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Atherosclerosis
Atherosclerosis is a chronic inflammatory disease that represents the primary cause of heart disease and stroke. It is a progressive disease characterized by the accumulation and gradual build-up of lipid material in the artery wall.
Although atherosclerosis was traditionally considered a simple lipid disorder, recent scientific advances incorporated inflammation as an important factor in all stages of the disease, from initiation to plaque rupture and associated thrombotic complications.
The recruitment of inflammatory cells in the intima is an essential step in the development and progression of atherosclerosis. This process is triggered by local production of chemokines and chemokine receptors from activated endothelial cells and inflammatory cells.
Circulating monocytes are the precursors of foam cells in the atherosclerotic lesion, and chemokines are important in directing monocyte migration from the blood to the vessel wall.
The atheroma is preceded chronologically by the so-called fatty streaks, which are sites of accumulation of lipid droplets and immune cells.
Fatty streaks are not clinically significant, but they are the precursors of more advanced lesions, which typically have a fibrous cap consisting of SMCs and extracellular matrix that encloses a lipid-rich necrotic core. Plaques can become increasingly complex, with calcification, ulceration at the luminal surface, and hemorrage from small vessels that grow into the lesion from the media of the blood vessel wall. Although advanced lesions can grow sufficiently large to block blood flow, the most important clinical complication is an acute occlusion due to the formation of a thrombus or blood clot, resulting in myocardial infarction or stroke. Usually thrombosis is associated with rupture or erosion of the lesion, which frequently occurs at the lesion edges.
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Classical Chemoattractants
Classical chemoattractants activate most leukocyte subsets. These chemoattractants can be divided into at least 3 different groups:bacterial peptides such as fMLP, serum factors such as C5a and C3a, and bioactive lipids such as LTB4 and PAF.
Chemokines
Chemokines are a family of cytokines, and they induce directed chemotaxis in nearby responsive cells, hence the name chemotactic cytokines. Members of the chemokine family are classified into four groups depending on the spacing of their first two cysteine residues: CC, CXC, C and CX3C.
Some chemokines are inflammatory and are released from a wide variety of cells in response to bacterial infection, viruses and agents that cause physical damage. Inflammatory chemokines function mainly as chemoattractants for leukocytes, recruiting monocytes, neutrophils and other effector cells from the blood to sites of inflammation. During inflammation, endothelial cells are activated by inflammatory cytokines to express adhesion molecules and synthesize chemokines and lipid chemoattractants that are presented on their luminal surface.Activated endothelial cells also transport chemoattractants from their abluminal surface. Other chemoattractants can be generated by proteolytic cleavage in activated mast cells and platelets, and delivered to endothelial cells through circulating microparticles or exocytosis of intracellular granules.
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E-selectin
E-selectin, also known as CD62E, is a cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation.
E-selectin recognises and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes. These carbohydrates include members of the Lewis X and Lewis A families found on monocytes, granulocytes, and T-lymphocytes.
During inflammation, E-selectin plays an important part in recruiting leukocytes to the site of injury. The local release of cytokines IL-1 and TNF by damaged cells induces the over-expression of E-selectin on endothelial cells of nearby blood vessels. Leukocytes in the blood expressing the correct ligand will bind with low affinity to E-selectin, causing the leukocytes to \"roll\" along the internal surface of the blood vessel as temporary interactions are made and broken with exceptionally high on- and off-rates.
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Fractalkine
Chemokine (C-X3-C motif) ligand 1 (CX3CL1) is a large cytokine protein of 373 amino acids, it contains multiple domains and is the sole known member of the CX3C chemokine family. CX3CL1 has an extended mucin-like stalk and a chemokine domain on top. Fractalkine is bound directly to the cell membrane by a transmembrane region and mucin-like stalk. A soluble form of Fractalkine also exists through cleavage with an endogenous protease and this form may act more like a conventional chemokine, inducing integrin mediated adhesion and chemotaxis.
Soluble CX3CL1 potently chemoattracts T cells and monocytes, while the cell-bound chemokine promotes strong adhesion of leukocytes to activated endothelial cells, where it is primarily expressed. The interaction between fractalkine and its receptor, CX3CR1, has a very low dissociation rate, resulting in very strong interactions between fractalkine and CX3CR1-expressing cells (monocytes, NK cells, some T cell subsets). Like other chemokine receptors, CX3CR1 is a seven-transmembrane domain G protein-coupled receptor, but the adhesion does not require transmembrane signaling and is independent of calcium fluxes.
Membrane-bound Fractalkine is highly expressed in human inflammatory diseases such as rheumatoid arthritis, psoriasis and atherosclerosis.
Flow Assay
In vitro cell-based flow assays can be designed to reproduce and study adhesion systems under defined shear stress conditions, given the importance of shear in many steps of the adhesion cascade. The shear stress can be calculated from the channel geometry and the flow rate. The most common type of flow chamber system is the parallel-plate type, where cells are introduced in a laminar flow field between two flat surfaces.
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Inflammation
Inflammation is a reaction of the body to injury or to infectious, allergic, or chemical irritation.
