Lecture 3 ACUTE INFLAMMATION.pptx.pdf

General Pathology Acute Inflammation KIER MAINIT TAMPARONG, MD  General Pathology outline: Definition of inflammation and importance in normal physiology Mechanisms to recognize microbes and damaged cells Acute inflammation Mediators of acute inflammation Morphol...

General Pathology Acute Inflammation KIER MAINIT TAMPARONG, MD  General Pathology outline: Definition of inflammation and importance in normal physiology Mechanisms to recognize microbes and damaged cells Acute inflammation Mediators of acute inflammation Morphologic patterns of acute inflammation  General Pathology OVERVIEW OF INFLAMMATION: DEFINITIONS AND GENERAL FEATURES Inflammation is a response of vascularized tissues that delivers leukocytes and molecules of host defense from the circulation to the sites of infection and cell damage in order to eliminate the offending agents.  General Pathology Typical Inflammatory Reaction: sequential steps 1 RECOGNITION of the noxious agent that is the initiat- ing stimulus for inflammation. Engagement of the receptors leads to the production of mediators of inflammation, which then trigger the subsequent steps in the inflammatory response. General Pathology Inflammation & Physiology phagocytic leukocytes, antibodies, and 1 complement proteins normally circulate in a resting state in the blood, from where they can be rapidly recruited to any site in the body. Some of the cells involved in inflammatory responses also reside in tissues, where they function as sentinels on the lookout for threats The process of inflammation delivers circulating 2 cells and proteins to tissues and activates the recruited and resident cells as well as the soluble molecules, which then function to get rid of the harmful or unwanted substances.  General Pathology Typical Inflammatory Reaction: sequential steps 2 RECRUITMENT of leukocytes and plasma proteins into the tissues. When pathogenic microbes invade the tissues, or tissue cells die, leukocytes (first mainly neutrophils, later monocytes and lymphocytes) and plasma proteins are rapidly recruited from the circulation to the extravascular site where the offending agent is  General Pathology Typical Inflammatory Reaction: sequential steps 3 REMOVAL of the stimulus for inflammation is accomplished mainly by phagocytic cells, which ingest and destroy microbes and dead cells.  General Pathology Typical Inflammatory Reaction: sequential steps 4 REGULATION of the response is important for terminating the reaction when it has accomplished its purpose.  General Pathology Typical Inflammatory Reaction: sequential steps 5 REPAIR consists of a series of events that heal damaged tissue. In this process the injured tissue is replaced through regeneration of surviving cells and filling of residual defects with connective tissue (scarring).  General Pathology Recognition of Microbes & Damaged Cells Recognition of microbial components or substances released from damaged cells is the initiating step in inflammatory reactions.  General Pathology Recognition of Several cellular receptors and circulating Microbes & Damaged Cells proteins are capable of recognizing microbes and products of cell damage and triggering inflammation. Cellular Receptors for Microbes Cells express receptors in the plasma membrane (for extracellular microbes), the endosomes (for ingested microbes), and the cytosol (for intracellular microbes) that enable the cells to sense the presence of foreign invaders in any cellular compartment. Toll-like receptors (TLRs) Engagement of these receptors triggers production of molecules involved in inflammation includ- ing adhesion molecules on endothelial cells, cytokines, and General Pathology Recognition of Microbes & Damaged Cells Sensors of Cell Damage All cells have cytosolic receptors, such as NOD-like receptors (NLRs), that recognize diverse molecules that are liberated or altered as a consequence of cell damage. These molecules include uric acid (a product of DNA breakdown), adenosine triphosphate (ATP) (released from damaged mitochondria), reduced intracellular K+ concentrations (reflecting loss of ions because of plasma membrane injury), even DNA when it is released into the cytoplasm General Pathology Recognition of Microbes & Damaged Cells Other Cellular Receptors involved in Inflammation In addition to directly recognizing microbes, many leukocytes express receptors for the Fc tails of antibodies and for complement proteins. These receptors recognize microbes coated with antibodies and complement (the coating process is called opsonization) and promote ingestion and destruction of the microbes as well as inflammation. General Pathology Recognition of Microbes & Damaged Cells Circulating Proteins: the Complement System The complement system reacts against microbes and produces mediators of inflammation. A circulating protein called mannose- binding lectin recognizes microbial sugars and promotes ingestion of the microbes and the activation of the complement system. Other proteins called collectins also bind to and combat microbes.  