Inflammation 2

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  • Suffixing ‘itis’ to tissue name describes the inflammation of that tissue. However, there are some exceptions. See the next slide.
  • Here tissue names are slightly or totally different. Like balanitis which is the inflammation of the glans penis. Typhlitis=inflammation of caecum, Posthitis=inflammation of prepuce.
    Panniculitis=inflammation of adipose tissue. And in some cases suffix “itis” is not used and they are highlighted by the red rectangle in the slide.
    Cellulitis is inflammation of the soft tissue and not inflammation of cells.
  • Cellulitis.
  • Inflammation of joints: arthritis.
  • Inflammation of fingers (this is sickle cell anemia patient): Dactylitis
  • Inflammation of kidney: Glomerulonephritis, pyelonephritis.
  • Inflammation of subcuneous fat: Panniculitis
  • Inflammation of prepuce: Posthitis
  • Inflammation of glans penis: Balanitis
  • Caecal inflammation: Tiphlitis
  • Inflammation of nail bed: paronichia
  • Inflammation of subcutaneous tissue: Cellulitis.
  • Eosinophils
    However, in some circumstances eosinophils rather than neutrophils predominate in acute inflammation. This tends to occur with parasitic worms, against which neutrophils have little success, or with a response involving the antibody IgE. Eosinophils release several proteins, such as major basic protein, which are often effective against parasites. Eosinophils also release several regulatory molecules that increase endothelial permeability. Note that eosinophils are also linked to certain types of allergies.
  • FIGURE 2-1  The major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation and increased blood flow (causing erythema and warmth); (2) extravasation and extravascular deposition of plasma fluid and proteins (edema); (3) leukocyte emigration and accumulation in the site of injury.
  • An exudate is an extravascular fluid that has a high protein concentration, contains cellular debris, and has a high specific gravity. Its presence implies an increase in the normal permeability of small blood vessels in an area of injury and, therefore, an inflammatory reaction ( Fig. 2-2 ). In contrast, a transudate is a fluid with low protein content (most of which is albumin), little or no cellular material, and low specific gravity. It is essentially an ultrafiltrate of blood plasma that results from osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability ( Chapter 4 ). Edema denotes an excess of fluid in the interstitial tissue or serous cavities; it can be either an exudate or a transudate. Pus, a purulent exudate, is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells and, in many cases, microbes.
  • FIGURE 2-2  Formation of transudates and exudates. A, Normal hydrostatic pressure (blue arrows) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrows), which is equal to the mean capillary pressure. Therefore, the net flow of fluid across the vascular bed is almost nil. B, A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic pressure. C, An exudate is formed in inflammation, because vascular permeability increases as a result of increased interendothelial spaces.
  • Changes in vascular flow and caliber begin early after injury and consist of the following.   
    •    Vasodilation is one of the earliest manifestations of acute inflammation; sometimes it follows a transient constriction of arterioles, lasting a few seconds. Vasodilation first involves the arterioles and then leads to opening of new capillary beds in the area. The result is increased blood flow, which is the cause of heat and redness (erythema) at the site of inflammation. Vasodilation is induced by the action of several mediators, notably histamine and nitric oxide (NO), on vascular smooth muscle. 
     •    Vasodilation is quickly followed by increased permeability of the microvasculature, with the outpouring of protein-rich fluid into the extravascular tissues; this process is described in detail below.  
    •    The loss of fluid and increased vessel diameter lead to slower blood flow, concentration of red cells in small vessels, and increased viscosity of the blood. These changes result in dilation of small vessels that are packed with slowly moving red cells, a condition termed stasis, which is seen as vascular congestion (producing localized redness) upon examination of the involved tissue.  
    •    As stasis develops, blood leukocytes, principally neutrophils, accumulate along the vascular endothelium. At the same time endothelial cells are activated by mediators produced at sites of infection and tissue damage, and express increased levels of adhesion molecules. Leukocytes then adhere to the endothelium, and soon afterward they migrate through the vascular wall into the interstitial tissue, in a sequence that is described later.
    Histamine dilates post-capillary venules, activates the endothelium, and increases blood vessel permeability.
