4. Discuss the process of leukocyte adhesion in the blood vessels 
    during inflammation. What durgs may affect this process? 
The emigration of circulating leukocytes from the blood into inflamed tissues have been refined into a ''three step'' process comprising: (a) rolling of leukocytes along the vasculature (mediated through transient interactions between selectin proteins and their carbohydrate ligands), followed by (b) activation of both neutrophils and endothelial cells and a high affinity interaction between integrins and glycoproteins of immunoglobulin superfamily, leading ultimaely to (c) extravasation (crawling along the endothelium, diapedesis, and migration into tissue) in response to a chemoattractant gradient  

Rolling leukocytes are generally defined as white cells that move through microvessels at a rate that is lower than that of red blood cells. In 30m diameter postcapillary venules, the red blood cell velocity is usually 1-3mm/s, whereas leukocytes roll at velocities ranging between 5 and 300m/s, with the most frequently observed rolling velocities lying between 20 and 60m/s. Rolling leukocytes are not always commited to either firmly adhering to the vessel wall or rolling along the entire vessel length; rolling leukocytes frequently detach and return to the mainstream of flowing blood. Leukocyte rolling is likely to occur also under normal physiological conditions in all tissues (gastrointestinal mucosa, skin, lung) that are continually exposed to extermal inflammatory stimuli that are physical and/or chemical in nature.  

In inflamed tissue, leukocyte rolling frequently (but not always) leads to a stationary state in which the leukocyte remains firmly attacked to the endothelial cell surface, without rotation motion. This strong (high-affinity) adhesive interaction is often referred to as leukocyte sticking, firm adhesion, or adherence, terms that denote the absence of movement of the leukocyte along the length of the venule.  

In the initial phase of an acute inflammatory response, circulating leukocytes are activated by exposure to inflammatory mediators including complement fragments (C5a), cytokines such as IL-1, IL-8 and TNF- and lipopolysaccharide or classical chemoattractants such as formylated methionine -- leucine - phenylalanine (FMLP) leading to their microvascular sequestration due in part to decreased deformability (i.e. increased cell stiffness) and in part to increased adhesiveness of the circulating leukocytes. Endothelial cells are similary activated, leading to enhanced expression of several adhesion molecules. Platelet activating factor (PAF) produced by endothelial cells may act on nearby neutrophils to potentiate their adhesion to the endothelium.  

Transmigration of neutrophils across the endothelial barrier involves interaction between leukocyte integrins and endothelial ICAM, and between glycosylated aminoglycans on the neutrophil plasma membrane and PECAM-1, which is localized in the intercellular junctions of endothelial cells. In extravascular locations, interaction between extracellular matrix proteins and adhesion molecules, possibly by activation of cytosolic tyrosine kinases, facilitate the release of large quantities of toxic oxygen radicals and proteolytic enzymes.  

The inflammatory response begins with a release of inflammatory chemicals into the extracellular fluid. Sources of these inflammatory mediators, the most important of which are histamine, prostaglandins, and cytokines, are injured tissue cells, lymphocytes, mast cells and blood proteins. The presence of these chemicals promote and further the reactions to inflammation, which are redness, heat, swelling, and pain. 

Anti-inflammatory drugs block or suppress the inflammatory response, preventing or reducing the appearance of adverse reactions to the irritant. Diseases and cases such as asthma, arthritis, organ transplants, and surgical trauma, for example, are treated with non-steroidal or steroidal anti-inflammatory agents. Aspirin and some other anti-inflammatory drugs exert their analgesic effects by inhibiting prostaglandin synthesis. 

More model answers