General Pathology Acute Inflammation Acute inflammation has three major components: (1) dilation of small vessels leading to an increase in blood flow; (2) increased permeability of the microvasculature enabling plasma proteins and leukocytes to leave the circulation; and (3) emigration of leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent Reactions of Blood Vessels in Acute Inflammation The vascular reactions of acute inflammation consist of changes in the flow of blood and the permeability of vessels, both designed to maximize the movement of plasma proteins and leukocytes out of the circulation and into the site of infection or injury. EXUDATION The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities General Pathology Exudate vs Transudate EXUDATE an extravascular fluid that has a high protein concentration and contains cellular debris. Its presence implies the existence of an inflammatory process that has increased the permeability of small blood vessels. TRANSUDATE 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 is produced as a result of osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability.  General Pathology 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. General Pathology Changes in Vascular Flow & Caliber 1 VASODILATION induced by the action of several mediators, notably histamine, on vascular smooth muscle. It is one of the earliest manifestations of acute inflammation. The result is increased blood flow, which is the cause of heat and redness (erythema) at the site of inflammation. 2 INCREASED PERMIABILITY TO MICROVASCULATURE Vasodilation is quickly followed by increased permeability of the microvasculature, with the outpouring of protein-rich fluid into the extravascular tissues; General Pathology Changes in Vascular Flow & Caliber 3 STASIS 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 engorgement of small vessels with slowly moving red cells - as vascular congestion and localized redness of the involved tissue. As stasis develops, blood leukocytes, principally neutro- 4 phils, 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  General Pathology Increased Vascular Permiability (Vascular Leakage) Several mechanisms are responsible for the increased permeability of postcapillary venules, a hallmark of acute inflammation. CONTRACTION OF ENDOTHELIAL CELLS ENDOTHELIAL INJURY  General Pathology Contraction of Endothelial Cell resulting in opening of interendothelial gaps is the most common mechanism of vascular leakage. It is elicited by histamine, bradykinin, leukotrienes, and other chemical mediators. It is called the immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15 to 30 minutes)  General Pathology Endothelial Injury resulting in endothelial cell necrosis and detachment. Direct damage to the endothelium is encountered in severe physical injuries, for example, in thermal burns, or is induced by the actions of microbes and microbial toxins that damage endothelial cells.  General Pathology Responses of Lymphatic Vessels & Lymph Nodes The system of lymphatics and lymph nodes filters and polices the extravascular fluids. Lymphatics drain the small amount of extravascular fluid that seeps out of capillaries in the healthy state. In inflammation, lymph flow is increased and helps drain edema fluid that accumulates because of increased vascular permeability.  General Pathology Leukocyte Recruitment to Sites of Inflammation The changes in blood flow and vascular permeability are quickly followed by an influx of leukocytes into the tissue. The most important leukocytes in typical inflammatory reactions are the ones capable of phagocytosis, namely neutrophils and macrophages. They ingest and destroy bacteria and other microbes, as well as necrotic tissue and foreign substances. Macrophages also produce growth factors that aid in repair.  General Pathology Phagocytosis & Clearance of Offending Agent The two major phagocytes are neutrophils and macrophages. Recognition of microbes or dead cells induces several responses in leukocytes that are collectively called leukocyte activation General Pathology Phagocytosis Phagocytosis involves sequential steps Recognition and attachment of the particle to be ingested by the leukocyte; Engulfment, with subsequent formation of a phagocytic vacuole; and Killing of the microbe and degradation of the ingested material. General Pathology Termination of Acute Inflammatory Response Such a powerful system of host defense, with its inherent capacity to cause tissue injury, needs tight controls to minimize damage. In part, inflammation declines after the offending agents are removed simply because the mediators of inflammation are produced for only as long as the stimulus persists, have short half-lives, and are degraded after their release.  General Pathology MEDIATORS OF ACUTE INFLAMMATION Inflammatory mediators are the substances that initiate and regulate inflammatory reactions.  General Pathology MEDIATORS OF ACUTE INFLAMMATION The most important mediators of acute inflammation are vasoactive amines, lipid products (prostaglandins and leukotrienes), cytokines (including chemokines), and products of complement activation Vasoactive Amines: Histamine& Serotonin The two major vasoactive amines, so named because they have important actions on blood vessels, are histamine and serotonin. 1 HISTAMINE causes dilation of arterioles and increases the permeability of venules. considered to be the principal mediator of the immediate transient phase of increased vascular permeability Mast Cells are considered to be the richest source. 