  • Increased Vascular Permeability (Vascular Leakage)
    A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich exudate into the extravascular tissue, causing edema. Several mechanisms are responsible for the increased vascular permeability ( Fig. 2-3 ):   •    Contraction of endothelial cells resulting in increased interendothelial spaces is the most common mechanism of vascular leakage and is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other chemical mediators.[6,][7] It is called the immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15–30 minutes). In some forms of mild injury (e.g. after burns, x-irradiation or ultraviolet radiation, and exposure to certain bacterial toxins), vascular leakage begins after a delay of 2 to 12 hours, and lasts for several hours or even days; this delayed prolonged leakage may be caused by contraction of endothelial cells or mild endothelial damage. Late-appearing sunburn is a good example of this type of leakage.  •    Endothelial injury, resulting in endothelial cell necrosis and detachment.[8] Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or by the actions of microbes that target endothelial cells.[9] Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction. In most instances leakage starts immediately after injury and is sustained for several hours until the damaged vessels are thrombosed or repaired.  •    Increased transport of fluids and proteins, called transcytosis, through the endothelial cell. This process may involve channels consisting of interconnected, uncoated vesicles and vacuoles called the vesiculovacuolar organelle, many of which are located close to intercellular junctions.[10] Certain factors, such as VEGF ( Chapter 3 ), seem to promote vascular leakage in part by increasing the number and perhaps the size of these channels.
  • Increased Vascular Permeability (Vascular Leakage)
    A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich exudate into the extravascular tissue, causing edema. Several mechanisms are responsible for the increased vascular permeability ( Fig. 2-3 ):   •    Contraction of endothelial cells resulting in increased interendothelial spaces is the most common mechanism of vascular leakage and is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other chemical mediators.[6,][7] It is called the immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15–30 minutes). In some forms of mild injury (e.g. after burns, x-irradiation or ultraviolet radiation, and exposure to certain bacterial toxins), vascular leakage begins after a delay of 2 to 12 hours, and lasts for several hours or even days; this delayed prolonged leakage may be caused by contraction of endothelial cells or mild endothelial damage. Late-appearing sunburn is a good example of this type of leakage.  •    Endothelial injury, resulting in endothelial cell necrosis and detachment.[8] Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or by the actions of microbes that target endothelial cells.[9] Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction. In most instances leakage starts immediately after injury and is sustained for several hours until the damaged vessels are thrombosed or repaired.  •    Increased transport of fluids and proteins, called transcytosis, through the endothelial cell. This process may involve channels consisting of interconnected, uncoated vesicles and vacuoles called the vesiculovacuolar organelle, many of which are located close to intercellular junctions.[10] Certain factors, such as VEGF ( Chapter 3 ), seem to promote vascular leakage in part by increasing the number and perhaps the size of these channels.
  • Increased Vascular Permeability (Vascular Leakage)
    A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich exudate into the extravascular tissue, causing edema. Several mechanisms are responsible for the increased vascular permeability ( Fig. 2-3 ):   •    Contraction of endothelial cells resulting in increased interendothelial spaces is the most common mechanism of vascular leakage and is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other chemical mediators.[6,][7] It is called the immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15–30 minutes). In some forms of mild injury (e.g. after burns, x-irradiation or ultraviolet radiation, and exposure to certain bacterial toxins), vascular leakage begins after a delay of 2 to 12 hours, and lasts for several hours or even days; this delayed prolonged leakage may be caused by contraction of endothelial cells or mild endothelial damage. Late-appearing sunburn is a good example of this type of leakage.  •    Endothelial injury, resulting in endothelial cell necrosis and detachment.[8] Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or by the actions of microbes that target endothelial cells.[9] Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction. In most instances leakage starts immediately after injury and is sustained for several hours until the damaged vessels are thrombosed or repaired.  •    Increased transport of fluids and proteins, called transcytosis, through the endothelial cell. This process may involve channels consisting of interconnected, uncoated vesicles and vacuoles called the vesiculovacuolar organelle, many of which are located close to intercellular junctions.[10] Certain factors, such as VEGF ( Chapter 3 ), seem to promote vascular leakage in part by increasing the number and perhaps the size of these channels.
