Role of Inflammation in the Development of Atherosclerosis - Essay Example

?RUNNING HEAD: Role of Inflammation in the Development of Atherosclerosis Role of Inflammation in the Development of Atherosclerosis of the student Under the guidance of University APA format Number of pages Date of submission Role of Inflammation in the Development of Atherosclerosis Introduction The role of inflammation in the development of atherosclerosis has been burgeoned over the last decade (Libby et al, 2011). Initially, the condition was thought to be lipid storage disease. However, based on experimental and basic sciences, it has been concluded that various molecular and cellular mechanism leading to inflammation actually contribute to atherosclerosis. This aspect is important because, such data helps in prognosis and prediction. In several animal models of atherosclerosis, there is evidence that inflammation is the key in the pathogenesis of atherosclerosis. Normal endothelium does not allow binding of white blood cells. It is only after the damage of endothelium, that a series of events are initiated which ensues in inflammation. In this essay, the role of inflammation in atherosclerosis will be discussed through review of suitable literature. Types of plaques Atherosclerosis is a condition in which the wall of the artery thickens due to accumulation of fatty substances like cholesterol and triglycerides (Binder & Witztum, 2011). The condition affects arterial blood vessels secondary to chronic inflammation of the innermost wall of the arteries and is mainly caused due to accumulation of macrophages. Accumulation of macrophages is promoted by low density lipoproteins. Stiffening of arteries occurs due to formation of multiple plaques within the arteries. There are basically 3 groups of atherosclerotic lesions and they are progressive atherosclerotic lesions, nonatherosclerotic intimal lesions and healed atherosclerotic plaques (Libby et al, 2011). Certain preexisting intimal lesions have intimal thickening and fatty streaks and adult lesions can arise from these Intimal thickening mainly involves the smooth muscles cells which lie in a proteoglycan-rich matrix. In early lesions, moderate cell replication can occur, but in adult lesions, they are mainly clonal. Fatty streaks are basically intimal xanthomata in which there is accumulation of fat-laden macrophages. These lesions have lesser number of smooth muscle cells and lesser number of T-lymphocytes. These are nonatherosclerotic lesions. In progressive atherosclerosis lesions, there can be stable or non stable plaques. The plaques have intimal thickening with deposition of lipid. But there is no evidence of necrosis (Binder & Witztum, 2011). Smooth muscle cells and proteoglycans overly the area of plaques along with T-lymphocytes and macrophages. Healed atherosclerotic plaques are those which have had thrombotic lesions, but have recovered. They are likely to progress to stenosis or aneurysms. Figure 1. Types of plaques (Spagnoli et al, 2007). Each atheromatous plaque has 3 distinct components (Libby et al, 2011). The first is the atheroma which is nothing but a nodular lump that is soft and flaky and has yellowish material in the center. The yellowish material has macrophages. The next component is cholesterol crystal complex that underlies the atheroma. The outer base of the lesions is calcified and this is the third component of plaque. Fibrous cap atheromas have a large lipidic-necrotic core that have cholesterol crystals, extracellular lipid and necrotized debris. All these are covered with a fibrous cap which is made up of smooth muscle cells amidst collagen-proteoglycan matrix and T-lymphocytes and macrophages. Table-1: Classification of atherosclerotic lesions (Spagnoli et al, 2007). Inflammation in the development of atherosclerosis The exact process of development of atherosclerosis is unknown. But, there is some evidence that the process is initiated by inflammation in response to low-density lipoprotein molecules. This is because; LDL particles are small in size and have a density that is suitable to get behind the endothelial layer. These particles and their contents get oxidized by free oxygen radicals, especially while in blood stream. They also carry triglycerides, cholesterol and cholesteryl esters from the liver to various tissues in the body and thus are able to deposit them under the endothelium. Inside the vessel wall, the LDL particles are more prone to oxidation. The oxidized LDL articles cause damage to the vessel wall, triggering a cascade of immune responses, which eventually leads to atheroma (Charo and Taub, 2011). Macrophages and T-lymphocytes gets accumulated resulting in specialized cells known as foam cells. The cells cannot process oxidized LDL and hence LDL eventually grows and ruptures. Since LDL carries cholesterol, rupture of LDL releases cholesterol that deposits in the vessel wall. This further triggers white blood cells and this is a vicious cycle. The artery eventually becomes inflamed. The cholesterol plaque causes enlargement of the muscle cells forming a hard cover over the area that is affected. It is this hard cover that causes narrowing of the artery causing reduction in the blood flow and increasing the blood pressure. The process of development of atheromas is known as atherogenesis. The process is characterized by remodelling of the arteries in which fatty substances known as plaques are