-PA and of urokinase in all conditions, suggesting that this fast-acting inhibitor reacts with both plasminogen activators.These data suggest that the appearance of this fast-acting PA-inhibitor is very sensitive to endotoxin stimulation. The marked increase in the level of PA-inhibitor in blood may contribute to the pathogenesis of DIC in septicemia.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation.

Colucci¹,

Paramo²,

Collen³

1985

J. Clin. Invest.

414

159

View full text Add to dashboard Cite

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“…4). Thus, a distinct disturbance of vascular endothelium can be produced by endotoxin, as observed in brains of newborn kittens that developed PVL after endotoxin injection (122,164,165). Additionally, endotoxin has been shown to cause arterial hypotension in newborn dogs, in sublethal doses, and to produce in the same animals periventricular WM injury (166).…”

Section: Maternal/fetal Infection or Inflammation And Cytokine Releasmentioning

confidence: 99%

Neurobiology of Periventricular Leukomalacia in the Premature Infant

2001

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Brain injury in the premature infant is a problem of enormous importance. Periventricular leukomalacia (PVL) is the major neuropathologic form of this brain injury and underlies most of the neurologic morbidity encountered in survivors of premature birth. Prevention of PVL now seems ultimately achievable because of recent neurobiologic insights into pathogenesis. The pathogenesis of this lesion relates to three major interacting factors. The first two of these, an incomplete state of development of the vascular supply to the cerebral white matter, and a maturation-dependent impairment in regulation of cerebral blood flow underlie a propensity for ischemic injury to cerebral white matter. The third major pathogenetic factor is the maturation-dependent vulnerability of the oligodendroglial (OL) precursor cell that represents the major cellular target in PVL. Recent neurobiologic studies show that these cells are exquisitely vulnerable to attack by free radicals, known to be generated in abundance with ischemia-reperfusion. This vulnerability of OLs is maturation-dependent, with the OL precursor cell highly vulnerable and the mature OL resistant, and appears to relate to a developmental window characterized by a combination of deficient antioxidant defenses and active acquisition of iron during OL differentiation. The result is generation of deadly reactive oxygen species and apoptotic OL death. Important contributory factors in pathogenesis interact with this central theme of vulnerability to free radical attack. Thus, the increased likelihood of PVL in the presence of intraventricular hemorrhage could relate to increases in local iron concentrations derived from the hemorrhage. The important contributory role of maternal/fetal infection or inflammation and cytokines in the pathogenesis of PVL could be related to effects on the cerebral vasculature and cerebral hemodynamics, to generation of reactive oxygen species, or to direct toxic effects on vulnerable OL precursors. A key role for elevations in extracellular glutamate, caused by ischemia-reperfusion, is suggested by demonstrations that glutamate causes toxicity to OL precursors by both nonreceptor-and receptor-mediated mechanisms. The former involves an exacerbation of the impairment in antioxidant defenses, and the latter, an ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor-mediated cell death. Most importantly, these new insights into the pathogenesis of PVL suggest potential preventive interventions. These include avoidance of cerebral ischemia by detection of infants with impaired cerebrovascular autoregulation, e.g. through the use of in vivo near-infrared spectroscopy, the use of free radical scavengers to prevent toxicity by reactive oxygen species, the administration of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor antagonists to prevent glutamatemediated injury, or the use of maternal antibiotics or anticytokine agents to prevent toxicity from maternal/fetal infection or inflammation and cytokines.

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“…The authors concluded that circulating endothelium must have attached and proliferated to cover the suspended material. Gaynor et al 5 measured the number of circulating endothelial cells (CECs) in the blood of rabbits administered a dose of endotoxin, and reported an increase in the CEC concentration, which suggested that CECs could serve as a marker to measure vascular injury. Indeed, CEC concentrations have been found to be altered in patients with a variety of vascular injury and disease, including coronary angioplasty, 6 acute coronary syndromes and unstable angina, 7 peripheral vascular disease, 8 and inflammatory vasculitis, 9 when conditioning for bone marrow transplantation, 10 and during organ transplant rejection.…”

Section: Introduction and Initial Discovery Of Endothelial Progenitormentioning

confidence: 99%

Working hypothesis to redefine endothelial progenitor cells

et al. 2007

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Vascular Lesions: Possible Pathogenetic Basis of the Generalized Shwartzman Reaction

Cited by 143 publications

References 13 publications

Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation.

Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation.

Neurobiology of Periventricular Leukomalacia in the Premature Infant

Working hypothesis to redefine endothelial progenitor cells

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