2 SEROTONIN (5-hydroxytryptamine) is a preformed vasoactive mediator present in platelets and certain neuroendocrine cells, such as in the gastrointestinal tract. Its primary function is as a neurotransmitter in the gastrointestinal tract and the central nervous system. It is also a vasoconstrictor,  Arachidonic Acid Metabolites: Prostaglandins & Leukotrienes The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid (AA) present in membrane phospholipids and stimulate vascular and cellular reactions in acute inflammation. 1 PROSTAGLANDINS (PG) produced by mast cells, macrophages, endothelial cells, and many other cell types, and are involved in the vascular and systemic reactions of inflammation. 2 LEUKOTRIENES produced in leukocytes and mast cells by the action of They are generated by the actions of two lipoxygenase and are involved in vascular and smooth cyclooxygenases, called COX-1 and muscle reactions and leukocyte recruitment. COX-2. COX-1 is constitutively expressed in most tissues,  ACTIONS OF THE PRINCIPAL MEDIATORS OF INFLAMMATION Vasoactive amines, mainly histamine:Vasodilation and increased vascular permeability. Arachidonic acid metabolites (prostaglandins and leukotrienes): Several forms exist and are involved in vascular reactions, leukocyte chemotaxis, and other reactions of inflammation; antagonized by lipoxins. Cytokines: Proteins produced by many cell types; usually act at short range; mediate multiple effects, mainly leukocyte recruitment and migration; principal ones in acute inflammation are TNF, IL-1, and chemokines.  ACTIONS OF THE PRINCIPAL MEDIATORS OF INFLAMMATION Complement proteins: Activation of the complement system by microbes or antibodies leads to the generation of multiple breakdown products, which are responsible for leukocyte chemotaxis, opsonization, phagocytosis of microbes and other particles, and cell killing. Kinins: Produced by proteolytic cleavage of precursors; mediate vascular reaction, pain.  General Pathology Morphologic Patterns of Acute Inflammation The morphologic hallmarks of acute inflammatory reactions are dilation of small blood vessels and accumulation of leukocytes and fluid in the extravascular tissue.  General Pathology Serous Inflammation is marked by the exudation of cell- poor fluid into spaces created by cell injury or into body cavities lined by the peritoneum, pleura, or pericardium. Typically, the fluid in serous inflammation does not contain microbes or large numbers of leukocytes. In body cavities the fluid may be derived from the plasma (as a result of increased vascular permeability) or from the secretions of mesothelial cells (as a result of local irritation); accumulation of fluid in these cavities is called an  Deposits of fibrin in the Pericardium Histologically, fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum Fibrinous With greater increase in vascular permeability, large molecules such as fibrinogen pass out of the blood, and fibrin is formed and deposited in the Inflammation extracellular space. A fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant stimulus (e.g., caused by cancer cells). Multiple bacterial abscesses (arrows) in the The abscess contains neutrophils and cellular debris and lung in a case of bronchopneumonia. is surrounded by congested blood vessels. Purulent inflammation is characterized by the production of pus, Purulent an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid. The most frequent cause of purulent (also called suppurative) inflammation is (Suppurative) infection with bacteria that cause liquefactive tissue necrosis, such as staphylococci; these pathogens are referred to as pyogenic (pus-producing) Inflammation bacteria. Abscesses are localized collections of pus caused by suppuration buried in a tissue, an organ, or a confined space. They are produced by seeding of  Ulcers A chronic duodenal ulcer a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue most common in (1) the mucosa of the mouth, stomach, intestines, or genitouri- nary tract, and (2) the skin and subcutaneous tissue of the lower extremities in individuals with disorders that predis- pose to vascular insufficiency, such as diabetes, sickle cell anemia, and peripheral vascular disease. Low-power cross-section view of a duodenal ulcer crater with an acute inflammatory exudate in the base.  Outcomes of Acute Inflamation acute inflammatory reactions typically have one of three outcomes 1 COMPLETE RESOLUTION In a perfect world, all inflammatory reactions, once they have succeeded in eliminating the offending agent, would end with restoration of the site of acute inflammation to normal. 3 CHRONIC INFLAMMATION Acute to chronic transition occurs when the acute 2 HEALING by connective tissue inflammatory response cannot be resolved, as a replacement (scarring, or fibrosis) result of either the persistence of the injurious occurs after substantial tissue destruction, when the inflammatory injury agent or some interference with the normal involves tissues that are incapable of regeneration, or when there is process of healing. abundant fibrin exudation in tissue or in serous cavities (pleura, peritoneum) that cannot be adequately cleared. General Pathology Thank You