Lecture-inflamation_Engl_.ppt
- 1. Lecture 1-6 INFLAMMATION Definition and causes. Inflammation is a fundamentally protective response whose ultimate goal is to rid the organism of both the initial cause of cell injury (microbes or toxins) and its consequences. Humans could not long survive injury without the protective responses of inflammation. Inflammation is typical pathological process, cause it owns the different diseases (for example, gastritis, meningitis, nephritis, pneumonia, angina and others). It is the most numerous pathological process, which has perfected in evolution as protective response. Different side of this process – own pathological and defense with various compensatory mechanisms are presented. Although inflammation and repair are basically defense mechanisms, they are potentially harmful. Indeed, an over-active inflammatory response (hypersensitivity) to a bee sting can cause death. Inflammation has local and common breaches of biochemical, morphological, structural characters with functional and vascular changes. This components accounts for the classical sings of acute inflammation, written by Celsus: 1. heat (calor) 2. redness (rubor) 3. swelling (tumor) 4. pain (dolor) A fifth clinical sign, loss of function (function laesa), later added by Virchov. Common clinical manifestation: 1. fever 2. headache 3. neutrophilia 4. sleepless 5. decreased of appetite 6. haemodynamic effects (chock).
- 3. Causes. Microbes and its toxin, parasites, viruses. Environmental factors – ultraviolet rays of sunlight, X-rays, nuclear fission, radionuclides, Roentgen rays. Injury by chemical agents – mechanical trauma, thermal injury (thermal burns), electrical injury, by ionizing radiation. Chemical agents – alcohol and other drug abuse, medicine. Tissue-destructive enzymes, activation of the B-cell system, as result production of antibodies, some of which are directed against self- constitutions. Inflammation has three major components, which is caused various exogenous and endogenous stimuli. It is complex reaction with structural and vascular changes and increased function of connective tissue: I. Alteration II. Vascular changes with emigration of the leucocytes and exudation III. Proliferation
- 4. I. Alteration There is primary and secondary alteration. When flogogen (injuring factor) act on the tissue – the first massive tissue destruction develop. Following cell death, cell organelles are progressively degraded and there is leakage of cellular enzymes. Consequences of these disorders are increased metabolic processes (“the fire of metabolism”), focal hypoxia and its result acidosis (normal pH equils 7,34 –7,36; under acute inflammation 5,6 – 6,0; under chronic inflammation – 6,0 – 7,5). It’s induce lasting tissue damage (secondary alteration) and may also prolong inflammation because leakage enzymes, chemical mediators and toxic carbooxygen more breaches metabolism. In the tissue osmotic and oncotic pressure increased, because developing acidosis stimulate those processes. Than next phase of inflammation develops. 2.VASCULAR CHANGES. (changes in microcirculation) The vascular phenomena and changes in microcirculation (it involves arterioles, precapillares, capillares, venules) breaches local blood circulation. It's very important phase, because increased blood flow to the injured area and opening of capillary beds forms exudate and its stimuli to phagocytosis and repair. Changes in vascular flow and caliber begin very early after injury and develop at varying rates, depending on the severity of the injury.