  • Increased Vascular Permeability (Vascular Leakage)
    A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich exudate into the extravascular tissue, causing edema. Several mechanisms are responsible for the increased vascular permeability ( Fig. 2-3 ):   •    Contraction of endothelial cells resulting in increased interendothelial spaces is the most common mechanism of vascular leakage and is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other chemical mediators.[6,][7] It is called the immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15–30 minutes). In some forms of mild injury (e.g. after burns, x-irradiation or ultraviolet radiation, and exposure to certain bacterial toxins), vascular leakage begins after a delay of 2 to 12 hours, and lasts for several hours or even days; this delayed prolonged leakage may be caused by contraction of endothelial cells or mild endothelial damage. Late-appearing sunburn is a good example of this type of leakage.  •    Endothelial injury, resulting in endothelial cell necrosis and detachment.[8] Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or by the actions of microbes that target endothelial cells.[9] Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction. In most instances leakage starts immediately after injury and is sustained for several hours until the damaged vessels are thrombosed or repaired.  •    Increased transport of fluids and proteins, called transcytosis, through the endothelial cell. This process may involve channels consisting of interconnected, uncoated vesicles and vacuoles called the vesiculovacuolar organelle, many of which are located close to intercellular junctions.[10] Certain factors, such as VEGF ( Chapter 3 ), seem to promote vascular leakage in part by increasing the number and perhaps the size of these channels.
  • Increased Vascular Permeability (Vascular Leakage)
    A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich exudate into the extravascular tissue, causing edema. Several mechanisms are responsible for the increased vascular permeability ( Fig. 2-3 ):   •    Contraction of endothelial cells resulting in increased interendothelial spaces is the most common mechanism of vascular leakage and is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other chemical mediators.[6,][7] It is called the immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15–30 minutes). In some forms of mild injury (e.g. after burns, x-irradiation or ultraviolet radiation, and exposure to certain bacterial toxins), vascular leakage begins after a delay of 2 to 12 hours, and lasts for several hours or even days; this delayed prolonged leakage may be caused by contraction of endothelial cells or mild endothelial damage. Late-appearing sunburn is a good example of this type of leakage.  •    Endothelial injury, resulting in endothelial cell necrosis and detachment.[8] Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or by the actions of microbes that target endothelial cells.[9] Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction. In most instances leakage starts immediately after injury and is sustained for several hours until the damaged vessels are thrombosed or repaired.  •    Increased transport of fluids and proteins, called transcytosis, through the endothelial cell. This process may involve channels consisting of interconnected, uncoated vesicles and vacuoles called the vesiculovacuolar organelle, many of which are located close to intercellular junctions.[10] Certain factors, such as VEGF ( Chapter 3 ), seem to promote vascular leakage in part by increasing the number and perhaps the size of these channels.
  • Increased Vascular Permeability (Vascular Leakage)
    A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich exudate into the extravascular tissue, causing edema. Several mechanisms are responsible for the increased vascular permeability ( Fig. 2-3 ):   •    Contraction of endothelial cells resulting in increased interendothelial spaces is the most common mechanism of vascular leakage and is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other chemical mediators.[6,][7] It is called the immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15–30 minutes). In some forms of mild injury (e.g. after burns, x-irradiation or ultraviolet radiation, and exposure to certain bacterial toxins), vascular leakage begins after a delay of 2 to 12 hours, and lasts for several hours or even days; this delayed prolonged leakage may be caused by contraction of endothelial cells or mild endothelial damage. Late-appearing sunburn is a good example of this type of leakage.  •    Endothelial injury, resulting in endothelial cell necrosis and detachment.[8] Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or by the actions of microbes that target endothelial cells.[9] Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction. In most instances leakage starts immediately after injury and is sustained for several hours until the damaged vessels are thrombosed or repaired.  •    Increased transport of fluids and proteins, called transcytosis, through the endothelial cell. This process may involve channels consisting of interconnected, uncoated vesicles and vacuoles called the vesiculovacuolar organelle, many of which are located close to intercellular junctions.[10] Certain factors, such as VEGF ( Chapter 3 ), seem to promote vascular leakage in part by increasing the number and perhaps the size of these channels.
  • Increased Vascular Permeability (Vascular Leakage)
    A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich exudate into the extravascular tissue, causing edema. Several mechanisms are responsible for the increased vascular permeability ( Fig. 2-3 ):   •    Contraction of endothelial cells resulting in increased interendothelial spaces is the most common mechanism of vascular leakage and is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other chemical mediators.[6,][7] It is called the immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15–30 minutes). In some forms of mild injury (e.g. after burns, x-irradiation or ultraviolet radiation, and exposure to certain bacterial toxins), vascular leakage begins after a delay of 2 to 12 hours, and lasts for several hours or even days; this delayed prolonged leakage may be caused by contraction of endothelial cells or mild endothelial damage. Late-appearing sunburn is a good example of this type of leakage.  •    Endothelial injury, resulting in endothelial cell necrosis and detachment.[8] Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or by the actions of microbes that target endothelial cells.[9] Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction. In most instances leakage starts immediately after injury and is sustained for several hours until the damaged vessels are thrombosed or repaired.  •    Increased transport of fluids and proteins, called transcytosis, through the endothelial cell. This process may involve channels consisting of interconnected, uncoated vesicles and vacuoles called the vesiculovacuolar organelle, many of which are located close to intercellular junctions.[10] Certain factors, such as VEGF ( Chapter 3 ), seem to promote vascular leakage in part by increasing the number and perhaps the size of these channels.
