Endothelial cell damage

There is a long-standing hypothesis that the microvasculature plays a pathological role in forms of chronic inflammatory polyarthritis, particularly RA (Rothschild and Masi, 1982). One of the proposed mechanisms of vascular damage in connective tissue disease is the direct action of a cytotoxic serum factor inducing endothelial cell damage. Blake et al. (1985) have su ested that the vascular abnormalities associated with RA may be linked to oxidized lipoproteins because they are cytotoxic to endothelial cells. 

M. (1982). Auto-oxidative damage in Beh het s disease-endothelial cell damage following the elevated oxygen radicals generated by stimulated neutrophils. Clin. Exp. Imunol. 49, 247-255. 

Sala, R., Moriggi, E., Corvasce, G. and Morelli, D. (1993). Protection by N-acetylcysteine a iinst pulmonary endothelial cell damage induced by oxidant injury. Eur. Respir. J. 6, 440-446. 

EHEC all ages/primarily in US, Canada, Europe, South America and Japan 12-60h acute bloody (hemorrhagic colitis in 31— 61%) occasionally nonbloody diarrhea SLT-I and -II - bloodstream - inhibition of protein synthesis - endothelial cell damage - microvascular thrombosis - hemolytic-uremic syndrome... 

Hypoxia-ischemia disrupts the blood-brain barrier and damages endothelial cells. Damage to the blood-brain barrier (BBB), which occurs gradually following isch-emia-reperfusion, reflects the vulnerability of the cellular... 

TNF-a is considered the primary mediator of sepsis, and concentrations are elevated early in the inflammatory response during sepsis, and there is a correlation with severity of sepsis. TNF-a release leads to activation of other cytokines associated with cellular damage and it stimulates release of arachidonic acid metabolites that contribute to endothelial cell damage. IL-6 is a more consistent predictor of sepsis as it remains elevated for longer periods of time than does TNF-a. 

The superoxide anion (O2 ) exhibits numerous physiological toxic effects including endothelial cell damage, increased microvascular permeability, formation of chemotactic factors such as leukotriene B4, recruitment of neutrophils at sites of inflammation, lipid peroxidation and oxidation, release of cytokines, DNA singlestrand damage, and formation of peroxynitrite anion (ONOO-), a potent cytotoxic and proinflammatory molecule generated according to equation 7.210 ... 

Normal endothelial cells modulate the effects of homocysteine by facilitating the S-nitrosilation of homocysteine by nitric oxide. The formed S-nitrosothiol adduct is a potent vasorelaxing substance [2,108]. So, when high levels of homocysteine occur, they may overcome or impair the endothelial capacity for NO synthesis. Endothelial cell damage may result from increased production of reactive oxygen species or from impaired production of nitric oxide [3,102]. In endothelial cells, total homocysteine reduces the levels of tetra-hydrobiopterin (BH4), relative to dihydrobiopterin (BH ), thereby creating a dysfunctional eNOS causing a reduced amount of nitric oxide [1,101],... 

A rapidly reversible first-dose syndrome (dyspnea, hypoxia, tachycardia, and hypotension) can occur within the first hour after the first continuous infusion in 15-30% of patients (5). A dose-limiting vascular leak syndrome was consistently described in patients receiving GM-CSF 30 micrograms/kg/day or more, but lower doses were also reported to induce a clinically relevant capillary leak syndrome (SEDA-22, 408) (20,21). Continuation of GM-CSF treatment at the same dose or lower and careful management was possible in some patients. Endothelial cell damage with an increase in the transcapUlary escape rate of albumin and the possible role of IL-1 and TNE production by GM-CSF-activated monocjdes were... 

The above-mentioned studies have suggested or proposed a direct renal injury by IL-2, but none of them have been able to conclusively distinguish a direct IL-2 renal effect from simple renal under-perfusion severe enough to cause ischemia and ATN. The toxicity of IL-2 has been dearly assodated with widespread endothelial cell damage and capillary leak [25]. This is consistent with a generahzed, systemic effect of IL-2 rather than proof of a specific direct effect on the kidney. 

A second form of cyclosporine-induced nephrotoxicity is acute thrombotic microangiopathy. The mechanism for induction of this toxicity is unclear but may be due to a direct toxic effect of cyclosporine on renal arterioles and glomerular capillaries. Histologically, arterioles exhibit protein deposits while glomeruli show thrombosis and endothelial cell damage. These effects are similar in nature to transplant rejection thrombotic microangiopathy, but arcuate and interlobular arteries rather than arterioles are primarily affected with transplant rejection. 

Gram-negative bacteria contain lipopolysaccha-rides (endotoxins) in their outer cell membranes (Chapter 19) these can remain in an active condition in products even after cell death and some can survive moist heat sterilization. Although inactive by the oral route, endotoxins can induce a number of physiological effects if they enter the bloodstream via contaminated infusion fluids, even in nanogram quantities, or via diffusion across membranes from contaminated haemodialysis solutions. Such effects may include fever, activation of the cytokine system, endothelial cell damage, all leading to septic and often fatal febrile shock. 

Sacks, T., Moldow, C. F., Craddock, P. R., Bowers, T. K., and Jacob, H. A., Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes, J. Clin. Invest., 61, 1161, 1978. 

Endothelial cell damage, platelet dysfunction, myocardial suppression, release of cytokines and other mediators of shock/ inflammation... 

Many of the features observed in poisoning can be explained by ricin-induced endothelial cell damage, with fluid and protein leakage and tissue oedema, causing a so-called vascular leak syndrome . Disseminated intravascular coagulation has been observed in experimental animals following intravenous ricin administration and this is also likely to reflect endothelial cell damage. 

Cryoglobulinaemic vasculitis. Cutaneous or systemic vasculitis caused by fiigolabile proteins ( - cryoglobulins, cryofibrinogen) that leads to increased viscosity, protein precipitation or gelatin-ification, complement activation, and endothelial cell damage, especially in the cold. Frequently associated with chronic hepatitis C or B infection, but can also be induced by other infections and malignancies. 

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