International journal of tissue reactions最新文献

The scavenger receptor BI is a cell surface lipoprotein receptor for selective high-density lipoprotein (HDL) cholesterol uptake in the liver and steroidogenic tissues. Studies of genetically manipulated strains of mice have revealed that SR-BI plays a key role in regulating HDL metabolism, cholesterol transport to steroidogenic tissues and bile cholesterol secretion. Furthermore, SR-BI protects against the development of atherosclerosis and is required for normal female fertility. If SR-BI has similar functions in lipoprotein metabolism and atherosclerosis in humans, it may represent a new target for the prevention and/or treatment of atherosclerotic cardiovascular disease.

Hepatic lipase (HL) and lipoprotein lipase (LPL) are the two major lipolytic enzymes responsible for the hydrolysis of triglycerides and phospholipids present in circulating plasma lipoproteins. Both lipases are attached to the vascular endothelium via cell surface proteoglycans. HL is primarily involved in the metabolism of chylomicron remnants, intermediate density lipoproteins and high-density lipoproteins whereas LPL catalyzes the hydrolysis of triglycerides from chylomicrons and very low-density lipoproteins. In addition to their traditional function as lipolytic enzymes, HL and LPL appear to serve as ligands that mediate the interaction of lipoproteins to cell surface receptors and/or proteoglycans. Over the past several years significant advances have been made in our understanding of new, alternative mechanisms by which HL and LPL modulate lipoprotein metabolism and the development of atherosclerosis in vivo. This review will summarize some of the new insights generated from the study of transgenic and knockout HL and LPL animal models as well as somatic gene transfer of these two lipases.

Several in vivo studies have been performed on the role of the macrophage scavenger receptor class A (SR-A) in atherosclerosis using SR-A knockout mice. The results indicate both an antiatherogenic and a proatherogenic role of SR-A, depending on the nature of the animal model serving as the athero-susceptible background. To study the role of SR-A in a different model, we generated a transgenic mouse model with high level expression of the human SR-A gene using a 180 Kb yeast artificial chromosome (MSR1 transgenic mice). These mice show increased expression of SR-A according to the natural expression pattern. The MSR1 transgenic mice were crossed onto a low-density lipoprotein receptor deficient background and were fed a high fat diet for 10 weeks. After this period, the size of the atherosclerotic lesions in the proximal aorta was measured. Surprisingly, atherosclerosis was significantly reduced in the MSR1 transgenic mice. In a second study, the effect of SR-A was examined in APOE-3 Leiden mice providing a different athero-susceptible background. To exclude nonmacrophage effects, bone marrow was transplanted from MSR1 mice and wild-type littermates to APOE-3 Leiden transgenic mice. After 8 weeks on a high fat diet, atherosclerosis in the mice that had received MSR1 bone marrow was reduced compared with mice that had received wild-type bone marrow. This difference reached statistical significance when individual cholesterol exposure of the mice was taken into account. Both experiments indicated an antiatherogenic role of the SR-A. This observation cannot be explained easily by SR-A function in foam cell formation because in MSR1 macrophages in vitro foam cell formation is increased. Alternatively, however, SR-A may affect the activation of macrophages. Hence the response to lipopolysaccharide was measured in MSR1-transgenic macrophages. These macrophages showed a reduction in their activation in response to lipopolysaccharide, as measured by nitric oxide production. These data show that an elevated level of SR-A expression reduces atherosclerosis, potentially by modifying the response of macrophages to activation signals in the plaque.

Insight into the role of apolipoprotein (apo) E in lipoprotein metabolism and atherosclerosis has increased dramatically with the generation and analysis of novel transgenic, knockout and knockin mouse models. Moreover, the recent development and application of somatic gene and cell transfer technologies which can express (or delete) apoE in specific tissues of virtually any mouse model have further added to this increase in knowledge. It is now well established that apoE plays a role in virtually every step in the metabolism of very low-density lipoproteins and in the efflux of cholesterol from macrophages. In this review we will discuss recent insights into the role of apoE in these processes with particular emphasis on the specific effects of variation in apoE structure and quantity.

Studies in humans on the in vivo metabolism of apolipoprotein (apo) Cs have been hampered by the highly complex nature of lipoprotein metabolism, which can be influenced by multiple genetic and environmental factors. In order to gain new insights into the function of the individual apoCs in lipoprotein metabolism, several laboratories have created mouse models lacking or overexpressing the respective APOC genes through the technologies of gene targeting and transgenesis. Until now, the only well-established in vivo metabolic function of apoC-I has been its inhibitory action on the uptake of very low-density lipoprotein (VLDL) via hepatic receptors, particularly the low-density lipoprotein (LDL) receptor-related protein. Consequently, the presence of apoC-I on the lipoprotein particle may prolong its residence time in the circulation and subsequently facilitate its conversion to LDL. ApoC-II, on the other hand, is a major activator of lipoprotein lipase, which is required for an efficient processing of triglyceride-rich lipoproteins in the circulation. However, an excess of apoC-II on the lipoprotein particle has been suggested to inhibit the lipoprotein-lipase-mediated hydrolysis of triglycerides. From studies with APOC3 transgenic and ApoC3-knockout mice, it appears that apoC-III inhibits the lipolysis of triglyceride-rich lipoproteins by hampering the interaction of these lipoproteins with the heparan sulfate proteoglycan-lipoprotein lipase complex. Subsequently, the poorly lipolyzed apoC-III-containing lipoprotein particles may accumulate in plasma because of their lower binding affinity towards hepatic receptors due to a change in lipid composition, particle size or the presence of apoC-III on the particle itself. From these data it can thus be concluded that all C apolipoproteins specifically modulate the metabolism of triglyceride-rich lipoproteins, which may contribute to the development of hyperlipidemia and other lipoprotein abnormalities in humans.