- 5. The changes occur in the following order: 1) Vasoconstriction of arterioles, lasting a few seconds (it occurs very rapidly). Mechanism connected with binding to receptors of sympathetic nervous system and released adrenalin (noradrenalin), which at once degraded. 2) Arteriole hyperemia (arteriole dilatation) - the longest phase, because it account for sustained not only nervous but humeral stimuli. This first involves the arterioles and men results in opening of new microvascular beds in the area. Thus comes about increased blood flow and the cause of the heat (calor) and the redness (rubor). This is by fat the most common mechanism of vascular leakage and is elicited by histamine, bradykinin, H+-ions, and virtually all other chemical mediators. 3) Venular hyperemia - venular dilatation is characterized by following: 1. Slowing of blood circulation; 2. High hydrostatic pressure; 3. Increased permeability by mediators of inflammation; 4. The out flow of protein-rich fluid into the extravascular tissue (its called local sign-swelling); 5. Increased viscosity of blood; 6. Concentration of red cells in small vessels; 7. Platelet adhesion as result endothelial cell detachment; 8. Thrombosis (dilated small vessels packed with red cells; 9. Prestasis; 10. Stasis - it is the last phase. 4) Of the vascular changes. As venous hyperemia develops one begins to see peripheral orientation of leukocytes, principally neutrophils, along the vascular endothelium, a process called leukocytic margination. Leukocytes stick to the endothelium at first transiently then more avidly, and soon afterward they migrate trough the vascular wall into the interstitial tissue (process called emigration). The leukocytes to leave the circulation, chemical mediators may be activated in consecutive phases of the inflammatory response and account for sustained and prolonged responses.
- 7. Cellular events: leukocyte exudation and phagocytosis. A critical function of inflammation is the delivery of leukocytes to the site of injury. Leukocytes kill bacteria and other microbes and degrade necrotic tissue and foreign antigens. Unfortunately, leukocytes may also prolong inflammation and induce tissue damage by releasing enzymes, chemical mediators and toxic oxygen radicals. The sequence of events in the leukocyte journey can be divided. 1. Margination. Rolling and adhesion. 2. Emigration toward a chemotactic stimulus. 3. Phagocytosis and intracellular degradation. 4. Leukocyte activation with extracellular release of leukocyte products. Margination, rolling and adhesion. In normally flowing blood erythrocytes and leukocytes are confident to a central axial column, leaving a cell-poor layer of plasma in contact with endothelium. As blood flow slows early in inflammation (as a result of the increased vascular permeability) white cells fall out of the central column, tumble slowly and roll along the endothelium of venules and finally rest at some point where there adhere. The initial process is called margination and in time the endothelium appears to be virtually lined by white cells, a phenomenon called pavementing. When the leukocytes adhere, they resemble pebbles or marbles over which a stream runs without disturbing them. This process of leukocyte- endothelial adhesion is a necessary prelude to all the subsequent leukocytic events. Chemical mediators such as interleukin stimulate leukocyte adhesion and expression on endothelial cells "an endothelium - dependent effect".
- 9. Emigration and chemotaxis. Following adhesion leukocytes move along the endothelial surface, insert pseudopods into the junction between the endothelial cells squeeze through interendothelial junctions, and assume a position between the endothelial cell and the basement membrane. Eventually they traverse the basement membrane and escape into the extravascular space. Neutrophils, monocytes, lymphocytes, eosinophils and basophils all use the same pathway. In most types of acute inflammation, neutrophils emigrate first and monocytes later. In the first 24 to 48 hours most acute inflammatory infiltrates are predominantly neutrophilic. By 48 hours, however, monocytes take over, owing to three factors: 1. Short-liver neutrophils disintegrate and disappear after 24 to 48 hours, whereas monocytes survive longer. 2. Monocyte emigration is sustained long after neutrophil emigration. 3. Chemotactic factors for neutrofils and monocytes are activated at different phases of the response.
- 10. Both exogenous and endogenous substances can act as chemotactic agents for leukocytes, among them (1) soluble bacterial products; (2) components of complement system; (3) arachidonic acid (AA) and its product leukotriene (result disorders metabolism). But how does the headless leukocyte "see" or "smell" the chemotactic agents and how do these diverse substances actually induce directed cell movement? Although not all the answers are known, several important steps and second messengers are recognized. Binding of chemotactic agents to specific receptors on the cell membranes of leukocytes results in activation of phospholipase C (mediated by a unique G protein) and me release of calcium (intra- and extracellular). It is the increased cytosolic calcium that triggers the assembly of contractile elements responsible for cell movement. It also activates phospholipase A2, which as we shall see converts membrane phospholipids to arachidonic acid. In addition, DAY and through its activation of protein kinase C, is involved in various phases of leukocyte activation, degranulation, and secretion, which occur when these is a very strong chemotactic stimulus or during phagocytosis.
