| Chlamydia pneumoniae(C. pneumoniae)is a pathogen causing respiratory infections such as sinusitis,bronchitis, and pneumonia,has recently been implicated as a potential risk factor in atherosclerosis. A potential role for C. pneumoniae in atherosclerosis has been suggested by studies docu -menting an association between patients with coronary artery diseas e and increased antibody titers to this organism.Furthermore, the presenc e of C. pneumoniae in atherosclerotic lesions has been shown by differen t techniques, such as electron microscopy, immunocytochemistry, PCR and culture. Still, the mechanisms by which C. pneumoniae might contribute to the pathogenesis of atherosclerosis remain unclear. Additional evi -dence supporting a relationship between C. pneumoniae and atherosclero-sishas come from in vitro experiments showing the ability of this organi -sm to replicate in cells of the vascular wall (i.e, endothelial cells, aorti c smooth muscle cells, and macrophages). A major inflammatory event that takes placeduring atherosclerosis is the accumulation of monocytes from the circulation into the arterial intima .Chemokines, a family oflow-molecular-weight proteins(8-12kDa), which can cause the directed migration of leukocytes in vitro,are produced by endothelial cells(Ecs)inresponse to molecules involved in inflammatory reactions,immunity andthrombosis.The Ecs chemokine including members of both CXC(IL-8,epithelial-cell-derived neutrophil ) and CC (monocyte chemoattractant protein MCP-l).Monocyte adhesion , migration, and infiltration into the atheroma are crucial to cause atherosclerosis. Chemokines mediate in part,in recruiting monocytes and lymphocytes into sites of atheroscleroticlesion.Monocyte chemotactic protein 1 (MCP-1), a member of the C-C chemokine family, has been proposed to play an important role in the early events of atherogenesis. Recent studies suggest that mice deficient in MCP-1 are less susceptible to experimental atherosclerosis. MCP-1 isa 14-kDa glycoprotein secreted by many cells, including endothelial cells and vascular smooth muscle cells, which can be transcriptionally activated by different stimuli, such as tumor necrosis factor alpha, interl-eukin-l,and lipopolysaccharide (LPS). A variety of signaling mechanismsare involved in the intracellular activation of MCP-1 gene expression by these stimuli, including activation of phospholipaseC, generation ofdiacylglycerol, and activation of protein kinase C and tyrosine kinases. Subsequent events include generation of reactive oxygen intermediates and activation of transcription factor NF- k B.There is evidence that NF-k B is a major regulator of the transcriptional activation of MCP-1 in cytokine-activated human endothelial cells.In addition, other studies haveshown that NF- k B is activated during the early stages of atheroscleros is and may function as apoint of convergence of the diverse risk factorsassociated with this disease .Previous studies from this laboratory have shown that C.pneumoniae induces MCP-1 secretion from human endot-helial cells and promotes the trans endothelial migration of monocytes in vitro.Interestingly, infection with Chlamydia trachomatis does not result in stimulation of MCP-1.This divergence between species may reflect the presence of specific features in C. pneumoniae that activate different signaling pathways within human endothelial cells. To provide a better understanding of the underlying mechanisms involved in the C.pneumoniae dependent activation of MCP-1 in infected endothelial cells, this study investigated the role of NF- k B in MCP-1 gene expression.In the present study, we have used RT-PCR to analyze mRNA expression for monocyte chemotactic protein 1 (MCP-1) and interleukin 8 (IL-8) in human microvascular endothelial cell(HUVEC) at various tim -es following infection with C.pneumoniae ,and regulate effect of nuclear factor-kappa B on the expression of IL-8, MCP-1. As compared with expression of IL-8 and MCP-1 stimulated with TNF-a alone HUVECs. We have shown that the levels of IL-8 and MCP-1 were increased, but their time course were significantly different, the levels of IL-8 and MCP-1 production began to increase at 0.5 hour, but maximal IL-8 production was seen at the 8-hour time point, and MCP-1 production is 12-hour. The NF- k B activity was observed at 30 minute after infect with C.pneumoniae by immunofluorescence .Cytoplase to nuclear tanslocation of NF- k B was necessary for the response. Mice are a natural host for two pneumonia-causing chlamydial agents. Experience showed that mice were susceptible to intranasal inoculation with C. pneumoniae. wereport on a mouse of pneumonitis that should be useful for studing the pathagenesis of C. pneumoniae. We therefore evaluated the effect ofC.pneumoniae infection on atherosclerosis in atherosclerosis- wild-type C57BL/6J mice. Six-to 8-week-old female mice were infected intranasallywith live C.pneumoniae and then fed a standard chow orhyperlipidemicdiet for 12 weeks. Total cholesterol, HDL cholesterol, and triglyceride measurements on serum samples were performed with the useof standardenzymatic colorimetric methods. Polymerase chain reaction analysis oflung tissue confirmed successful infection with C. pneumoniae, and radi -oimmunity assays demonstrated levels of IL-6 and IL-8. Then observedwhether C. pneumoniae infection plays a causal role in atherosclerosis and whether serum cholesterol contributes to the atherogenic effects of C. pneumoniae, and that antibiotic therapy might prevent this process. The present study suggests that the levels of IL-6 and IL-8 significantly increase after infect with C. pneumonia in In hyperlipidaemic mouses , chronic chlamydial infection by itself does not initiate atherosclerotic lesions and thus must act in concert with other cardiovascular risk factors to promote induction and progression of atherosclerosis. In the C57BL/6J mouse model, we were able to demonstrate that chronic C. pneumoniae infection accelerates atherosclerotic lesion development in diet-induced hyperlipidemic mice, but not in normolipidemic mice. Clarithromycin, like all macrolides, shows potent in vitro activity against C. pneumoniae and is a recommended treatment for community-acquired pneumonia and lower-respiratory-tract infection with this organism. The objectives of the present study was that a macrolide (clarithromycin) active against C. pneumoniae could prevent or reduceatherosclerotic changes in rabbits fed cholesterol-enriched chow in the mice. In the future, it would be worthwhile to evaluate whether chronic C. pneumoniae infection promotes induction and progression of atherosclerosis in conjunction with other cardiovascular risk factors, such as cigarette smoking, hypertension, or diabetes. In conclusion, C. pneumoniae infection plays a causal role in atherosclerosis... |
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