Inflammation and its Role in Diseases - OCR - PDF

Inflammation and its Role in Diseases Unit II Inflammation Introduction Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as necrotic cells and tissues resulting from the original insult. It sets into motion the events that eventually heal and recon...

Inflammation and its Role in Diseases Unit II Inflammation Introduction Inflammation is a protective response intended to eliminate the initial cause of cell injury as well as necrotic cells and tissues resulting from the original insult. It sets into motion the events that eventually heal and reconstitute the sites of injury. Definition: Inflammation is a response of vascularized tissues to infections and damaged tissues that brings cells and molecules of host defense from the circulation to the sites where they are needed, in order to eliminate the offending agents. History Although clinical features of inflammation were described in an Egyptian papyrus dated around 3000 BC, Celsus, a Roman writer of the first century AD, first listed the four cardinal signs of inflammation: rubor (redness), tumor (swelling), calor (heat), and dolor (pain). These signs are hallmarks of acute inflammation. A fifth clinical sign, loss of function (functio laesa), was added by Rudolf Virchow in the 19th century. In 1793, the Scottish surgeon John Hunter noted what is now considered an obvious fact: inflammation is not a disease but a stereotypic response that has a salutary effect on its host. In the 1880s, Russian biologist Elie Metchnikoff discovered the process of phagocytosis by observing the ingestion of rose thorns by amebocytes of starfish larvae and of bacteria by mammalian leukocytes. He concluded that the purpose of inflammation was to bring phagocytic cells to the injured area to engulf invading bacteria. Sir Thomas Lewis, studying the inflammatory response in skin, established the concept that chemical substances, such as histamine (produced locally in response to injury), mediate the vascular changes of inflammation. This fundamental concept underlies the important discoveries of chemical mediators of inflammation and the use of antiinflammatory drugs in clinical medicine. Cause of Inflammation 1. Infective agents like bacteria, viruses and their toxins, fungi, parasites. 2. Immune reactions - autoimmune diseases, allergies. 3. Physical agents like heat, cold, radiation and mechanical trauma. 4. Chemical agents like organic and inorganic poisons. 5. Inert materials such as foreign bodies (splinters, sutures, dirt) 6. Excess deposition of some endogenous substances like urate crystals, cholesterol, lipids, etc. The inflammatory response has many players. These include : Circulating Cells Connective tissue cells ○ Neutrophils ○ Mast cells ○ Eosinophils ○ Macrophages ○ Basophils ○ Lymphocytes ○ Lymphocytes ○ Monocytes ○ Fibroblasts ○ Platelets Circulating Proteins Extracellular Matrix ○ Clotting factors ○ Fibrous structural proteins (e.g., ○ Kininogens collagen and elastin) ○ Complement components ○ Gel forming proteoglycans ○ Adhesive glycoprotein (e.g., Vascular wall cells fibronectin) ○ Endothelial cells ○ Smooth muscle cells Sequence of events in an inflammatory reaction The offending agent, which is located in extravascular tissues, is recognized by host cells and molecules. Leukocytes and plasma proteins are recruited from the circulation to the site where the offending agent is located. The leukocytes and proteins are activated and work together to destroy and eliminate the offending substance. The reaction is controlled and terminated. The damaged tissue is repaired. 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 the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent Vascular changes  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. The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities is known as exudation. Exudate vs. Transudate Changes in Vascular Flow and Caliber – begin early after injury and consist of the following: Vasodilation is induced by the action of several mediators, notably histamine, on vascular smooth muscle. It is one of the earliest manifestations of acute inflammation. 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 quickly followed by increased permeability of the microvasculature, with the outpouring of protein rich fluid into the extravascular tissues.  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, a condition termed stasis, which is seen as vascular congestion and localized redness 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. Increased Vascular Permeability (Vascular Leakage) 1. Contraction of endothelial cells resulting in increased interendothelial spaces is the most common mechanism of vascular leakage. It is elicited by histamine, bradykinin, leukotrienes, and other chemical mediators. An immediate transient response that occurs rapidly after exposure to the mediator and is usually short lived (15 to 30 minutes). 2. Endothelial injury, resulting in endothelial cell necrosis and detachment. Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or is induced by the actions of microbes and microbial toxins that target endothelial cells. 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. 3. Increased transport of fluids and proteins, called transcytosis, through the endothelial cell. This process may involve intracellular channels that may be stimulated by certain factors, such as vascular endothelial growth factor (VEGF), that promote vascular leakage. However, the contribution of this process to the vascular permeability of acute inflammation is uncertain. Responses of Lymphatic Vessels and Lymph Nodes Lymphatic vessels and lymph nodes are also involved in inflammation, and often show redness and swelling. The system of lymphatics and lymph nodes filters and polices the extravascular fluids. In inflammation, lymph flow is increased and helps drain edema fluid that accumulates because of increased vascular permeability. Leukocytes and cell debris, as well as microbes, may find their way into lymph. Lymphatic vessels proliferate during inflammatory reactions to handle the increased load. The lymphatics may become secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis). Inflamed lymph nodes are often enlarged because of hyperplasia of the lymphoid follicles and increased numbers of lymphocytes and macrophages. This constellation of pathologic changes is termed reactive, or inflammatory, lymphadenitis