Basics of inflamatory processes in surgical patients.pptx

Basics of inflamatory processes in surgical patients

1. Basics of Inflammation By Dr Ankit Singh (Jr2) General surgery Resident

2. Definition 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. . It consist in vascular, metabolic, cellular changes, triggered by the entering of pathogen agent in healthy tissues of the body. The process of inflammation delivers circulating 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. Without inflammation, infections would go unchecked, wounds would never heal, and injured tissues might remain permanent sores.

3. Etiology The causes of inflammation are many and varied: Exogenous causes: Physical agents Mechanic agents: fractures, foreign corps, sand, etc. Thermal agents: burns, freezing Chemical agents: toxic gases, acids, bases Biological agents: bacteria, viruses, parasites Endogenous causes: Circulation disorders: thrombosis, infarction, hemorrhage Enzymes activation – e.g. acute pancreatitis Metabolic products deposals – uric acid, urea

4. Cardinal Signs Celsus described the local reaction of injury in terms that have come to be known as the cardinal signs of inflammation. These signs are: rubor (redness) tumor (swelling) calor (heat) dolor (pain)

5. Inflammation The inflammatory reaction takes place at the microcirculation level and it is composed by the following changes: Tissue damage Cellular – vascular - cellular response Metabolic changes Tissue repair

6. Types

7. Acute Inflammation Acute inflammation has three major components: (1) dilation of small vessels leading to an increase in blood f low; (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

8. Changes in Vascular Flow and Caliber 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 is quickly followed by increased permeability of the microvasculature, with the outpouring of protein-rich f luid 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

9. The Vascular Response Phase I = vasoconstriction (momentary constriction of small blood vessels in the area). Vascular spasm begins very quickly (30 sec.) after the injury at it last a few minutes. The mechanism of spasm is nervous – through catecholamine liberated from sympathetic nerves endings. Phase II = active vasodilation (through catabolism products that act through receptors and directly stimulates vascular dilation – nervous mechanism). Dilation of arterioles and capillaries ( redness = rubor ); Blood flow increases and gives pulsate sensation; Active hyperemia in skin territory and increased metabolism leads to higher local temperature ( heat = calor ).

10. The Vascular Response Phase III = passive vasodilation Blood vessels in the affected area loose their reactivity to nervous and humoral stimuli and passive vasodilation occurs. Progressively fluid move into the tissues (increased vascular permeability and structural alteration of blood vessels) and cause swelling ( tumor ), pain, and impaired function. The exudation or movement of the fluid out of the capillaries and into the tissue spaces dilutes the offending agent. As fluid moves out of the capillaries, stagnation of flow and clotting of blood in the small capillaries occurs at the site of injury. This aids in localizing the spread of infectious microorganisms, if case.

11. 2. Increased Vascular Permeability (Vascular Leakage)

12. 3.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. These leukocytes perform the key function of eliminating the offending agents. 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

13. The journey of leukocytes from the vessel lumen to the tissue is a multistep process that is mediated and controlled by adhesion molecules and cytokines called chemokines. 1. In the lumen: margination, rolling, and adhesion to endothelium. Vascular endothelium in its normal state does not bind circulating cells or allow their passage. In inflammation the endothelium is activated and can bind leukocytes as a prelude to their exit from blood vessels. 2. Migration across the endothelium and vessel wall. 3. Migration in the tissues toward a chemotactic stimulus.

14. Various cytokines promote expression of selectins and integrin ligands on endothelium (e.g., TNF, IL-1), increase the avidity of integrins for their ligands (e.g., chemokines), and promote directional migration of leukocytes (also chemokines); many of these cytokines are produced by tissue macrophages and other cells responding to the pathogens or damaged tissues. • Neutrophils predominate in the early inflammatory infiltrate and are later replaced by monocytes and macrophages

15. Phagocytosis and Clearance of the 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 Phagocytosis involves sequential steps • Recognition and attachment of the particle to be ingested by the leukocyte; • Engulfment, with subsequent formation of a phagocytic vacuole; • Killing of the microbe and degradation of the ingested material.

16. Cellular Response The cellular response of acute inflammation is marked by movement of phagocytic white blood cells (leukocytes) into the area of injury. Two types of leukocytes participate in the acute inflammatory response - the granulocytes and monocytes. The sequence of events in the cellular response to inflammation includes: pavementing emigration chemotaxis phagocytosis

17. Pavementing The release of chemical mediators ( i.e., histamine, leukotrienes and kinins) and cytokines affects the endothelial cells of the capillaries and causes the leukocytes to increase their expression of adhesion molecules. As this occurs, the leukocytes slow their migration and begin to marginate , or move to and along the periphery of the blood vessels.