- 11. The activation and functions of the complement system. Activation of complement by different pathways leads to cleavage of C3. The functions of the complement system are mediated by breakdown products of C3 and other complement proteins, and by the membrane attack complex (MAC).
- 12. Interrelationships among the four plasma mediator systems triggered by activation of factor XII (Hageman factor).
- 13. Sequence of leucocyte events in inflammatin, shown here for neutrophils. The leukocyte first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoatractants amanating from the source of injure. Note the roles of selectins in rolling; chemoattractants in activating the neutrophils to increase avidity of integrins (in green); ICAM-1 and VCAM-1 in firm adhesion and PECAM-1 in transmigration.
- 15. PHAGOCYTOSIS AND DEGRANULATION. Phagocytosis consists of recognition and attachment of the particle to be ingested by the leukocyte. Opsonins, which bind to specific receptors the leukocytes, and other fragment of complement generated by immune or nonimmune mechanisms. Pseudopods flow around the object to be engulfed, eventually forming a phagocytic vacuole. The vacuole then fuses with the limiting membrane of a lysosomal granule, resulting in discharge of the granule's contents into the phagolysome and degranulation of the leukocyte. The ultimate step in phagocytosis of bacteria is killing and degranulation. Bacterial killing is accomplished largely by reactive oxygen species. Microbes can also be killed by non oxygendependent substances in the leukocyte granules, including bacterial permeability - increasing (BPI) protein, lysozyme, lactoferrin, and a group of newly discovered arginine-rich cationic peptides called defensins. The pH of the phagolysosome drops to between 4 and 5 after phagocytosis, allowing acid hydrolases to degrade me dead microorganisms. Phagocytosis of the offending agent follows, which may lead to the death of the microorganism. During chemotaxis and phagocytosis activated leukocytes may released toxic metabolites and proteases extracellularly, potentially causing endothelial and tissue damage. Phagocytosis and degranulation. Phagocytosis consists of: I. Recognition II. Attachment III. Absorbtion Attachment Discharge of the granule’s – degranulation. Bacterial killing is accomplished by reactive oxygen species. Microbes can also be killed by non – oxygen dependent substances. The pH of the phagolysosome drops to between 4 and 5 after phagocytosis, allowing acid hydrolases to degrate the dead microorganism.
- 16. Summary of the acute inflammatory response. The vascular phenomena are characterized by increased blood flow to the injured area, resulting mainly from arteriolar dilatation end opening of capillary beds. Increased vascular permeability results in the collection of protein-rich extravascular fluid, which forms the exudate. Plasma proteins leave the vessels, either through widened interendothelial cell junction of the venules or by direct endothelial cell injury. The leukocytes, predominantly neutrophils, first adhere to the endothelium via adhesion molecules, then leave the microvasculature and migrate to the site of injury under the influence of chemotactic agent.
- 19. Inflammation may be: Serous inflammation is marked by the outpouring of thin fluid that, depending on the site of injury, is derived from either the blood serum or the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities. Fibrinosis inflammation - it's resulting greater vascular permeability, larger molecules pass the vascular barrier. A fibrinous exudate is characteristic of inflammation in body cavities, such as the pericardium and pleura. Fibrinous exudates may be removed by fibrinolysis, and other debris by macrophages. This process called resolution, may restore normal tissue structure, but when the fibrin is not removed it may stimulate the ingrowth of fibroblasts and blood vessels and thus lead to scarring. Conversion of the fibrinous exudate to scar tissue (organization) within the pericardial sac will lead either to opaque fibrous thickening of the pericardium and epicardium in the area of exudation or, more often, to the development of fibrous strands that bridge the pericardial space. It is evident, then, that fibrinous exudation may have more serious consequences than serous exudation. Purulent inflammation (suppurative) this form of inflammation is characterized by the production of large amounts of pus or purulent exudate. A common example of an acute suppurative inflammation is acute appendicitis, abscesses. Abscess has a central region that appears as a mass of necrotic white cells and tissue cells. There is usually a zone of preserved neutrophils about this necrotic focus, and outside this region vascular dilatation and parenchymal and fibroblastic proliferation occur, indicating the beginning of repair. In time, the abscess may become walled off by the connective tissue that limits further spread. Furuncle, carbuncles - purulent inflammation (called cellulitis) tends to trek rapidly through large areas of tissue such as an entire arm, the face, or the abdominal wall.