accumulated in the subendothelial region. The process of building of atheroma is a slow process and occurs over several years. The first event in the pathophysiology of development of atherosclerosis is the endothelial injury (Feletou and Vanhoutte, 2006). Those who have dysfunction of the endothelial system are infact at increased risk of atherosclerosis and subsequent events like stroke. Endothelial damage or dysfunction leads to decreased production of nitric oxide, a natural selective vasodilator and also leads to increased expression of various factors like cytokines, prothrombotic factors, proinflammatory adhesion molecules and chemotactic factors. These inflammatory mediators, especially the cytokines can cause decreased bioavailability of nitric oxide, thereby causing increase in reactive oxygen species. This, inturn causes upregulation of vascular adhesion molecule 1 (VCAM-1) expression. VCAM-1 binds to the lymphocytes and monocytes present in the endothelium through nuclear factor expression induction, which infact is the first step in the vascular wall invasion. The next step is inhibition of leukocyte adhesion and induction of expression of monocyte chemotactic protein 1 (MCP-1) (McLaren et al, 2010). The latter causes recruitment of monocytes. Reduced nitric oxide levels cause increased endothelin-1 levels which are responsible for vascular tone. These levels are elevated significantly in patients with atherosclerosis and they also correlate with severity of the disease. Monocytes gradually get differentiated into macrophages which ingest oxidized LDL and get converted to foam cells (Gui et al, 2012). These are called so because of multiple cytoplasmic vesicles that occur due to high lipid content. The foam cells die but propagate inflammation. Smooth muscles proliferate and migrate from tunica media into tunica intima in response to cytokines that are secreted by the endothelial cells. This leads to formation of fibrous capsule that covers the fatty streak. Intact endothelium prevents such proliferation by release of nitric oxide. In the smooth muscles of the vascular muscular layer, several intracellular microcalcifications occur, especially in those adjacent to the atheromas. As the cells die, this eventually leads to extracellular calcium deposition between the outer portion of the atheromas and the muscular wall (Glakina and ley, 2009). One of the key steps in the ongoing inflammation is the delivery of cholesterol into the vessel wall by LDL protein particles. Only oxidized cholesterol particles are involved in the process of inflammation. Presence of high density lipoprotein prevents the inflammatory process as this removes cholesterol from the tissues and shuffles it back to the liver (Hansson et al, 2006). The platelets and the foam cells encourage proliferation and migration of smooth muscle cells which ingest lipids and get transformed to foam cells as discussed above. The cells become replaced by collagen. A protective fibrous cap forms between the lining of the artery and the fatty deposits. The capped fatty deposits which are now called atheromas produce certain enzymes which cause enlargement of the artery over a period of time. As long as the enlargement of artery occurs in a sufficient manner, there is no narrowing or stenosis that can be noted. If it is not so, then stenosis is seen. If the enlargement is beyond the proportion of the thickness of the thickened arterial wall, then it ensues in an aneurysm (Ley et al, 2011). There are basically 2 types of plaque and they are fibrolipid plaque and fibrous plaque. The fibrolipid plaque is characterized by accumulation of lipid laden cells below the tunica intima and the arterial wall. This type of plague does not cause narrowing of the lumen because the surrounding muscular layer expands to compensate. The core of the plaque consists of lipid-laden cells which are nothing but smooth muscle cells and macrophages. Other constituents include collagen, elastin, cholesterol esters, proteoglycans, fibrin and cellular debris (Binder and Chang, 2002). In advanced plaques, the core contains extracellular cholesterol deposits which are mainly released from burst or dead cells. The fibrous plaque, on the other hand lies under the intima and it results in expansion of the wall and thickening of the arteries. Atrophy of the muscular layer of the artery is frequently noted. The plaque contains collagen fibers, calcium precipitates and very rarely some lipid laden cells (Libby et al, 2009). The process of atherosclerosis is slow and occurs over several years. The condition is usually asymptomatic. Symptoms start appearing when ulceration of the atheromas occurs. This leads to thrombosis at the site of ulcer. This triggers a sequence of events that eventually leads to enlargement of clot. Sudden enlargement of clot can lead to obstruction of blood flow and if this complete, it can lead to ischemia (Spagnoli et al, 2007). This condition is frequently seen in coronary arteries and this can lead to myocardial ischemia and infarction. In non-fatal cases of myocardial infarction, the clot gets organized within the lumen and covers the rupture. When such episodes occur frequently, it can ensue in stenosis. Whenever the fibrous cap separating the soft atheroma ruptures, various fragments of the tissue are released and exposed. The fragments contain tissue factors and collagen. They activate platelets and also the coagulation