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Principles of the Inflammatory Response

Introduction Inflammation is a biochemical and cellular response that occurs in all vascularized tissue whose health and vitality is threatened by either an internal or an external source. Most of the essential components of the inflammatory response can be found in the blood, and most of the early mediators (facilitators) of inflammation function to increase the movement of plasma and infectionfighting blood cells from the capillary bed into or around the injured tissue. Collectively known as exudate, usually a clear serous fluid, these substances defend the host against infection and facilitate tissue repair and healing. The superficial hallmarks of inflammation have been described since antiquity. They are: Redness (rubor) Heat (calor) Pain (dolor) Swelling (tumor Loss of function (functio laesa).
Classic clinical presentation with acute deep vein thrombosis (DVT). The leg is red, hot, painful, swollen and difficult to use

On a microscopic level, three characteristic changes in the microcirculation occur near the site of tissue injury. Increased blood flow to the area. Increased vascular permeability which allows leakage of plasma into the damaged area. An increased number of white blood cells immigrating through vessel walls to the site of injury.

Histological sections through a normal and an inflamed retina (age-related macular degeneration)

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Gross pathologic and correlative sonographic sections through an acutely inflamed gallbladder (GB). Edematous and necrotic changes in the GB wall (left) produce heterogeneous sonographic appearance (right). Increased fluid content in GB produces posterior acoustic enhancement. Anechoic pericholecystic fluid is inflammatory serous exudate.

The overall purpose of the inflammatory response is to: Destroy injurious agents and remove them from the inflammatory site. Wall off and confine these agents so as to limit their effects on the host Stimulate and enhance the immune response. Promote healing. In contrast to the immune system, which is antigen specific and has memory, the inflammatory response is nonspecific as it takes place in about the same way, regardless of the stimulus. It also occurs in the same manner, even on a subsequent exposure to the same stimulus. The acute response is self-limiting; that is, it runs a predicable course and continues only until the threat to the host is eliminated, this usually takes 8 to 10 days, from onset to healing. Inflammation is considered chronic if it persists longer than 2 weeks. Acute Inflammatory Response The acute inflammatory response begins after lethal or non-lethal cellular insult or injury. Initially, arterioles near the site of injury constrict briefly. This vasoconstriction is followed by vasodilatation which increases blood flow to the inflamed site. Exudation causes edema and swelling. Leukocytes (white blood cells) migrate and adhere to vessel walls in the injured area. At the same time, biochemical mediators stimulate the endothelial cells that line capillaries and venules to retract, creating spaces at junctions between the cells. The leukocytes, which otherwise could not pass through vessel walls, are able to squeeze out through these spaces created by endothelial retraction. Neutrophils are the first phagocytic leukocytes to arrive at the inflamed site. They phagocytose (ingest) bacteria, dead cells, and

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cellular debris, and then they die and are removed as pus through the epithelium or the lymphatic system. The next phagocytes on the scene are monocytes and macrophages, which perform many of the same functions as neutrophils but for a longer time and later in the inflammatory response. Other cells found in inflamed tissues are eosinophils, which help to control the inflammatory response and act directly against parasites; basophils, which have a function similar to that of mast cells; and platelets, which are cytoplasmic fragments that stop bleeding if vascular injury has occurred.

The cells and platelets carry out their roles with the assistance of four major plasma protein systems: Complement system not only activates and assists inflammatory and immune processes but also plays a major role in the direct destruction of cells (especially bacteria). Clotting system traps bacteria in injured tissues and interacts with platelets to prevent hemorrhage. Kinin systems helps to control vascular permeability. Immunoglobulins.

The inflammatory response.

All these cells and protein systems, along with the substances they produce, act at the site of tissue injury to kill microorganisms and remove the debris of battle, including exudate and dead cells. The biochemical mediators and cellular components of the acute inflammatory response form a complex system of interactions that frequently begins with degranulation of mast cells and ends with healing. Mast Cells Mast cells are cellular bags of granules located in the loose connective tissues close to blood vessels. Mast cells activate the inflammatory response in two ways. Degranulation, by which they release preformed granular contents into the extracellular matrix. Synthesis of certain mediators in response to a stimulus. Mast cell degranulation is stimulated by one of the following means: Physical injury, such as heat, mechanical trauma, ultraviolet light, or xrays. Chemical agents, such as toxins, snake and bee yenoms, tissue proteases (enzymes), etc.

