Acute Inflammation PDF

Inflammation PROF. DR. DALYA BASIL  Introduction Inflammation is a complex response intended to minimize the effects of injury or infection, remove the damaged tissue, and generate new tissue. It accomplishes this by diluting, destroying, or otherwise neutralizing the har...

Inflammation PROF. DR. DALYA BASIL  Introduction Inflammation is a complex response intended to minimize the effects of injury or infection, remove the damaged tissue, and generate new tissue. It accomplishes this by diluting, destroying, or otherwise neutralizing the harmful agents. Inflammation is the reaction of vascularized tissues to cell injury or death, characterized by the elaboration of inflammatory mediators and the movement of fluid and leukocytes from the vascular system into the extravascular tissues.  General Features of Inflammation Inflammatory conditions are commonly named by adding the suffix -itis to the affected organ or system. For example, appendicitis refers to inflammation of the appendix, pericarditis to inflammation of the pericardium, and neuritis to inflammation of a nerve. Inflammation can be acute or chronic. Acute inflammation is the adaptive response that is triggered by noxious stimuli and conditions, such as infection and tissue injury, and is of relatively short duration, lasting from a few minutes to several days. It is characterized by the exudation of fluid and plasma proteins and emigration of leukocytes, predominantly neutrophils. Chronic inflammation is of a longer duration, lasting for days to years, and is associated with the proliferation of blood vessels, tissue necrosis, and fibrosis (scarring).  Cells of Inflammation Many cells and tissue components are involved in the inflammatory process, including the endothelial cells that line blood vessels, circulating platelets and leukocytes, connective tissue cells (mast cells, fibroblasts, tissue macrophages), and components of the extracellular matrix. The principal leukocytes in acute inflammation are neutrophils, whereas macrophages, lymphocytes and plasma cells, eosinophils, and mast cells predominate in chronic inflammation.  Cells of Inflammation Endothelial Cells: Endothelial cells comprise the single-cell-thick epithelial lining of blood vessels. They produce antiplatelet and antithrombotic agents that maintain vessel patency, as well as vasodilators and vasoconstrictors that regulate blood flow. Endothelial cells are also key players in the inflammatory response. As such, they provide a selective permeability barrier to exogenous (microbial) and endogenous inflammatory stimuli; regulate leukocyte extravasation, and release of inflammatory mediators; and regulate immune cell proliferation through secretion of hematopoietic colony-stimulating factors (CSFs).  Cells of Inflammation Platelets or thrombocytes are small membrane-bound disks circulating in the blood that play an active role in normal hemostasis. Activated platelets also release a number of potent inflammatory mediators, thereby increasing vascular permeability and altering the chemotactic, adhesive, and proteolytic properties of the endothelial cells. Leukocytes (WBCs) are the major cellular components of the inflammatory response. They include the granulocytes (neutrophils, eosinophils, and basophils), which contain specific cytoplasmic granules and a multilobed nucleus, and the agranulocytes (monocytes/macrophages and lymphocytes), which lack cytoplasmic granules and have a single nucleus.  Cells of Inflammation Neutrophils: Neutrophils are the most numerous leukocytes in the circulating blood, accounting for 60% to 70%of all white blood cells. These leukocytes are referred to polymorphonuclear neutrophils (PMNs). Because of their ability to form pseudopods used in ameboid movement, neutrophils are highly mobile and are therefore the first cells to appear at the site of acute inflammation, usually arriving within 90 minutes of injury. They are capable of engulfing bacteria and other cellular debris through phagocytosis. They have oxygen-dependent metabolic pathways that generate toxic oxygen (e.g., hydrogen peroxide) and nitrogen (e.g., nitric oxide) products that aid in the destruction of engulfed pathogens.  Cells of Inflammation Eosinophils: Eosinophils account for 2% to 3% of circulating leukocytes and are recruited to tissues similar to neutrophils. Their appearance at the site of inflammation occurs 2 to 3 hours after the neutrophils. This is, in part, because of their slower mobility and comparatively slower reaction to chemotactic stimuli. The granules of eosinophils, which stain pink with the acid dye eosin, contain a protein that is highly toxic to large parasitic worms that cannot be phagocytized. Eosinophils have a longer life span than neutrophils and therefore present in chronic inflammation.  Cells of Inflammation Basophils and Mast Cells: Basophils are account for less than 1% of the circulating leukocytes, they are important participants in inflammatory reactions and are most prominent in allergic reactions mediated by immunoglobulin E (IgE). Monocyte/Macrophages: Monocytes constitute 3%to 8% of the white blood cell count. They have a single kidney-shaped nucleus and are the largest of the circulating leukocytes. The half-life of circulating monocytes is about a day, after which they begin to migrate to the site of injury and undergo transformation into larger macrophages, which have a longer half-life and greater phagocytic ability than do blood monocytes.  