  • Responses of Lymphatic Vessels
    Normally interstitial fluid is drained by lymphatics
    During inflammatory edema lymphatics proliferate in order to handle the increased load
    Hence they may carry injurious substances away from the site
    In this process they may get inflammed - Lymphangiitis
  • As mentioned earlier, a critical function of inflammation is to deliver leukocytes to the site of injury and to activate the leukocytes to eliminate the offending agents. The most important leukocytes in typical inflammatory reactions are the ones capable of phagocytosis, namely neutrophils and macrophages. These leukocytes ingest and kill bacteria and other microbes, and eliminate necrotic tissue and foreign substances. Leukocytes also produce growth factors that aid in repair. A price that is paid for the defensive potency of leukocytes is that, when strongly activated, they may induce tissue damage and prolong inflammation, because the leukocyte products that destroy microbes and necrotic tissues can also injure normal host tissues.
  • The processes involving leukocytes in inflammation consist of: their recruitment from the blood into extravascular tissues, recognition of microbes and necrotic tissues, and removal of the offending agent.
  • A critical function of the vascular inflammatory response (stasis and vascular permeability) is to deliver leukocytes to the site of injury in order to clear injurious agents .
  • Here remind them of EXUDATION, which is escape of fluid part of the blood – plasma – in to the interstitium.
    Extravasation is escape of cellular component of the blood in to the interstitium.
  • The journey of leukocytes from the vessel lumen to the interstitial tissue, called extravasation, can be divided into the following steps[13] ( Fig. 2-4 ):   1.    In the lumen: margination, rolling, and adhesion to endothelium. Vascular endothelium in its normal, unactivated state does not bind circulating cells or impede their passage. In inflammation the endothelium is activated and can bind leukocytes, as a prelude to their exit from the blood vessels.  2.    Migration across the endothelium and vessel wall  3.    Migration in the tissues toward a chemotactic stimulus
  • Tumor necrosis factor (TNF, tumor necrosis factor alpha, TNFα, cachexin, or cachectin) is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. It is produced chiefly by activated macrophages, although it can be produced by many other cell types such as CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons.
    IL 1, otherwise known as lymphocyte-activating factor, is a macrophage-derived 12,000- to 15,000-dalton polypeptide.
  • Tissue resident inflammatory cells:
    1-MAST CELLS (Histamine, TNF-alfa)
    2-Macrophages (TNF-alfa, IL 1)
  • The journey of leukocytes from the vessel lumen to the interstitial tissue, called extravasation, can be divided into the following steps[13] ( Fig. 2-4 ):   1.    In the lumen: margination, rolling, and adhesion to endothelium. Vascular endothelium in its normal, unactivated state does not bind circulating cells or impede their passage. In inflammation the endothelium is activated and can bind leukocytes, as a prelude to their exit from the blood vessels.  2.    Migration across the endothelium and vessel wall  3.    Migration in the tissues toward a chemotactic stimulus.
  • FIGURE 2-4  The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles in different steps of this process—selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. Neutrophils express low levels of L-selectin; they bind to endothelial cells predom in antly via P- and E-selectins. ICAM-1, intercellular adhesion molecule 1; TNF, tumor necrosis factor.
  • Circulating pool - functioning cells in circulation, in transit to tissues. The blood we draw for evaluation comes from this pool. The circulating pool is found more towards the center of the tubular blood vessel.
    Marginating pool – Primarily a term used for white blood cells. The cells are adhered to walls of blood vessels and are ready to move through into the tissues (diapedesis). There is constant movement between the circulating and marginating pools. At a given time the ratio of cells in the circulating pool to the cells in the marginating pool is 50:50. Neutrophils move freely between the two pools.