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Immunologic means, such as the triggering of IgE mediated hypersensitivity reactions or direct processes, such as activation of complement components. Preformed biochemical mediators found in the granules including: o Histamine and serotonin: Histamine and serotonin are both vasoactive amines. They cause temporary, rapid constriction of the smooth muscle of Electron microscope image of a large vessel walls; dilation of the postmast cell. capillary venules, resulting in increased blood flow into the microcirculation; and increased vascular permeability resulting from retraction of endothelial cells lining the capillaries. o Chemotactic factors are biochemical substances that attract a specific type of leukocyte to the site of inflammation. Chemotaxis is directional movement of cells along a chemical gradient formed by a chemotactic factor. o Neutrophil chemotactic factor attracts neutrophils to the site of inflammation. Neutrophils are the predominant leukocytes at work during early phases of acute inflammation. o Eosinophil chemotactic factor attracts eosinophils to the inflamed site. Eosinophils are leukocytes that have several functions in the inflammatory response. They are phagocytic and are the bodys primary defense against some parasites. Their most important role, however, is to control the mediators of acute inflammation released from mast cells. Eosinophils contain several enzymes that degrade the vasoactive amines, thereby controlling the vascular effects of inflammation.

Plasma Protein Systems Complement system: The complement system is perhaps the most important of the plasma protein systems of inflammation because, once activated, its components participate in virtually every inflammatory response. In addition, the last few proteins in the complement cascade are capable of killing microorganisms directly. The complement system can be activated by antigenantibody complexes, as well as by products released from invading bacteria and by components of the other plasma protein systems. There are two routes by which the complement system cascade is initiated: Classical pathway: Activation of the classical pathway is preceded by formation of an antigen-antibody complex. Alternative pathway: A non-antibody activated complement cascade initiated by a number of naturally occurring enzymes.

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Clotting system: The clotting (coagulation) system is a plasma protein system that forms a fibrinous meshwork at the inflamed site to trap exudates, microorganisms, and foreign bodies. This: Prevents the spread of infection and inflammation to adjacent tissues. Keeps microorganisms and foreign bodies at the site of greatest phagocytic activity. Forms a clot that stops bleeding and provides a framework for future repair and healing. The main substance in this fibrinous mesh is an insoluble protein called fibrin that is the end product of the coagulation cascade. Kinin system: The primary kinin is bradykinin, which, at low doses, causes dilation of vessels, acts with prostaglandins to cause pain, causes extravascular smooth muscle contraction, increases vascular permeability and may increase leukocyte chemotaxis. Cellular Components of Inflammation Granulocytes are leukocytes named because of the many enzyme-containing lysosomal granules in their cytoplasm include: Neutrophils: Phagocytes that normally circulate in the bloodstream and are stimulated by inflammation to migrate through vessel walls near an inflammatory lesion. They are the first white blood cells to arrive at a site of inflammation. Once in the exudate, each is attracted to the lesion by specific chemotactic factors and kept there by the meshwork formed by fibrinous exudate. Once at the site, these cells phagocytose (ingest) foreign or dead cells until its life span is over. The dead phagocyte then becomes part of the purulent exudate, or pus, which leaves the body through the lymphatic system or through the epithelium. Eosinophils: Appear at allergic response sites and seem to perform a protective role for the host by ending, or modulating, the inflammatory reaction. Basophils: Circulate in the bloodstream and when activated by injury or infection, release histamine, bradykinin, amd serotonin. These substances increase capillary permeability and blood flow to the area. Similar to mast cells. Phagocytes: the engulfment and destruction of microorganisms, dead cells, and foreign particles, begins when the phagocytic cell enters the inflammatory site. There are four steps in phagocytosis: Recognition of the target and its adherence to the phagocyte Engulfment (ingestion, or endocytosis) Fusion with lysosomes within the phagocyte Destruction of the target by lysosomal enzymes

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Schematic representation of the stages of phagocytosis

Scanning electron microscope of a phagocyte in action.

Monocytes/macrophages: Monocytes: Immature white blood cells that mature into macrophages after several hours in inflamed tissue. They circulate in the blood and enter injured tissue across capillary membranes. They are not phagocytic but become so after maturing into macrophages. Macrophages: Large cells capable of ingesting very large quantities of cell debris and bacteria. Some macrophage cells colonize tissues, such as skin, lymph nodes, and lungs for months or years. These cells are readily available to scavenge microorganisms that may enter the body through these routes. The monocyte-macrophage cell system is called the reticuloendothelial system. Lymphocytes (B and T cells) These immune system cells respond with specificity and memory to prevent infection. B and T cells are derived in utero from cells found in lymphoid tissue of the liver and spleen. After birth, lymphocytes continue to proliferate in those sites as well as in the bone marrow, lymph glands, thymus, and tonsils. B lymphocytes comprise the humoral immune system, meaning they circulate in the blood (the humor). B-cell maturation occurs during passage through the liver, spleen, or lymph nodes. A mature B cell circulates in the blood in an inactive state. It becomes active only after exposure to a specific microorganism (or protein) to which it has been genetically programmed during development to respond. When activated, the B cell destroys the substance that caused its activation. T cells comprise the cellular immune s stern. T-cell maturation occurs during passage rough the thymus gland. When a T-cell encounters a microorganism (or other protein) to which it has been programmed during development to respond, it can directly attack or destroy the substance.