Cells of Inflammation Lymphocytes and Plasma Cells: Lymphocytes are participate in immune-mediated inflammation caused by infectious agents as well as non–immune-mediated inflammation associated with cell injury and death. Both T and B lymphocytes (T and B cells) migrate into inflammatory sites using some of the same adhesion molecules and chemokines that recruit neutrophils and other leukocytes. Plasma cells develop from activated B lymphocytes and produce antibodies directed against persistent antigens in the inflammatory site and against altered tissue components. In some intense chronic inflammatory reactions, the accumulation of lymphocytes and plasma cells may assume the appearance of lymphoid organs, such as lymph nodes. This pattern of lymphocyte accumulation is often seen in the inflamed synovium of persons with long-standing rheumatoid arthritis.  Cells of Inflammation Cell Adhesion Molecules and Leukocyte Recruitment: Several families of cell adhesion molecules, including selectins, integrins, and the immunoglobulin superfamily, are involved in leukocyte recruitment and trafficking. The selectins are a family of three closely related proteins (E-selectin, L-selectin, P-selectin) that differ in their cellular distribution but all function in adhesion of leukocytes to endothelial cells. The integrin superfamily consists of 30 structurally similar proteins that promote cell-to-cell and cell–to–extracellular matrix interactions.  Cells of Inflammation The importance of the leukocyte adhesion molecules is demonstrated in persons with an inherited disorder called leukocyte adhesion deficiency (LAD) type I, in which deficiency of a member of the integrin superfamily leads to severe leukocytosis and recurrent infections. A similar deficiency is seen in individuals with impaired expression of a member of the selectin superfamily and has been labeled LAD type 2. There is also evidence that excessive expression of cell adhesion molecules or their receptors contributes to the pathogenesis of some chronic inflammatory diseases such as rheumatoid arthritis.  Steps of inflammatory response 1- Recognition of injurious agent 2- Recruitment of leukocytes 3- Removal of the agent 4- Regulation of response 5- Resolution  Acute Inflammation Acute inflammation is the early (almost immediate) reaction of local tissues and their blood vessels to injury. It typically occurs before the adaptive immune response becomes established and is aimed primarily at removing the injurious agent and limiting the extent of tissue damage. Acute inflammation can be triggered by a variety of stimuli, including infections, immune reactions, blunt and penetrating trauma, physical or chemical agents (e.g., burns, frost-bite, irradiation, caustic chemicals), and tissue necrosis from any cause.  Cardinal Signs of Inflammation Pain: the inflamed area is likely to be painful, especially when touched. Chemicals that stimulate nerve endings are released, making the area much more sensitive. Redness: this is because the capillaries are filled up with more blood than usual. Swelling: caused by an accumulation of fluid. Heat: as with the reason for the redness, more blood in the affected area makes it feel hot to the touch. Immobility: there may be some loss of function.  Vascular and Cellular Stages Acute inflammation has two stages: the vascular stage, which is characterized by increased blood flow (vasodilation) and structural changes (increased vascular permeability) that allow plasma proteins to leave the circulation, and the cellular stage, which involves the emigration of leukocytes (mainly neutrophils) from the microcirculation and their accumulation at the site of injury or infection.  Vascular Stage Vascular Stage: The vascular changes that occur with inflammation involve the arterioles, capillaries, and venules of the microcirculation. These changes begin almost immediately after injury and are characterized by vasodilation and changes in blood flow followed by increased vascular permeability and leakage of protein-rich fluid into the extravascular tissues. Vasodilation, which is one of the earliest manifestations of inflammation, follows a transient constriction of the arterioles, lasting a few seconds. As a result, the area becomes congested, causing the redness (erythema) and warmth associated with acute inflammation. Vasodilation is induced by the action of several mediators, most notably histamine and nitric oxide.  Vascular Stage Vasodilation is quickly followed by increased permeability of the microvasculature, with the outpouring of a protein-rich fluid (exudate) into the extravascular spaces. The loss of fluid results in an increased concentration of blood constituents (red blood cells, leukocytes, platelets, and clotting factors), stagnation of flow, and clotting of blood at the site of injury. This aids in localizing the spread of infectious microorganisms. The loss of plasma proteins reduces the intracapillary osmotic pressure and increases the osmotic pressure of the interstitial fluid, causing fluid to move from the vascular compartment into the tissues and produce the swelling, pain, and impaired function that are the cardinal signs of acute inflammation. The exudation of fluid into the tissue spaces also serves to dilute the offending agent. The most common mechanism of vascular leakage is elicited by histamine, bradykinin, leukotrienes, and many other classes of chemical mediators.  