18. Emigration and chemotaxis Emigration is a mechanism by which the leukocytes extend pseudopodia, pass through the capillary walls by ameboid movement, and migrate into the tissue spaces. The emigration of leukocytes also may be accompanied by an escape of red blood cells. Once they have exited the capillary, the leukocytes move through the tissue guided by secreted cytokines, bacterial and cellular debris, and complement fragments (C3a, C5a). The process by which leukocytes migrate in response to a chemical signal is called chemotaxis .

19. Phagocytosis During the next and final stage of the cellular response, the neutrophils and macrophages engulf and degrade the bacteria and cellular debris in a process called phagocytosis. Phagocytosis involves three distinct steps: Adherence plus opsonization Engulfment Intracellular killing through enzymes, toxic oxygen and nitrogen products produced by oxygen-dependent metabolic pathways (nitric oxide, peroxyonitrites, hydrogen peroxide, and hypochlorous acid) If the antigen is coated with antibody or complement, its adherence is increased because of binding to complement. This process of enhanced binding of an antigen caused by antibody or complement is called opsonization .

20. Inflammatory Mediators TNF-a and IL-1 are responsible for fever and the release of stress hormones (norepinephrine, vasopressin, activation of the renin-angiotensin-aldosterone system). TNF-a and IL-1 are responsible for the synthesis of IL-6, IL-8, and interferon gamma. Cytokines, especially IL-6, stimulate the release of acute-phase reactants such as C-reactive protein (CRP). The proinflammatory interleukins either function directly on tissue or work via secondary mediators to activate the coagulation cascade, complement cascade, and the release of nitric oxide, platelet-activating factor, prostaglandins, and leukotrienes.

21. Complement fragments and cytokines It stimulates chemotaxis of neutrophils, eosinophils and monocytes; C3a, C5a increase vascular permeability; Cytokines Interleukins (IL1, IL 6, IL8) Stimulates the chemotaxis, degranulation of neutrophils and their phagocytic activity Induce extravascularization of granulocytes Fever Tumor necrosis factor (TNF) and IL 8 Leukocytosis Fever Stimulates prostaglandins production

22. Prostaglandins The prostaglandins are ubiquitous, lipid soluble molecules derived fro arachidonic acid, a fatty acid liberated from cell membrane phospholipids, through the cyclooxygenase pathway. Prostaglandins contribute to vasodilation, capillary permeability, and the pain and fever that accompany inflammation. The stable prostaglandins (PGE1 and PGE2) induce inflammation and potentiate the effects of histamine and other inflammatory mediators: They cause the dilation of precapillary arterioles (edema), lower the blood pressure, modulates receptors activity and affect the phagocytic activity of leukocytes. The prostaglandin thromboxane A2 promotes platelet aggregation and vasoconstriction.

23. Leukotrienes The leukotrienes are formed from arachidonic acid, but through the lipoxygenase pathway. Histamine and leukotrienes are complementary in action in that they have similar functions. Histamine is produced rapidly and transiently while the more potent leukotrienes are being synthesized. . The leukotrienes also have been reported to affect the permeability of the postcapillary venules, the adhesion properties of endothelial cells, and stimulates the chemotaxis and extravascularization of neutrophils, eosinophils, and monocytes.

24. Platelet-activating factor (PAF) It is generated from a lipid complex stored in cell membranes; It affects a variety of cell types and induces platelet aggregation; It activates neutrophils and is a potent eosinophil chemoattractant; It contributes to extravascularization of plasma proteins and so, to edema. Histamine It is found in high concentration in platelets, basophils, and mast cells. Causes dilation and increased permeability of capillaries (it causes dilatation of precapillary arterioles, contraction of endothelial cells and dilation of postcapillary venules). It acts through H1 receptors.

25. Plasma Proteases The plasma proteases consist of: Kinins Bradykinin - causes increased capillary permeability (implicated in hyperthermia and redness) and pain; Clotting factors The clotting system contributes to the vascular phase of inflammation, mainly through fibrin peptides that are formed during the final steps of the clotting process.

26. 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 . Serous Inflammation Serous inflammation is marked by the exudation of cellpoor fluid into spaces created by cell injury or into body cavities lined by the peritoneum, pleura, or pericardium.

