Pathology chapter 02
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- Define Acute inflammation
- A rapid response to an injurious agent that serves to deliver mediators of host defense-leukocytes and plasma proteins-to the site of injury.
- Define Chronic inflammation
- Inflammation of prolonged duration in which active inflammation, tissue injury, and healing proceed simultaneously.
- List the cardinal signs of acute inflammation
- Heat, redness, swelling, pain, loss of function
- List the major etiological factors in inflammation
- Infections (bacterial, viral, parasitic) and microbial toxins, trauma (blunt and penetrating), physical and chemical agents (thermal injury, irradiation, environmental chemicals), tissue necrosis (from any cause), foreign bodies (splinters, dirt, sutures), and immune (hypersensitivity) reactions.
- Describe the two major components of the inflammatory response
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1. Vascular changes-increased vascular caliber and, therefore, increased blood flow to the site of injury as well as increased vascular permeability.
2. Leukocyte emigration (from blood vessels), accumulation (at site of injury) and activation. - List the sequential events transpiring during acute inflammation
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1. Alterations in vascular caliber leading to increased blood flow (heat and redness)
2. Structural changes in the vasculature permitting leakage and leading to edema. The increased permeability is caused, in part, by IL-1, TNF, and IFN-gamma
3. Leukocyte emigration to the site leading to edema and pain. The steps in leukocyte migration are: rolling along the endothelium (due to E-selectin), stable adhesion to the endothelium (interaction b/t LFA-1 and ICAM-1), transmigration across the endothelium (diapedesis), and migration within the tissue towards the chemotactic stimulus. After arrival, leukocytes can phagocytose foreign material. The inflammation stops, in part, because the mediators have short half-lives. - Describe the major consequences of vasodilation as an inflammatory response
- Increased flow to the area of injury causes increases in hydrostatic pressure. Increased vascular permeability causes exudation of protein-rich fluid and decreases plasma osmotic pressure. Statis then occurs, and white cells accumulate along the endothelium (margination)
- List the major mediators of the vascular response to inflammation
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1. Vasoactive amines (Histamine and serotonin)
2.Complement system
3. Kinin system (bradykinin)
4. Clotting system
5. Arachidonic acid metabolites: Prostaglandins, Leukotrienes and Lipoxins
6.Platelet activating factor
7. Cytokines and Chemokines
8. Nitrix oxide
9. Neuropeptides (substance P) - Origin and chief function of Vasoactive amines
- Originate in cells (histamine-mast cells, serotonin-platelets) and cause vasodilatation of arterioles, increased venular permeability and contraction of smooth muscles.
- Origin and chief functions of nitric oxide
- Produced by epithelial cells as well as macrophages (both constitutively and induced) that acts as a potent vasodilator due to relaxation of smooth muscle; also has important microbicidal activity.
- Origins and chief functions of the complement system
- Present as inactive plasma forms; activated to become proteases. Functions include MAC-induced cell lysis and changes in vascular permeability, chemotaxis, and opsonization. C3a and C5a stimulate histamine release. C5a is a powerful chemoattractant.
- Origin and chief functions of the kinin system
- Plasma protein kininogens are cleaved to form bradykinin, which causes blood vessel dilation, increased vascular permeability and pain
- Origins and chief functions of the intrinsic pathway clotting system
- Activation of thrombin and cleavage of fibrinogen generates a fibrin clot. Thrombin has inflammatory properties
- Origins and chief functions of the extrinsic pathway
- Factor XIIa can produce plasmin, which degrades fibrin, solubilizing the clot. Plasmin contributes to inflammation
- Origin and chief functions of lysosomal granule contents
- Produced by neutrophils and macrophages, reactive oxygen intermediate and products of arachidonic acid metabolism (prostaglandins and leukotrienes), serve the purpose of causing endothelial injury and tissue damage, thus amplifying the effects of the initial injurious agent (therefore, it must be held in check).
