Inflammation MED301 Pathology PDF

INFLAMMATION MED301 Pathology Wk 2 111024 Overview A response of vascularised tissues delivering leucocytes and molecules of host defense from circulation to sites of infection and cell damage. Purpose: Elimination of offending agents Protective response essential for survival M...

INFLAMMATION MED301 Pathology Wk 2 111024 Overview A response of vascularised tissues delivering leucocytes and molecules of host defense from circulation to sites of infection and cell damage. Purpose: Elimination of offending agents Protective response essential for survival Mediators: phagocytic leucocytes, Ab, complement proteins. Overview Resident cells- immediate response Circulating cells- recruited when needed Inflammation- delivery of circulating cells and proteins to tissues and activation of resident and recruited cells and soluble molecules. Suffix – “itis” denotes inflammation Series of sequential steps Sequence of events/steps in inflammation Recognition of noxious agent, the initiating stimulus Recruitment of leukocytes and plasma proteins into tissues Removal of stimulus Regulation of the response Repair Sequence of events in inflammatory reaction Fundamental properties of inflammatory response Components- Blood vessels and leukocytes Harmful consequences- Protection against infections accompany local tissue damage (sign and symptoms of pain and functional impairment). Typically self-limited , resolves as inflammation abates with little or no permanent damage. BUT many diseases where inflammatory reaction is misdirected, or inadequately controlled. Local and systemic – Mainly local reactions but may have systemic effects causing widespread pathologies. (sepsis, systemic inflammatory response syndrome) Fundamental properties of inflammatory response Mediators - vascular and cellular reactions triggered by soluble factors produced by various cells or derived from plasma proteins- activated or generated in response to inflammatory stimulus. Mediators initiate and amplify the response and determine its pattern, severity and clinical and pathological manifestations. Acute and Chronic – difference NOT just duration but several. Features of Acute and Chronic Inflammation Causes of Inflammation Infections (bacterial, fungal, viral, parasitic) Tissue necrosis (due to ischemia, trauma, physical or chemical injury etc) Foreign bodies (splinters, dirt, sutures) Immune reactions (hypersensitivity)- autoimmune reactions to self Ag or environmental Ag that can not be eliminated- autoimmune or allergic reactions- associated with chronic inflammation induced largely by cytokines produced by T lymphocytes and other cells of immune system. Recognition of Microbes and Damaged Cells Initiating step in inflammatory reactions. Cellular receptors and circulating proteins recognize the noxious agent and trigger inflammation. Cellular receptors for microbes – receptors in plasma membrane (extracellular microbes), endosomes (for ingested microbes), cytosol (intracellular microbes)- thus cells “sense” invaders. Best defined- family of Toll-like receptors (TLRs) Engagement of receptors triggers production of inflammation-inducing molecules e.g. adhesion molecules on EC, cytokines and other mediators. Recognition of Microbes and Damaged Cells Sensors of cell damage- cytosolic receptors e.g. NOD- like receptors (NLRs), recognizing diverse molecules liberated or altered as a result of cell damage. E.g. uric acid (DNA breakdown product), ATP (damaged mitochondria), reduced intracellular K+ concentrations (loss of ions due to plasma membrane injury) as well as DNA. Receptors activate a multiprotein cytosolic complex, the inflammasome, which induced production of cytokine IL- 1, recruits leukocytes, inducing inflammation. Recognition of Microbes and Damaged Cells Other cellular receptors- Many leukocytes express receptors for Fc tails of Ab and for complement proteins. Receptors recognize microbes coated with Ab and complement. Coating (opsonization) promote ingestion of microbes and activation of complement system. Other proteins, “Collectins” also bind to and combat microbes. ACUTE INFLAMMATION 3 major components: 1. Dilation of small vessels – increase in blood flow 2. Increased permeability of microvasculature- plasma proteins and leukocytes leave the circulation 3. Emigration of leukocytes from microcirculation, accumulation in focus of injury, their activation to eliminate offending agent. Vascular Reaction Changes in blood flow and permeability- to maximize movement of proteins and leukocytes out of circulation into site of infection or injury. This movement is “Exudation” Exudate- high protein with cellular debris, shows increased permeability Transudate- low protein content, no cellular material, low specific gravity, no increase in vascular permeability Oedema- excess fluid in interstitial tissue or serous cavities- can be exudate or transudate. Pus- purulent exudate (neutrophil rich), debris of dead cells, microbes. Vascular Reaction Changes in vascular flow and caliber involve vasodilation- induced by mainly histamine action on vascular smooth muscle. Result: increased blood flow (heat and redness) Quickly followed by increased permeability Loss of fluid , increased vessel diameter- slower blood flow, RBCs concentrate, thus increased viscosity. Slowly moving RBCs- stasis- vascular congestion and localized redness. EC activated by mediators, express increased levels of adhesion molecules; leukocytes adhere to endothelium, migrate through vascular wall into interstitial tissue. Vascular leakage Contraction of EC- elicited by histamine, bradykinin, leukotrienes and other chemical mediators- immediate transient response (15-30 min) In some cases, delayed prolonged leakage (after 2-12 hours, lasting for several hours or even days) due to contraction of EC or mild EC damage. Endothelial injury – EC necrosis and detachment results. Neutrophils adhering may also injure EC amplifying the reaction. Most cases- Leakage start immediately, sustained for several hours until damaged vessel thrombosed or repaired. Principal mechanisms of increased vascular permeability Responses of Lymphatic Vessels and Lymph Nodes Lymphatic vessels also participate in acute inflammation. Lymphatics and lymph nodes filters and polices extravascular fluids. Lymph flow increased in inflammation, lymphatics help drain oedema fluid accumulating because of increased permeability. Also, leukocytes and cell debris and microbes may get into lymph. Lymphatic vessels proliferate to cope with increased load. May become secondarily inflamed (lymphangitis), as well as draining lymph nodes (lymphadenitis). Responses of Lymphatic Vessels and Lymph Nodes Inflamed lymph nodes enlarged due to hyperplasia of lymphoid follicles and increased nos. of lymphocytes and macrophages. This is reactive or inflammatory lymphadenitis. Red streaks near skin wound diagnostic of lymphangitis, may be accompanied by painful enlargement of draining lymph nodes- indicate lymphadenitis. Cellular Response- Leukocyte recruitment