Mice given sodium valproate 0.71% weight/volume in drinking water for 7, 14 and 21 days were assessed for pathomorphological changes in liver and kidney tissues at certain time points. This treatment caused a marked alteration in liver and kidney cell morphology, which was proportional to the period of treatment. This treatment induced fatty degeneration of hepatocytes, increased the number of Kupffer cells and caused them to swell. These changes were irregular after days 7 and 14 of treatment but with time increased in intensity, producing inflammation of the portal tracts, albuminous degeneration and necrosis of septa. Precirrhotic conditions, cirrhosis, acidophilic degeneration of hepatocytes and glassy eosinophilic homogenous cytoplasm were a constant feature after 21 days' treatment. In some cases the portal area was invaded by small, round inflammatory cells. Hepatocytes in this group were swollen, with large nuclei and increased amounts of condensed chromatin. The kidney sections of the same animals revealed severe morphological changes, indicated by significant epithelial necrosis and sloughing of tubules, as well as cast formation and mild lymphocytic infiltrate after 21 days' treatment. The results suggest that the histopathologic changes induced by sodium valproate are dependent upon the duration of exposure of these organs to the drug. Prolonged use of this drug should be carefully assessed.

Resveratrol is a grape component with complex pharmacology related to its antioxidant activity. Little is known about the direct effects of resveratrol on the myocardium. We tested whether resveratrol administration before ischemia could attenuate ischemic/reperfusion damage. We examined how resveratrol affects high-energy phosphate metabolism (31P-nuclear magnetic resonance) and contractility of isolated Langendorff perfused rat hearts subjected to 20 min no-flow ischemia and 30 min reperfusion. During 10 min resveratrol infusion (10 microM) before ischemia, basal phosphorylation potential dropped by 40% (p < 0.05 vs. preinfusion value) without affecting contractility. The level of effluent adenosine was increased by 68%, parallel to a 50% increase in coronary flow. Resveratrol significantly improved postischemic recovery of rate-pressure product (62 +/- 5.2 vs. 23 +/- 8.1% of controls; p < 0.05). The metabolic pattern following resveratrol infusion was similar to that produced by ischemic preconditioning, suggesting that an increase in adenosine availability is involved in cardioprotection.

Oxidative damage to DNA, RNA, proteins and cell membranes occurs when the cellular concentration of reactive oxygen species exceeds the capacity of the cell to eliminate them. Aerobic prokaryotic and eukaryotic organisms have developed a set of cell defense systems to mitigate the damaging effects of reactive oxygen species. Epithelial surfaces contain antioxidants that could be expected to provide a defence against environmental stress caused by reactive oxygen and nitrogen species. Skin, which has a highly differentiated and complex structure, is particularly vulnerable to free radical damage because of its contact with oxygen and with other environmental stimuli. Fruit and vegetables contain several classes of compounds that when ingested can potentially contribute to endogenous modulation of antioxidant defences. The purpose of this study was to investigate the effectiveness of a natural extract derived from rosemary to protect free radical-induced skin damage. We provide evidence that an alcoholic extract of rosemary leaves, Rosm1, is endowed with strong antioxidant activity and, as evaluated by both in vitro and in vivo systems, is capable of inhibiting oxidative alterations to skin surface lipids. The present study provides a preclinical perspective on the interface between the biochemical properties of a natural extract isolated from rosemary leaves, a better understanding of the endogenous antioxidant potential of skin and the real validity of natural antioxidant biotechnology in antiaging skin management.

Chondrocalcinosis is a joint disease caused by deposits of calcium pyrophosphate dihydrate (CPPD) crystals with manifestations that may include intermittent attacks of acute arthritis or enthesitis. If no crystals are found on synovial analysis, the diagnosis in clinical practice is based on typical radiographic findings, although it is now recognized that some signs of the disease could also be seen by ultrasound. We studied six patients with elbow enthesopathy without radiographic evidence of CPPD that presented ultrasound findings suggesting joint calcification. On the basis of these echographic findings, the diagnosis was then ascertained by x-ray examination of the most commonly involved joints. Ultrasound is a method of proven interest in the evaluation of rheumatic patients and could be an important tool in diagnosing CPPD.