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Platelets are cytoplasmic fragments that circulate in the bloodstream until vascular injury occurs. After injury, platelets squeeze out of the capillaries and interact with components of the coagulation cascade to stop bleeding.

Cellular Products: Interleukins: Biochemical messengers produced by macrophages or lymphocytes in response to stimulation by an antigen or by products of inflammation. Lymphokines: Produced by T-cells in response to antigenic stimulation. They are biochemical mediators that affect other cells of the immune system inflammatory responses. Interferon: A protein that stimulate uninfected cells to produce antiviral substances. Systemic Manifestation of Acute Inflammation. The three primary systemic changes associated with the acute inflammatory response are: Fever: The generation of a febrile response can be beneficial to the defense of the host because the microorganisms that cause some conditions (e.g., syphilis, gonococcal urethritis) are very sensitive to small increases in body temperature. On the other hand, fever may have some harmful side effects, because it may enhance the hosts susceptibility to the effects of endotoxins associated with gramnegative bacterial infections. Leukocytosis (elevated white blood cell count): During many infections, numbers of circulating leukocytes, primarily neutrophils, increase. This increase is usually accompanied by a left shift in the ratio of immature to mature neutrophils, so that the more immature forms of neutrophils, such as band cells, metamyelocytes, and, occasionally, myelocytes, are present in greater than normal proportions Increase in circulating plasma proteins: Many plasma proteins, most of which are products of the liver, are increased during inflammation; these are referred to as acute-phase reactants. Chronic Inflammation The difference between acute and chronic inflammation is purely one of duration, in that chronic inflammation lasts 2 weeks or longer. Chronic inflammation may be precede by and unsuccessful acute inflammatory response. Chronic inflammation may occur as a distinct process without much acute inflammation.

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Local Manifestations of Inflammation All the local manifestations of acute inflammation are caused by vascular changes and exudation. Swelling occurs as exudate accumulates. Swelling is usually accompanied by pain caused by pressure exerted on local pain receptors by exudate accumulation and the presence of soluble biochemical mediators, such as prostaglandins and bradykinin. Heat and redness are the result of increased perfusion (increased blood flow through the area). The function of vascular changes and exudation is to deliver leukocytes, plasma proteins, and their biochemical mediators to the site of injury. Exudate and its contents have three functions: To dilute toxins produced by bacteria and toxic products released by dying cells. To carry plasma proteins (including antibody) and leukocytes (both phagocytes and lymphocytes) to the site. To carry away bacterial toxins, dead cells, debris, and other products of inflammation. Exudates vary in composition, depending on the stage of the inflammatory response and, to some extent, the injurious stimulus. In early or mild inflammation the exudate is watery, or a serous exudate, with very few plasma proteins or leukocytes. Examples include fluid in a blister and free fluid in the cul de sac in a patient with early acute pelvic inflammatory disease (PID). In more severe or advanced inflammation the exudate becomes thick and clotted, or a fibrinous exudate, such as in the lungs of individuals with lobar pneumonia. If a large number of leukocytes accumulate, as in persistent bacterial infections, the exudate consists of pus and is called a purulent (suppurative) exudate. Purulent exudate is characteristic of walled-off lesions (cysts or abscesses). If bleeding occurs, the exudate is filled with erythrocytes and is described as a hemorrhagic exudate. Wound Healing: Destruction of tissue is followed by a period of healing that begins during acute inflammation and may not be complete for as long as 2 years. The most favorable outcome of healing is complete return to normal structure and function. Repair: The replacement of destroyed tissue with scar tissue. Scar tissue is composed of collagen. It fills in the lesion and restores tensile strength but cannot carry out the physiologic functions of destroyed tissue. Debridement: Cleanup of the lesion, which involves dissolution of fibrin clots (or scabs) by fibrinolytic enzymes. After dbridement, exudate, toxic products, and particulate matter are drained away and vascular dilation and permeability are reversed, preparing the lesion for either regeneration or repair. Resolution: Restoration of original structure and physiological function.

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