system. They ultimately result in thrombus formation which causes acute obstruction of blood flow. The downstream tissues are then are depleted from nutrients and oxygen (Weber and Noels, 2011). Triggers for inflammation in atherosclerosis Based on the studies pertaining to animals with regard to inflammation and atherosclerosis, it is evident that certain biochemical markers help is evaluating atherosclerosis and help in prediction and prognosis. One such biomarker is C-reactive protein or CRP (Verma et al, 2006). The marker has a long half life. Infact, it is clear that CRP therapy may be useful to initiate statin therapy because they not only lower LDL but also attenuate inflammation related to plaque and influence the stability of plaque (Spagnoli et al, 2007). "In particular, prospective epidemiological studies have found increased vascular risk in association with increased basal levels of cytokines such as IL-6 and TNF-?; cell adhesion molecules such as soluble ICAM-1, P selectin, and E selectin; and downstream acute-phase reactants such as CRP, fibrinogen, and serum amyloid A" (Libby et al, 2002). Table. 2: Markers of inflammation in atherosclerosis (Spagnoli et al, 2007) Risk factors There are many risk factors for the development of atherosclerosis. Advanced age is one of the most important risk factors (Mc Carron et al, 1993). As age advances, the number and size of the plaque increases and thus increases the risk of coronary artery event. Men are at increased risk of development of atherosclerosis than women. However, the risk is same after menopausal age in women. Family history of atherosclerosis increases the risk of atherosclerosis. This is either due to genetic factors or due to similar diet, eating habits, lifestyle and smoking (Weber and Noels, 2011). This gene mutation has been linked to increased levels of ACE in the blood which also increases the risk of coronary artery disease. The most avoidable cause of atherosclerosis is smoking. Research has proved a strong, consistent and dose related association between smoking and atherosclerosis. The risk is highest in young people. The risk decreases significantly after quitting smoking for 6 months. Hypertension, both systolic and diastolic, increases the risk of atherosclerosis (Hansen and Libby, 2006). Hypercholesterolemia contributes to atherosclerosis and premature coronary artery disease. The risk is directly related to plasma levels of LDL cholesterol and inversely related to HDL cholesterol (Spagnoli et al, 2007). Hypertriglyceridemia also increases the risk of atherosclerosis. Lack of physical activity is considered as one of the risk factors for atherosclerosis. Diabetes mellitus allows diffusion of existing coronary atheroma and thus increases the risk of progression of atherosclerosis. Diabetes is frequently associated with obesity and physical activity, both of which are again risk factors for atherosclerosis. Obesity, by itself, is an independent risk factor for atherosclerosis. Heavy consumption of alcohol is associated with hypertension and increases the risk of cardiac events in atherosclerosis. Deficiency of polysaturated fatty acids or PUFA in the diet is associated with increased incidence of atherosclerosis. Low levels of antioxidants like vitamin C and vitamin E are independent risk factors for atherosclerosis and coronary artery disease (Weber and Noels, 2011). Conclusion Atheroma, also known as atherosclerosis is nothing but patchy focal disease of the intima of the artery. Of all the arteries in the body, coronary arteries are at increased risk of developing atheroma. The beginning of these plaques occurs in the second or third decade and gradually progresses. Initially, the circulating monocytes migrate into the intima of the arteries and take up oxidised low density lipoprotein from the plasma. These cells then become lipid-laden foam cells. Once these foam cells die, the contents of the cells are released which are mainly lipids. These form fatty streaks. Smooth muscles cells of the artery migrate in and around the fatty streaks and proliferate to form a plaque. The plaque encroaches into the lumen and also erodes the media layer of the artery. Gradually a thick collagen -rich fibrous tissue encapsules the plaque which is then called mature fibrolipid plaque. Mature plaques can rupture or fissure creating a pathway for blood to enter. The blood then disrupts the arterial wall. Disruption of arterial wall compromises the vessel lumen and precipitates thrombosis and vasospasm, all of which cause decrease in the blood flow through that vessel. Sometimes, the rupture itself can cause occlusion of the vessel or can cause rapid growth of the plaque which occludes the vessel resulting in acute coronary syndrome. References Binder, C. & Witztum, J. (2011). Is atherosclerosis an allergenic disease? Circulation Res., 109, 1103-4. Binder, C.J., Chang, M.K., Shaw, P.X., et al. (2002). Innate and acquired immunity in atherogenesis. Nat Med., 8, 1218–1226. Charo, I.F. & Taub, R. (2011). Anti-inflammatory therapeutics for the treatement of atherosclerosis Nature Reviews Drug Discovery, 10, 365 – 76. Gui, T. et al. (2012) Diverse roles of macrophages in atherosclerosis – from inflammatory biology to biomarker discovery. Circulation Res., 210, 1143-4. Galkina, E., Ley, K. (2009). Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol., 27, 165-97. 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