- What are the three main arachidonic acid metabolites
- Prostaglandins, Leukotrienes, and Lipoxins
- Arachidonic acid metabolites are synthesized by what two major enzyme classes
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Cyclooxygenases, which generate prosaglandins and thromboxanes
Lipoxygenases, which produced leukotrienes and lipoxins - Which Eicosanoids cause vasoconstriction
- Thromboxane A2, leukotriens C4,D4,E4
- Which eicosanoid metabolites cause vasodilation
- PGI2,PGE1,PGE2,PGD2
- Which Eicosanoids cause increased vascular permeability
- Leukotrienes C4,D4,E4
- Which eicosanoids cause chemotaxis and leukocyte adhesion
- Leukotrienes B4,HETE,lipoxins
- What are prostaglandins involved with
- Pain and fever in inflammation
- What do lipoxins do
- Their principle actions are to inhibit leukocyte recruitment and the cellular components of inflammation
- What is the origin and chief function of Oxygen-derived free radicals
- Released from leukocytes after exposure to microbes, chemokines and immune complexes. Low levels can lead to increase the expression of chemokines, cytokines, and endothelial leukocyte adhesion molecules, amplifying the inflammatory response cascade. They also serve to destroy phagocytosed microbes. At higher levels can cause endothelial cell damage and inactivate proteases.permeability); Inactivation of antiproteases; Injury to multiple cell types
- What is the origin and chief function of platelet activating factor
- From platelets, basophils (and mast cells), neutrophils, monocytes/macrophages, and endothelial cells. PAF stimulates platelets and causes vasoconstriction and bronchoconstriction. At extremely low concentrations it induces vasodilation and increased venular permeability. Also caused increased leukocyte adhesion to endothelium and chemotaxis.
- What roles do neuropeptides (substance P) play in inflammation
- From nerve fibers (lung and GI tract), serve to transmit pain signals, regulate blood pressure, stimulate section by endocrine cells, and increase vascular permeability.
- What is the origin and chief function of Cytokines and Chemokines
- Produced by activated lymphocytes and macrophages (and endothelium, epithelium, and CT cells). TNF and IL-1 (activated macros) cause endothelial activation, as well as leukocyte and fibroblast activation and also induce systemic acute-phase reactions (fever, loss of appetite, hypotension, decreased vascular resistance, and increased heart rate). Chemokines act primarily as chemoattractants for specific types of leukocytes.
- What are three systemic effects of inflammation
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1. Fever, produced by response to pyrogens
2. Acute-phase protein synthesis increases 100 fold (eg C reactive protein)
3. Leukocytosis increases - List the cellular events which comprise the acut inflammatory response (and major mediators)
- Rolling of leukocytes on endothelium (E-Selectin) (aided by presence of IL-1, TNF and chemokines released from macros and mast cells in response to injury); leukocyte adhesion (LFA-1:ICAM-1); Diapedesis (CD31/PECAM); leukocyte recruitment to sites of injury/chemotaxis (components of the complement system-C5a, leukotriene B4, and cytokines/chemokines); leukocyte activation (Toll Like Receptors, G-coupled receptors, receptors for cytokines, and receptors for opsonins).
- List three major steps in phagocytosis
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1. Recongnition and attachment, facilitated by mannose receptors and scavenger receptors
2. Engulfment
3. Killing and degradation (ROS mainly) - Role of platelets in inflammation
- the adherence, aggregation, and degranulation of platelets is critical in acute inflammation, coagulation, and wound healing.
- Role of lymphocytes in inflammation
- associated with both acute and chronic inflammation. In chronic inflammation T cells produce cytokines that are important (like IFN-gamma in activating macros), while B cells develop into plasma cells that produce antibody directed against the antigen or altered tissue components.
- Role of giant cells in inflammation
- found in granulomatous inflammation when activated macrophages develop an epitheliod appearance, sometimes fusing to form giant cells which help to encompass the foreign body (or infection).
- Role of Mast cells/Basophils in inflammation
- both acute and chronic inflammation. In acute, they degranulate to release histamine products that help to mend injury, however, in chronic inflammation may produce cytokines that contribute to fibrosis.
- Role of plasma cells in inflammation
- develop from B cells and produce antibody directed against the antigen or altered tissue components.
- Role of fibroblasts in inflammation
- in acute inflammation can contribute to fibrinous inflammation. Fibrinogen passes through the vascular barrier and fibrin is deposited in the extracellular space, this may stimulate the ingrowth of fibroblasts and blood vessels and thus lead to scarring.
- Role of Neutrophils in inflammation
- Mainly in acute inflammation. Help to phagocytose foreign material
- Role of eosinophils in inflammation
- chronic infection; contain major basic protein which is toxic to parasites, but also causes lysis of mammalian epithelial cells. Therefore, they help control parasitic infections, but also contribute to tissue damage in immune reactions.
- Role of cell adhesion molecules in inflammation
- important in acute inflammation. E and P-selectin help with leukocyte rolling and adhesion to the endothelium. There are also integrins (LFA-1 and VCAM-1) which are important for adhesion of leukocytes to the endothelium.
