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Victoria C Cogger

Publications and source records attributed to Victoria C Cogger.

11 recordsLinked to original sources
PubMed2006

Hyperlipidemia and surfactants: the liver sieve is a link.

Poloxamer 407 is a ubiquitous synthetic surfactant that causes massive hyperlipidemia and atherosclerosis in the rodent. The initial step in hepatic metabolism of lipoproteins is their transfer through 100-200 nm pores (fenestrations) in the liver sinusoidal endothelial cell, prior to receptor-mediated uptake. The 'liver sieve hypothesis' emphasizes the role of these fenestrations in the regulation of lipoprotein disposition. Here we show that P407 causes dramatic defenestration of the liver sinusoidal endothelium in vivo. By 24h after intraperitoneal administration in mice, fenestrations were reduced by approximately 80% coincident with a 10-fold increase in plasma lipids. Moreover impulse-response experiments in the perfused rat liver showed that P407 prevented the passage of small chylomicrons across the liver sinusoidal endothelium. Defenestration was also induced acutely with P407 in isolated liver sinusoidal endothelial cells, indicating this is a direct effect of P407 on fenestrations. The results establish the role of the porosity of the liver sinusoidal endothelial cell as a pivotal yet relatively unrecognised mechanism for hyperlipidemia. Furthermore, the results establish an intriguing mechanism for surfactant-induced hyperlipidemia. Thus the liver sieve is a new and untapped target for the treatment and prevention of hyperlipidemia.

Animals↗
PubMed2005

Hepatic pseudocapillarization in aged mice.

Age-related changes in the hepatic sinusoid of the rat, human and baboons called pseudocapillarization have been discovered and are important because they are considered to be implicated in the pathogenesis of some age-related diseases. In this study, we investigated whether similar changes occur in the livers of old mice. Livers of young (3-4 months) and old (20-24 months) mice were perfusion-fixed and studied using electron microscopy and immunohistochemistry. The thickness of the sinusoidal endothelium was increased in old mice (154+/-4 versus 244+/-8 nm, P<0.001). There was a reduction in fenestrations within the endothelium (porosity decreased from 4.1+/-0.3 to 2.2+/-0.2%, P<0.001). There was perisinusoidal staining with Sirius red in old mice, however, expression of laminin and von Willebrands factor was similar in young and old mice. Novel perisinusoidal fat-engorged stellate cells were found extensively in the old mice. This study confirmed that pseudocapillarization is a widespread aging change in the liver, now documented in several species including the mouse. Mice are an appropriate animal model for studying aging and the hepatic sinusoid.

Aging↗
PubMed2005

Age-related changes in the hepatic sinusoidal endothelium impede lipoprotein transfer in the rat.

The mechanisms for the association of old age with post-prandial hyperlipidemia and atherosclerosis are not well understood. Post-prandial hyperlipidemia has emerged as a significant risk for atherosclerosis. The liver is the central organ for lipoprotein metabolism. The initial step in the hepatic uptake of post-prandial lipoproteins is their transfer from the hepatic sinusoidal capillary lumen across the hepatic sinusoidal endothelium into the space of Disse. Here, they access hepatocytes for receptor-mediated uptake. We proposed that fenestrations (pores) within the hepatic sinusoidal endothelium filter lipoproteins on the basis of size. Recently we discovered age-related changes in the sinusoidal endothelium (pseudocapillarization), including reduction in the porosity of the endothelium. Using the impulse response technique in perfused rat livers, we found that aging is associated with impaired hepatic transendothelial transfer of chylomicrons with diameters smaller than those of fenestrations. In conclusion, age-related pseudocapillarization of the hepatic sinusoidal endothelium provides a novel mechanism for the association of old age with impaired hepatic lipoprotein metabolism and with atherosclerosis.

Aging↗
PubMed2004

The effects of oxidative stress on the liver sieve.

BACKGROUND/AIMS: Oxidative stress is implicated in the pathogenesis of age-related and disease-associated changes in the hepatic sinusoid. We studied the effects of oxidative stress on the morphology of the liver, focusing specifically on the hepatic sinusoidal endothelium (the 'liver sieve'). METHODS: The effects of tert-butyl hydroperoxide on the intact liver and isolated sinusoidal endothelial cells were assessed by electron microscopy, immunohistochemistry and biochemical analysis. RESULTS: Immunohistochemistry revealed a dose-dependent increase in peri-sinusoidal 3-nitrotyrosine staining, particularly in the regions adjacent to the portal triads. Electron microscopy showed dose-dependent formation of large intracellular gaps in the sinusoidal endothelium with reduction in the diameter of the remaining endothelial fenestrations. Activated Kupffer cells extending processes through the fenestrations to contact hepatocytes were noted. Biochemical analysis of total liver tissue showed no significant changes in malondialdehyde content but a decrease in the ratio of GSH to GSSG. tert-Butyl hydroperoxide administered directly onto isolated liver sinusoidal endothelial cells was associated with similar gap formation, indicating a direct effect on the endothelial cells by tert-butyl hydroperoxide. CONCLUSIONS: Oxidative stress selectively damages hepatic sinusoidal endothelial cells. This has implications for those processes associated with changes in the sinusoidal endothelium such as ageing, cirrhosis and exposure to hepatotoxins.

Animals↗
PubMed2004

The hepatic pharmacokinetics of doxorubicin and liposomal doxorubicin.