- 25. 3. Repair - proliferation. After leukocyte exudation and phagocytosis begins repair - endothelial cells proliferate and form new blood vessels (granulation tissue). Death is born life. For the life threading loss of fluid, the endothelial cells differentiate and form intercellular junction - it's characteristic of healing inflammation. Death will be born life. During repair, endothelial cells proliferate and form new blood vessels (granulation tissue). These capillary sprout remain leaky until the endothelial cells differentiate and form intercellular junctions, accounting for the edema characteristic of healing inflammation. It should be noted that although these four mechanisms are separable all may play a role m response to one stimulus. For example, in various stages of a thermal bum, leakage results from chemically mediated endothelial contraction as well as direct and leukocyte dependent injury - and from regenerating capillaries when the bums heal. This accounts for the life threatening loss of fluid in severally burned patients. In addition, different mechanisms may be actived killing mediated by anti-donor immunoglobulin plus complement (C). Modification of the endothelium by the direct effect of lymphokines contributes, as well.
- 27. The major components of the extracellular matrix (ECM), including collagens, proteoglycans, and adhesive glycoproteins. Note that although there are some overlaps in their constituents, basement membrane and interstitial ECM have different general compositions and architecture. Both epithelial and mesenchymal cells (e.g., fibroblasts) interact with ECM via integrins. For the sake of simplification, many ECM components have been left out (e.g., elastin, fibrillin, hyaluronan , syndecan).
- 28. Proteoglycans in the ECM and on cells act as reservoirs for growth factors. Heparan sulfate binds basic fibroblast growth factor (FGF-2) secreted into the ECM. Any subsequent injury to the ECM can release FGF-2, which stimulates the recruitment of inflammatory cells, fibroblast activation, and new blood vessel formation. Syndecan is a cell surface proteoglycan with a transmembrane core protein and attached extracellular glycosaminoglycan side chains. The glycosaminoglycan chains can also bind free FGF-2 from the ECM and mediate interactions with cell surface FGF receptors. The cytoplasmic tail of syndecan attaches to the intracellular actin cytoskeleton and helps maintain the architecture of epithelial sheets.
- 29. Mechanisms by which ECM components (e.g., fibronectin and laminin) and growth factors can influence cell proliferation, motility, differentiation, and protein synthesis. Integrins bind ECM and interact with the cytoskeleton at focal adhesion complexes (protein aggregates that include vinculin, α-actin, and talin). This can initiate the production of intracellular second messengers or can directly mediate nuclear signals. Cell surface receptors for growth factors activate signal transduction pathways that overlap with those activated by integrins. Signals received from growth factors and ECM components are integrated by the cell to yield various responses, including changes in cell proliferation, locomotion, and differentiation.
- 30. Phases of wound healing. Wound contraction occurs only in healing by second intention.
- 31. Steps in wound healing by first intention (left) and second intention (right). In the latter, note the large amount of granulation tissue and wound contraction.
- 33. Macrophage-lymphocyte interactions in chronic inflammation. Activated lymphocytes and macrophages stimulate each other, and both cell types release inflammatory mediators that affect other cells. IFN-γ - interferon-γ; IL-1 - interleukin 1; TNF- tumor necrosis factor.
- 34. Comparison of the morphologic features of RA and osteoarthritis