27. Fibrinous Inflammation With greater increase in vascular permeability, large molecules such as fibrinogen pass out of the blood, and fibrin is formed and deposited in the extracellular space. A fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant stimulus Develops when the vascular leaks are large or there is a local procoagulant stimulus (e.g., caused by cancer cells). A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium and pleura

28. Purulent (Suppurative) Inflammation and Abscess Purulent inflammation is characterized by the production of pus, 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 infection with bacteria that cause liquefactive tissue necrosis, such as staphylococci; these pathogens are referred to as pyogenic (pus-producing) 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 pyogenic bacteria into a tissue. Abscesses have a central liquefied region composed of necrotic leukocytes and tissue cells.

29. CHRONIC INFLAMMATION Chronic inflammation is a response of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist in varying combinations It may follow acute inflammation, or chronic inflammation may begin insidiously, as a low-grade, smoldering response without any manifestations of a preceding acute reaction

30. Causes of Chronic Inflammation Chronic inflammation arises in the following settings . • Persistent infections by microorganisms that are difficult to eradicate, such as mycobacteria and certain viruses, fungi, and parasites. These organisms often evoke an immune reaction called delayed-type hypersensitivity (Chapter 6). Chronic inflammatory responses sometimes develop a specific pattern called a granulomatous reaction (discussed later). In other cases an unresolved acute inflammation may evolve into chronic inflammation, as may occur in acute bacterial infection of the lung that progresses to a chronic lung abscess. Acute and chronic inflammation may coexist, as in a peptic ulcer . •

31. Hypersensitivity diseases. Chronic inflammation plays an important role in a group of diseases that are caused by excessive and inappropriate activation of the immune system. Under certain conditions, immune reactions develop against the individual’s own tissues, leading autoimmune diseases Prolonged exposure to potentially toxic agents, either exogenous or endogenous. An example of an exogenous agent is particulate silica, a nondegradable inanimate material that, when inhaled for prolonged periods, results in an inflammatory lung disease called silicosis Atherosclerosis is a chronic inflammatory process of the arterial wall induced, at least in part, by excessive production and tissue deposition of endogenous cholesterol and other lipids

32. Morphologic Features Ch ronic inflammation is characterized by the following: • Infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells • Tissue destruction, induced by the persistent offending agent or by the inflammatory cells. • Attempts at healing by connective tissue replacement of damaged tissue, accomplished by angiogenesis (proliferation of small blood vessels) and, in particular, fibrosis

33. Cells and Mediators of Chronic Inflammation Role of Macrophages The dominant cells in most chronic inflammatory reactions are macrophages, which contribute to the reaction by secreting cytokines and growth factors that act on various cells, destroying foreign invaders and tissues, and activating other cells, notably T lymphocytes. Macrophages are professional phagocytes that eliminate microbes and damaged tissues. They also serve important roles in the repair of injured tissues. Here we review the development and functions of macrophages. The products of activated macrophages eliminate injurious agents such as microbes and initiate the process of repair, but are also responsible for much of the tissue injury in chronic inflammation

34. Role of Lymphocytes Microbes and other environmental antigens activate T and B lymphocytes, which amplify and propagate chronic inflammation. By virtue of their ability to secrete cytokines, CD4+ T lymphocytes promote inflammation and influence the nature of the inflammatory reaction Activated B lymphocytes and antibody-producing plasma cells are also often present at sites of chronic inflammation.

35. Granulomatous Inflammation Granulomatous inflammation is a form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with necrosis tissues. The activated macrophages may develop abundant cytoplasm and begin to resemble epithelial cells and are called epithelioid cells. Some activated macrophages may fuse, forming multinucleate giant cells.

36. Types of granulomas Foreign body granulomas are incited by inert foreign bodies, which induce inflammation in the absence of T cellmediated immune responses. Typically, foreign body granulomas form around materials such as talc (associated with intravenous drug abuses), sutures. Immune granulomas are caused by a variety of agents that are capable of inducing a persistent T cell–mediated immune response. This type of immune response usually produces granulomas when the inciting agent is difficult to eradicate, such as a persistent microbe.

37. Metabolic changes Protein metabolism Is increased – cell destruction, metabolic products lead o increased osmotic pressure in interstitial space which attracts water and contributes to edema (swelling = tumor); The metabolic changes, including skeletal muscle catabolism, provide amino acids that can be used in the immune response and for tissue repair; Glucose metabolism Anaerobe utilization of glucose is increased because of hypoxia with increased formation of lactic and pyruvic acid; Lipid metabolism Increased formation of ketons and fatty acids Mineral metabolism Increased extracellular K + concentration Acid – base balance Metabolic acidosis (ketons, lactic acid)