Experimental Study On The Effects Of Chronic Inflammation In The Development Of Atherosclerosis

Background and Objective : Atherosclerosis(AS) is one of the commonest pathological changes of cardiovascular diseases, which brings great threaten to patients' health. The main factors that can cause atherosclerosis includes hyperlipoidemia, hypertension, infection etc. But the exact pathogenesis remains unclear.In recent years the hypothesis of response-injury has been accepted by most scholars.The hypothesis indicates that chronic inflammation and disordered iipid metabolism are the major characteristics of atherosclerosis, and in the development of AS, chronic inflammation and disordered lipid metabolism interact by immune responses. So, atherosclerosis is also considered as a autoimmune disease. But the hypothesis doesn't elucidate what the way by which they interact is.Toll-like receptors are the receptor family existing at the cell surface ,which may recognize the pathogen-associated molecular patterns and have a close relationship with innate immunity. In the course of innate immunity binding of their cognate ligands, TLRs recruit adaptor molecules to their intracellular signaling domain, leading to the activation of a series of kinases, NF-kB, and direct regulation of immune-responsive genes, and at last, some pre-inflammatory factors, such as TNF-α, IL-1 , IL-6 etc, got released. Up to date, 12 members of the TLR family have been identified in mammals, and each has a main ligand. Among the TLR family, TLR4 is found firstly and most researched.The latest study showed that TLR4 acted as a bridge connecting chronic inflammation and disordered lipid metabolism: on the one hand, oxidized lipoprotein can activate immune cells by TLR4 to let a series of inflammation cytokines free, and on the other hand, flammatory cytokines also may accelerate the speed of lipoprotein oxidation, and increase the percentage and content of biological activate lipoprotein.The uppermost ligand of TLR4 is lipopolysaccharides(LPS). LPS widely exist in gram negative bacteria, virus and Chlamydia etc. Among all the LPS , the one consist in adventitia of gram negative bacteria also called bacterial endotoxin . Bacterial endotoxin isa typical inflammation stimulator. It has the strongest tendency to cause inflammation and Lipid A is its biological activity centre. At present Bacterial endotoxin has been widely investigated in vascular inflammatory pathological changes . The researches of TLR and the inflammatory response of TLR-mediated have become a new hot research field about the etiopathogenesis of atherosclerosis. The further research about them can help us to better understand the etiopathogenesis of atherosclerosis at the level of molecule.This research is studying the relationship of chronic inflammation in the development of atherosclerosis in Wistar rat mainly from the follow part: 1. To construct the AS model by the way of imitating the chronic inflammation process by injecting bacterial endotoxin into abdominal cavity periodically and at the same time feeding rats the high fat. 2. To reveal the interaction between multiple factors in the process of AS by testing the level of blood fat metabolism and inflammation and the damage extent of the organism. 3. To investigate the role of chronic inflammation in the development of AS by quantitatively analyzing the expression of TLR4 in artery blood vessel endothelium.Methods: Femal Wistar rats of 2~3 months , weighing from 170-200g were used. To construct the AS animal model, bacterial endotoxin was injected into rat abdominal cavity and at the same time, high fat was fed. All the rats were divided into two four groups by different diets: normal control group, normal fed and bacterial endotoxin injected group, high fat fed group and high fat fed and bacterial endotoxin injected group. The rats were killed after 2, 4, 8 and 12 weeks and sample of blood and tissues were collected. ELAS technique was use to monitor the level of IL-6, the level of Superoxide Dismutase was monitored by the use of xanthine oxidase and the level of Maleic dialdehyde was monitored by TBA method. The morphological changes of coronary artery and aorta were watched by light microscope. The expression of TLR4 in artery endothium was displayed by using immunochemistry method.Results: 1. Injecting bacterial endotoxin into rat abdominal cavity on the base of high fat diet would mainly promote the occurrence of foam cells, the hyperplasia of smooth muscle cells and make the artery lumina narrow, and can also occurred some pathological changes in accord with atherosclerosis, and besides the artery morphologic change is clearer than that in other groups.2. Both constantly hyperlipemia and exterior inflammatory stimulates may causeinflammatory reaction, and when both of them are present at the same time, the extent of inflammatory reaction is even more stronger than the effect by just either of them.3. Both hyperlipemia and exterior inflammatory stimulates may disrupt the balance between oxidation and anti-oxidation , weaken the organism's ablity to resist oxidation and make the results caused by attack of free radical more serious. And when both of them were present, at the same time, the extent of disequilibrium will get even more serious than that affected by either of them.4. Both hyperlipemia and exterior inflammatory stimulates may promote the expression of TLR4 in vascular endothium. And when both of them were present, the level of TLR4 expression will get higher even than that affected by oneoConclusion: 1. the chronic infection inflammation would promote the atherosclerosis to some extent, and at the same time they also indicate that there are more complicated factors in the development of AS.2. Both hyperlipemia and chronic infection inflammation can affect balance between oxidation and anti-oxidation and the extent of inflammatory reaction. When these two factors exist together, the extent of affection gets stronger, inflammatory reaction and oxidative damage get more serious, and the vascular morphological changes gets more significantly. All of them indicate us to pay more attention to the synergism of all kinds of risk factors in coronary heart disease.3. During the process of hyperlipemia and chronic infection inflammation the expressions of endarterium TLR4 both get stronger. And when the two factors are present at the same time the expression of TLR4 gets stronger remarkably. TLR4 would play a role as a bridge between the internal environment changes and the artery morphological changes. Besides hyperlipemia and chronic infection inflammation probably both promote the artery changes through TLR4. Thus it provides a new thought to investigate and cure AS in future.