To determine the role of the hepatic sinusoidal endothelium in the hepatic disposition of liposomal doxorubicin, we compared the hepatic pharmacokinetics of doxorubicin hydrochloride and the pegylated, liposomal formulation of doxorubicin (Caelyx). The multiple indicator-dilution technique and electron microscopy were used to study the disposition of doxorubicin and liposomal doxorubicin in the rat liver. Doxorubicin had a volume of distribution 1.56 +/- 0.45 times greater than that of the extracellular marker, sucrose, whereas liposomal doxorubicin had a volume of distribution 0.56 +/- 0.30 times smaller than that of sucrose (P < 0.001). The recovery of doxorubicin was less than that of liposomal doxorubicin (70 +/- 24% versus 94 +/- 17%, P < 0.05). The disposition of liposomal doxorubicin was found to be flow-limited, whereas a permeability-limited sequestration model fitted doxorubicin. The transfer of doxorubicin across the hepatocyte membrane was symmetrical (permeability - surface area product for influx 0.02 +/- 0.01 ml s/g versus 0.03 +/- 0.02 ml s/g for efflux) and consistent with diffusion. Electron microscopy confirmed that liposomes were restricted entirely to the sinusoidal lumen and none were seen in the extracellular space of Disse. Liposomal doxorubicin is restricted to the sinusoidal lumen, presumably secondary to steric exclusion by fenestrations in the sinusoidal endothelium. This provides the mechanism for the longer half-life and reduced hepatic extraction of liposomal doxorubicin compared with doxorubicin. The sinusoidal endothelium and fenestrations within the sinusoidal endothelium have an important role in hepatic pharmacology and are important considerations when designing liposomal preparations.

Animals↗
PubMed2003

Age-related pseudocapillarization of the human liver.

Age-related changes in liver function are important because they may promote susceptibility to adverse drug reactions, neurotoxicity, atherosclerosis, and other important diseases in older people. Age-related changes in the rat hepatic sinusoidal endothelium, termed pseudocapillarization, have been described recently and these may contribute to hepatic impairment. The present study has examined surgical and post-mortem specimens with immunohistochemistry and transmission electron microscopy to determine whether pseudocapillarization also occurs in older humans. The age of the subject, independent of systemic disease or hepatic pathology in surgical and post-mortem samples of human liver, was associated with increased peri-sinusoidal expression of von Willebrand's factor, collagen I, collagen IV, and staining with Masson's trichrome. Electron microscopy revealed significant age-related thickening of the sinusoidal endothelium (young 165 +/- 17 nm, middle age 222 +/- 11 nm, older 289 +/- 9 nm, p < 0.001) with loss of fenestrations (young 7.7 +/- 0.7 per 10 micro m, middle age 3.6 +/- 0.5 per 10 micro m, older 1.5 +/- 0.4 per 10 micro m, p < 0.001), and age-related deposition of basal lamina and collagen. In conclusion, ageing in humans is associated with morphological changes in the sinusoidal endothelium and space of Disse which are presumptively related to the ageing process and potentially represent an important link between the ageing process and disease susceptibility.

Adult↗
PubMed2003

Hepatic sinusoidal pseudocapillarization with aging in the non-human primate.

BACKGROUND/AIMS: Age-related changes in the hepatic sinusoid termed pseudocapillarization have been reported in the rat and human and have implications for disease susceptibility in old age. In this study, we investigated whether similar changes occur in the livers of old baboons and thus represent a widespread aging change. METHODS: Liver tissue from five young baboons (5.4+/-0.5yrs) and five old baboons (21.8+/-0.7yrs) was compared by transmission electron microscopy, scanning electron microscopy and immunohistochemistry. RESULTS: The thickness of the sinusoidal endothelium was increased in old baboons (130+/-8 nm versus 186+/-9 nm, P<0.001) and the frequency of endothelial fenestrae decreased, with the porosity declining from 4.2+/-0.5% to 2.4+/-0.4% (P=0.006). The expression of laminin and von Willebrands factor was more extensive in old baboons. Novel perisinusoidal ring-shaped cells, probably fat-engorged stellate cells, were prominent in the old baboons. CONCLUSIONS: Pseudocapillarization is a significant age-related change in the baboon liver. Aging in baboons is associated with a novel aging change in the stellate cell not reported in other species. Hepatic pseudocapillarization is a widespread aging liver change found in several species including humans and other non-human primates.

Aging↗
PubMed2002

Hepatic pseudocapillarisation and atherosclerosis in ageing.

Cardiovascular disease secondary to atherosclerosis is the main cause of death and disability in industrialised countries, and ageing is the foremost risk factor for atherosclerosis. We present a hypothesis linking age-specific structural change in the liver with accepted pathogenic mechanisms leading to atherosclerosis. Ageing in the liver is associated with pseudocapillarisation of the sinusoidal endothelium, which is characterised by thickening of endothelium, basement membrane formation, and defenestration (loss of pores). Fenestrations (pores) normally form a liver sieve that allows passage of chylomicron remnants for subsequent uptake and metabolism by hepatocytes. Ageing is associated with impaired clearance of chylomicron remnants, postprandial hypertriglyceridaemia, and hence, atherosclerosis, which we propose is linked directly to loss of permeability of the liver sieve because of defenestration associated with pseudocapillarisation. Development of methods to maintain fenestrations of sinusoidal endothelium or to facilitate refenestration might be a new therapeutic strategy for management of cardiovascular disease in old people.

Age Factors↗