  • Figure 1 shows that the extravasation of leukocytes is initiated by tethering and rolling of the cells on activated endothelium (in inflamed tissues) and so called high endothelial venules (in secondary lymphoid organs). These transient interactions are mediated by the selectins, adhesion molecules which recognize a limited range of specifically modified glycoproteins and -lipids. Three selectins are known: E-selectin (expressed by endothelial cells), P-selectin (expressed by platelets and endothelial cells) and L-selectin (found on leukocytes). Selectin-mediated leukocyte rolling is required for the consecutive activation of the leukocytes by endothelial cell-bound chemokines. As a consequence of activation leukocyte integrins, another class of adhesion molecules, mediate firm cellular adhesion to the endothelial wall. Finally, leukocytes transmigrate through the endothelium into the underlying tissue.
  • Once outside the blood vessel, a neutrophil is guided towards an infection by various chemicals – “Chemotactic factors”
    Examples include the chemokines and the complement peptide C5a, which is released when the complement system is activated either via specific immunity or innate immunity.
  • This is a diagram showing the effect of chemokine concentration gradient on chemotaxis direction. The attracted cell moves through the gradient toward the higher concentration of chemokine.
  • Details of Leukocyte Chemotaxis:
    Neutrophil adheres via integrin binding
    Integrin binds to FN in ECM
    Actually recognizes RGD sequence (arg-gly-asp) in FN (not shown in figure)
    RGD is also found in other ECM proteins
    Integrin is recycled
  • Figure 3: Defective leukocyte-endothelial cell interacions in LAD II. LAD II patients exhibit a systemic hypofucosylation which includes selectin ligands. This inhibits selectin-mediated leukocyte-endothelial cell interactions. The consequence is decreased leukocyte extravasation causing immunodeficiency
    Leukocyte Adhesion Deficiency II
    Leukocyte Adhesion Deficiency II (LAD II) is a human congenital disease in which the biosynthesis of sLex and other fucosylated structures is blocked. Consequently, selectin-mediated adhesion is inhibited (Figure 3). The fucoslyation defect in LAD II leads to immunodeficiency, neutrophilia, as well as to psychomotor and growth retardation (Wild et al., 2002). LAD II is also termed "Congenital Disorder of Glycosylation-IIc (CDG-IIc)“.
  • Adhesion cascade in leukocyte adhesion deficiency (LAD) syndromes.
    <emedicine.medscape.com/article/886248-media>
  • Persistent umbilical cord for more than 10days may be a clue to: Leucocyte adhesion deficiency, Factor-XIII deficiency. Note: common cause for persistent umbilical stump is infection.
  • Inflammation is a complex reaction in tissues that consists mainly of responses of blood vessels and leukocytes.
    In inflammation, blood vessels undergo a series of changes that are designed to maximize the movement of plasma proteins and circulating cells out of the circulation and into the site of infection or injury. The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities is known as exudation.
  • FIGURE 2-4  The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles in different steps of this process—selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. Neutrophils express low levels of L-selectin; they bind to endothelial cells predom in antly via P- and E-selectins. ICAM-1, intercellular adhesion molecule 1; TNF, tumor necrosis factor.
  • Introduction to Chemokine Families and the Cells They Affect :
    Chemokines (Greek -kinos, movement) are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines. Proteins are classified as chemokines according to shared structural characteristics such as small size (they are all approximately 8-10 kilodaltons in size), and the presence of four cysteine residues in conserved locations that are key to forming their 3-dimensional shape. However, these proteins have historically been known under several other names including the SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, Platelet factor-4 superfamily or intercrines. Some chemokines are considered pro-inflammatory and can be induced during an immune response to promote cells of the immune system to a site of infection, while others are considered homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development. Chemokines are found in all vertebrates, some viruses and some bacteria, but none have been described for other invertebrates. These proteins exert their biological effects by interacting with G protein-linked transmembrane receptors called chemokine receptors, that are selectively found on the surfaces of their target cells.
  • In biochemistry and pharmacology, a ligand (Latin ligare = to bind) is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.
    The binding occurs by intermolecular forces, such as ionic bonds, hydrogen bonds and Van der Waals forces. The docking (association) is usually reversible (dissociation). Actual irreversible covalent binding between a ligand and its target molecule is rare in biological systems. In contrast to the meaning in metalorganic and inorganic chemistry, it is irrelevant whether the ligand actually binds at a metal site, as it is the case in hemoglobin.
    Ligand binding to a receptor alters the chemical conformation, that is the three dimensional shape of the receptor protein. The conformational state of a receptor protein determines the functional state of a receptor. Ligands include substrates, inhibitors, activators, and neurotransmitters. The tendency or strength of binding is called affinity.