It is traditionally defined by the four Latin words calor, dolor, rubor and tumor, meaning heat, pain, redness and swelling, all of which reflect the effects of cytokines and other inflammatory mediators on the local blood vessels. These hallmarks of inflammation were first described by Aulus Cornelius Celsus (c. 25 B.C.-c. 50), a Roman physician and medical writer, who lived from about 30 B.C. to 45 A.D.
They are the manifestations of the body\\\'s defence against injury or against invasion by foreign material or microorganisms, including the means of removal or destruction of the offending agent, restriction of the spread of infection, and preparations for the healing process. But the immune system that implements vital self-preservation may also sometimes cause inflammation by misdirected attack on some part of the body itself.
Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Cytokines have important effects on the adhesive properties of the endothelium, causing circulating leukocytes to stick to the endothelial cells of the blood vessel wall and migrate between them to the site of infection, to which they are attracted by chemokines.
Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterised by simultaneous destruction and healing of the tissue from the inflammatory process.
Icam-1 (inter-cellular Adhesion Molecule 1)
ICAM-1 (Inter-Cellular Adhesion Molecule 1) also known as CD54, is a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by Rhinovirus as a receptor.
Upon cytokine stimulation, the concentrations greatly increase. ICAM-1 can be induced by interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFα) and is expressed by the vascular endothelium, macrophages and lymphocytes. ICAM-1 is a ligand for LFA-1 (Lymphocyte function-associated antigen-1), a receptor found on leukocytes. When activated, leukocytes bind to endothelial cells via ICAM-1/LFA-1 and then transmigrate into tissues.
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Leukocyte Adhesion Cascade
The leukocyte adhesion cascade is a sequence of activation and adhesion events that ends with extravasation of the leukocyte, whereby the cell exerts its effects on the inflamed site. The traditional three-step cascade involves selectin-mediated rolling, chemokine-triggered activation and integrin-dependent arrest, but is has recently been augmented and refined including slow rolling, adhesion strengthening, intraluminal crawling and paracellular and transcellular migration, and migration through the basement membrane.
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Mcp-1
Chemokine (C-C motif) ligand 2 (CCL2) is a small cytokine belonging to the CC chemokine family that is also known as monocyte chemotactic protein-1 (MCP-1). CCL2 has a great ability to chemoattract monocytes to sites of tissue injury and infection.
Fibroblasts, tumor cells, smooth muscle cells, endothelial cells and phagocytes can produce MCP-1 either constitutively or upon stimulation by various stimuli.
Margination
Margination involves the movement of free flowing leukocytes from the centre of the blood vessel to the endothelial lining of the vessel wall in the early stages of inflammation.
Microfluidics
Microfluidics deals with the behavior, precise control and manipulation of fluids that are geometrically constrained to a small, typically sub-millimeter, scale. Typically, micro means one of the following features:
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small volumes(nl, pl, fl)
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small size
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low energy consumption
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effects of the micro domain.
It is a multidisciplinary field intersecting engineering, physics, chemistry, microtechnology and biotechnology, with practical applications to the design of systems in which such small volumes of fluids will be used. Microfluidic structures include micropneumatic systems, i.e. microsystems for the handling of off-chip fluids (liquid pumps, gas valves, etc), and microfluidic structures for the on-chip handling of nano- and picolitre volumes.
Advances in microfluidics technology are revolutionizing molecular biology procedures for enzymatic analysis, DNA analysis and proteomics. The basic idea of microfluidic biochips is to integrate assay operations such as detection, as well as sample pre-treatment and sample preparation on one chip. An emerging application area for biochips is clinical pathology, especially the immediate point-of-care diagnosis of diseases. In addition, microfluidics-based devices can serve as an useful tool for research purposes or in the drug-screening process, reducing time and reagents consumption.
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Selectins
Selectins are a family of single-chain transmembrane glycoproteins, expressed on the surface of leukocytes and activated endothelial cells.
L-selectin is the smallest of the vascular selectins, and can be found on most leukocytes. P-selectin, the largest selectin, is expressed on activated platelets and endothelial cells primarily. E-selectin is expressed on activated endothelium with chemically or cytokine-induced inflammation.
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Transendothelial Cell Migration
Transmigration through venular walls is the final step in the process of leukocyte emigration into inflamed tissues and can occur with minimal disruption to the complex structure of vessel walls. Before crossing the walls of postcapillary venules, neutrophils and monocytes crawl inside blood vessels, seeking preferred sites of transmigration. Leukocyte migration through the endothelial-cell barrier can be rapid (5–15 minutes). Transendothelial cell migration can be triggered by luminal chemoattractants that may act in concert with shear flow. The interaction of leukocyte integrins with their endothelial-cell ligands (such as ICAM1 and VCAM1) may also stimulate endothelial cells in a manner that promotes leukocyte migration through the endothelium.
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Vcam-1 (vascular Cell Adhesion Molecule-1)
VCAM-1 (Vascular Cell Adhesion Molecule-1), also known as CD106, is a cell surface sialoglycoprotein expressed by cytokine-activated endothelium. This type I membrane protein mediates leukocyte-endothelial cell adhesion and signal transduction, and plays a role in the development of atherosclerosis and rheumatoid arthritis. Primarily, VCAM-1 is an endothelial ligand for VLA-4 (Very Late Antigen-1 or α4β1) of the β1 subfamily of integrins, and for integrin α4β7.
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