Vascular Stage Depending on the severity of injury, the vascular changes that occur with inflammation follow one of three patterns of responses. 1. The first pattern is an immediate transient response, which occurs with minor injury. It develops rapidly after injury and is usually reversible and of short duration (15 to 30 minutes). Typically, this type of leakage affects venules 20 to 60 µm in diameter, leaving capillaries and arterioles unaffected. Although the precise mechanism for restriction of this effect to the venules is unknown, it may reflect the greater density of receptors in the endothelium of the venules. It has also been suggested that the later leukocyte events of inflammation (i.e., adhesion and emigration) also occur predominantly in the venules of most organs.  Vascular Stage 2. The second pattern is an immediate sustained response, which occurs with more serious types of injury and continues for several days. It affects all levels of the microcirculation (arterioles, capillaries, and venules) and is usually due to direct damage of the endothelium by injurious stimuli, such as burns or the products of bacterial infections. Neutrophils that adhere to the endothelium may also injure endothelial cells.  Vascular Stage 3. The third pattern is a delayed hemodynamic response, in which the increased permeability begins after a delay of 2 to 12 hours, lasts for several hours or even days, and involves venules as well as capillaries. A delayed response often accompanies injuries due to radiation, such as sun-burn. The mechanism of the leakage is unknown, but it may result from the direct effect of the injurious agent, leading to delayed endothelial cell damage.  Cellular Stage - Leukocytes emigration, accumulation, activation of leukocytes, enabling them to eliminate the offending agent. Principal leukocytes are polymorpho nuclear leukocytes (Neutrophils). - Leukocyte recruitment In this step there is sequence of events: 1) Margination and rolling: as blood flows, circulating cells are swept by laminar flow against the vessel wall. Larger leukocytes are pushed out of central axial column and thus interact with lining endothelial cells (margination).  Cellular Stage If endothelial cells are activated by cytokines and mediators--express adhesion molecules to which leukocytes attach loosely, these cells bind and detach and thus begin to tumble on endothelial surface, a process called rolling. Mediated by selectin family of adhesion molecules, three members are- E-selectin (on endothelial cells), P- selectin (on platelets and endothelium), and L selectin (on surface of most leukocytes). All selectins are induced after stimulation.  Cellular Stage 2) Adhesion: Rolling leukocytes sense changes, then initiate firm adhesion which is mediated by integrins - leukocyte cell surfaces and ligands on endothelial cells. Cytokine stimulated increased integrin affinity and increased expression of integrin ligands provides stable attachment of leucocytes to endothelial cells at sites of inflammation.  Cellular Stage 3) Transmigration: By squeezing between cells at intercellular junctions called diapedesis, mainly in venules of systematic vasculature. Leucocytes secrete collagenases, pass through the vascular basement membrane. 4) Chemotaxis: After extravasating from blood, leukocytes move toward sites of infection or injury along a chemical gradient by a process called chemotaxis. Chemotactic substances: such as soluble bacterial products, cytokines and others.  Cellular Stage Leukocytes move by extending pseudopods that anchor to ECM and then pull the cell in direction of extension. Neutrophils predominate in inflammatory infiltrate during first 6 to24 hours and are replaced by monocytes in 24 to 48 hours. 5) Leukocyte activation: Cellular receptors responses in leukocytes result in defensive function and leukocyte activation. Functions: - Phagocytosis of particles - Intracellular destruction of phagocytosed microbes and dead cells. - Liberation of substances that destroy extracellular microbes and dead tissues - Production of mediators. Phagocytosis steps: 1) Recognition and attachment 2) Engulfment, with subsequent formation of a phagocytic vacuole 3) Killing and degradation of ingested material. * Key to the normal function of leukocytes in host defense is to ensure that they are recruited and activated only when needed. Local manifestation of Acute Inflammation Local manifestation of acute inflammation can be range from mild swelling and redness to abscess or ulceration. Charactestically the acute inflammatory response involves the production of exudates, which vary in terms of fluid type, plasma protein content, and presence or absence of cells. Exudates can be: Serous Hemorrahgic Fibrinous Membranous Purulant Resolution THANK YOU