    Radioligands are radioisotope labeled compounds and used in vivo as tracers in PET studies and for in vitro .
  • Inflammation 2

    1. 1. How do you differentiate acute from chronic inflammation? • Onset / duration • Type of inflammatory cells May-2015-CSBRP
    2. 2. FIGURE 2-1 The major local manifestations of acute inflammation, compared to normal. (1)Vascular dilation and increased blood flow (causing erythema and warmth) (2)Extravasation and extravascular deposition of plasma fluid and proteins (edema); (3)Leukocyte emigration and accumulation in the site of injury.May-2015-CSBRP
    3. 3. May-2015-CSBRP
    4. 4. ExudationExudation The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities is known as exudation May-2015-CSBRP
    5. 5. Terms • Exudate • Transudate • Edema • Pus May-2015-CSBRP
    6. 6. May-2015-CSBRP Increased HP OR Decreased OP Increased vascular permeability
    7. 7. Differences between Transudate and Exudate Transudate • Usually seen in congestive states • Increased HP • Sp. Gr: <1.020 • Proteins: <2 gm/dl • Few leucocytes Exudate • Seen in inflammatory states • Increased vascular permeability • Sp. Gr: >1.020 • Proteins: >2 gm/dl • Many leucocytes May-2015-CSBRP
    8. 8. May-2015-CSBRP
    9. 9. Vascular Events May-2015-CSBRP
    10. 10. Vascular events 1. Changes in Vascular Flow and Caliber 2. Increased Vascular Permeability (Vascular Leakage) 3. Responses of Lymphatic Vessels May-2015-CSBRP
    11. 11. Vascular events 1. Changes in Vascular Flow and Caliber Begins early in inflammation Consists of the following: Vasoconstriction (transient – a few seconds) Vasodilation (first – arterioles, then vascular bed) Histamine, NO Vasodilation with increased vascular permeability May-2015-CSBRP Histamine dilates post-capillary venules
    12. 12. Vascular events 1. Changes in Vascular Flow and Caliber 2. Increased Vascular Permeability o Contraction of endothelial cells resulting in increased interendothelial spaces o [histamine, bradykinin, leukotrienes, substance P] o Immediate transient response occurs rapidly / short-lived (15–30 minutes) o Delayed prolonged leakage [begins after a delay of 2 to 12 hours] may be caused by contraction of endothelial cells or mild endothelial damage. Eg: sunburn o Endothelial injury, resulting in endothelial cell necrosis and detachment o Direct damage to the endothelium - in burns, or by the actions of microbes, Neutrophils that adhere to the endothelium o Transcytosis, VEGF o Newly formed capillaries are leaky May-2015-CSBRP
    13. 13. Vascular events May-2015-CSBRP
    14. 14. Normal tight Gap junction Contraction Causing vascular leakage May-2015-CSBRP
    15. 15. Vascular events May-2015-CSBRP
    16. 16. Vascular events May-2015-CSBRP
    17. 17. Vascular events May-2015-CSBRP
    18. 18. Vascular events May-2015-CSBRP
    19. 19. Vascular events Although various mechanisms can cause vascular leak, combination of mechanisms discussed earlier may play a role in a given setting May-2015-CSBRP
    20. 20. Vascular events 1. Changes in Vascular Flow and Caliber 2. Increased Vascular Permeability 3. Responses of Lymphatic Vessels • Normally interstitial fluid is drained by lymphatics • Lymphatics proliferate to handle the increased load • May carry injurious substances away from the site • In this process they may get inflammed - Lymphangiitis May-2015-CSBRP
    21. 21. May-2015-CSBRP
    22. 22. Cellular EventsCellular Events May-2015-CSBRP
    23. 23. REACTIONS OF LEUKOCYTES IN INFLAMMATION • A critical function of inflammation is to deliver leukocytes to the site of injury and to activate the leukocytes to eliminate the offending agents. • Most important leukocytes in inflammatory reactions are the ones capable of phagocytosis, namely neutrophils and macrophages. • These leukocytes ingest and kill bacteria and other microbes, and eliminate necrotic tissue and foreign substances. • Leukocytes also produce growth factors that aid in repair. • Collateral damage: When strongly activated, leucocytes may induce tissue damage May-2015-CSBRP
    24. 24. The processes involving leukocytes in inflammation consist of: Recruitment Recognition Removal May-2015-CSBRP
    25. 25. The inflammatory response consists of TWO main components: 1. Vascular reaction and 2. Cellular reaction May-2015-CSBRP

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