ATHEROSCLEROSIS AND HLAMYDOPHILA (CHLAMYDIA) PNEUMONIAE

http://www.old-herborn-university.de/literature/books/OHUni_book_18.pdf

str. 22

"ATHEROSCLEROSIS AND HLAMYDOPHILA (CHLAMYDIA) PNEUMONIAE
ÅSA LJUNGH
Department of Medical Microbiology, Dermatology and Infection,
Lund University, Lund, Sweden.

SUMMARY
The concept that atherosclerosis was induced by environmental factors such as smoking and high fat intake was perturbated when inflammation was found to be prominent in atherosclerotic lesions. Chlamydophila pneumoniae but also other microbes inducing chronic endothelial infections have been implicated, particularly cytomegalovirus (CMV) and the gastric pathogen Helicobacter pylori. Large sero-epidemiological studies in different parts of the world have shown seroconversion to C. pneumoniae in patients with myocardial infarction, stroke and other forms of cardiovascular disease. The seroprevalence rates vary between 50 and 75%. Older individuals show higher seropositivity rates, suggesting that re-infection may be common. Using polymerase chain reaction (PCR) and immunohistochemistry, several studies have shown C. pneumoniae DNA in atherosclerotic lesions but not in normal vessels, although other studies have failed. Animal models with C. pneumoniae inducing atherosclerotic lesions have been established. The chlamydia LPS induces foam cell formation of monocytes, and the heat shock protein (Hsp) 60 oxidises low-density lipoproteins. Hsp 60 causes transcription of NF-κB and initiates deleterious immune response. Hsp 60, cross-reacting with human Hsp60, may also be involved in molecular mimicry which is part of the chronicity of C. pneumoniae infection. A peptide produced by C. pneumoniae mimics human heart muscle protein, which causes immune sentries. A co-infection of C. pneumoniae with H. pylori increased expression of vascular cell adhesion molecules (VCAM-1) in ApoE knockout mice, which may enhance atherogenesis."

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"PATHOGENESIS OF ATHEROSCLEROSIS
Atherosclerosis starts with fatty streaks in the endothelium which, with time, develop into fibrous plaque, i.e. a lipid core with a fibrous cap. Monocytes and T-cells are recruited to the vessel wall across an intact epithelium. This requires expression of leukocyte adhesion molecules (e-selectin, ICAM-1 and VCAM-1) which are transcriptionally regulated by NF-κB. Modified smooth muscle cells (SMC), macrophages, monocytes, T-lymphocytes and several inflammatory cytokines are abundant in the plaques (Noll, 1998). This is a result of endothelial dysfunction with accumulation of monocytes, macrophages and lymphocytes in the intima. Macrophages ingest lipid and become foam cells. SMCs proliferate and secrete extracellular matrix (ECM). When sufficient lipid has accumulated the core of the lesion becomes necrotic, and in the latter stages they become calcified. During atherogenesis, cytokines, growth factors, lipids, nitric oxide (NO) and other small molecules induce and regulate migration and proliferation of cells as well as interfere with lipid and ECM protein synthesis. Of these, TNF-α, often found in atheromatous plaques, enhances production of platelet-derived growth factor, which promotes proliferation of SMCs. These secrete a proteoglycan matrix important for the uptake of low-density lipoproteins (LDL). TNF-α further induces increased expression of cell adhesion molecules and leukocytosis, and inhibit lipoprotein lipase which leads to (i) aggregation of lymphocytes on the endothelium, and (ii) altered lipid metabolism and accumulation of triglycerides in the blood (Coles et al., 1998). Matrix metalloprotease (MMP) expression in plaques is also induced by TNF-α whereas NO synthesis can be suppressed. Decreased NO availability is common in early stages of atherosclerosis. Homocysteine has been shown to have toxic effects on endothelial cells, promote proliferation of vascular SMCs, and enhance monocyte chemotaxis, all factors which can be involved in the pathogenesis of atherosclerosis (Poddar et al., 1997). Hyper-homocysteinaemia was further shown to activate NF-κB in endothelial cells as a result of oxidative stress (Au-Yeung et al., 2004). Microbial agents may promote atherogenesis by evoking local inflammation in the arterial wall or by inducing endothelial injury during systemic infection (Figure 1). The human heat shock protein 60 (HSP60) can crossreact with bacterial antigens. Microbes may also promote atherogenesis indirectly by the evoked inflammatory reaction or by inducing changes in lipids, coagulation factors, homocysteine, MMPs or oxidative metabolites."

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"CHLAMYDOPHILA PNEUMONIAE –THE BACTERIUM
C. pneumoniae was first isolated from the conjunctiva of a child in 1965 in Taiwan, and therefore labelled TW-183. In 1983, it was isolated from the respiratory tract and designated AR-39. During some years it was hence designated “TWAR” but DNA homology studies and ultrastructural analyses defined it as its own species, C. pneumoniae, in 1989, beside C. trachomatis, C. psittaci and C. pecorum, a cattle pathogen (Grayston et al., 1989). In 1999, based on DNA homology studies, C. trachomatis remained within the genus Chlamydia whereas C. pneumoniae and C. psittaci were transferred to the genus Chlamydophila (Everett, 1999). The life cycle of chlamydial organisms has three distinct forms (Figure 2):

• the infectious form, elementary bodies (EB), specialised to survive extracellularly,
• an intracellular form, reticulate bodies (RB), which are metabolically active and capable of reproduction, and
• persistent bodies (PB).

EBs are phagocytosed by endothelial cells and monocytes in the respiratory tract, and differentiate into RBs which localise in inclusion bodies. RBs can revert to EBs which are released by cell lysis or turn into metabolically inactive PBs which may remain dormant for many years (Ngeh and Gupta, 2000): PBs are unsusceptible to antibiotics as well as to the immune system."

 

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"CONCLUDING REMARKS
There are substantial reports on the association with chronic infection and development of atherosclerosis. It is likely that chronic infections caused by different microbial agents can induce similar vascular pathology, and that the infectious burden, as revealed by a high CFP is related to peripheral artery disease but not a normal or low CFP value (Nloemenkamp et al., 2002.). Hence linkage to one certain agent is hampered. During the last decade efforts have been made to standardise diagnostic methods, viz. serology and molecular microbiology methods. This will help to elucidate the issue of microbial infections as a cause of one of the greatest causes of morbidity and mortality. A clear link between infection and atherosclerosis will direct preventive therapies towards microbial disease and effects thereof. However, C. pneumoniae located in lymphocytes as well as in monocytes are refractory to antibiotic treatment (Yamaguchi et al., Gieffers et al., 2001).

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