- Role of endothelial cells in inflammation
- acute inflammation. Impt. b/c the development of endothelial gaps in venules allows vascular leakage which helps to advance the inflammatory response (ie-leukocytes can pass into the tissue).
- Role of monocytes/macrophages/histiocytes in inflammation
- acute and chronic inflammation. Their products serve to eliminate injurious agents such as microbes and to initiate the process of repair, and are responsible for much of the tissue injury in chronic inflammation.
- List the cytokines involved in acute, chronic, and granulomatous inflammation.
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Acute-TNF, IL-1, IL-6.
Chronic-IFN-gamma, TNF, IL-1.
Granulomatous-IL-2, IFN-gamma. - List the cells which give rise to tissue-derived mediators
- Mast cells, basophils, platelets, neutrophils (PMNs), macrophages, monocytes, endothelial cells, and nerve fibers
- Name at least five major mediator categories
- Some categories include: amines, plasma factors, eicosinoids (lipid mediators), platelet activating factor, neuropeptides, cytokines, and nitric oxide.
- Define exudate
- an inflammatory extravascular fluid that has a high protein concentration, cellular debris, and a specific gravity above 1.020
- Define edema
- an excess of fluid in the interstitial or serous cavities; may be either an exudate or transudate
- Define exudation
- Extravasation of fluid. proteins, and blood cells from vessels into the interstitial tissue or body cavitities
- Define pus
- A purulent inflammatory exudate rich in neutrophils and cell debris
- Define Transudate
- An extravascular fluid with low protein content and specific gravity below 1.012; essentially and ultrafiltrate of blood plasma resulting from elevated fluid pressure or diminished osmotic forces in the plasma
- List the major characteristics important to the recognition and function of Neutrophils
- Predominate in the inflammatory infiltrate during the first 6-24 hours because they are more numerous in the blood, respond more rapidly to chemokines, and may attach more firmly to the adhesion molecules that are rapidly induced on endothelial cells (such as E and P-selectins). Also, they are short-lived, so they can accomplish their role in phagocytosis and undergo apoptosis after 24-48 hrs.
- List the major characteristics important to the recognition and function of Eosinophils
- Abundant in parastic infections and immune reactions mediated by IgE. Have granules that contain major basic protein-toxic to parasites but also causes lysis of mammalian epithelial cells.
- List the major characteristics important to the recognition and function of Basophils
- Contain large, blue granules with histamine, the release of which causes vasodilation, increased venule permeability and contraction of smooth muscles. Like mast cells, but are circulating.
- List the major characteristics important to the recognition and function of Lymphocytes
- T cells provide cellular immunity (regulatory and effector cells). Also, produce IFN-gamma which activates macrophages. B cells develop into plasma cells which produce antibody directed either against persistent antigen in the inflammatory site or against altered tissue components.
- List the major characteristics important to the recognition and function of plasm cells
- Produce antibody directed either against persistent antigen in the inflammatory site or against altered tissue components.
- List the major characteristics important to the recognition and function of Monocytes/Macrophages
- Primitive scavenger cells which engulf and digest foreign particles, proteins, etc. Macrophages themselves make monokines such as IL-1 and TNF that can modify the inflammatory and immune responses. Are considered sentinel cells. Macrophages can develop into epithelioid cells and their fusion can lead to giant cells (which helps to wall off foreign material).
- List the major characteristics important to the recognition and function of Mast cells
- Contain large blue granules with histamine, the release of which causes vasodilation, increased venule permeability and contraction of smooth muscles. Like basophils, but are in the tissue. Considered sentinel cells.
- List the major characteristics important to the recognition and function of fibroblasts
- Presence of fibrin in the tissue (as a result of fibrinous exudates) can stimulate their growth and lead to scarring.
- List three possible defects of leukocyte function.
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Defects in leukocyte adhesion. An example is LAD 1, which is characterized by recurrent bacterial infections and impaired wound healing (LAD 2 is a milder form of 1).
Defects in phagolysosome function. An example is Chediak-Higashi syndrome characterized by neuropenia (decreased number of neutrophils), defective degranulation, and delayed microbial killing. Reduced transfer of lysosomal enzymes to the phagocytic vacuoles in phagocytes (causing susceptibility to infections) and abnormalities in melanocytes (leading to albinism), cells of the nervous system (associated with nerve defects), and platelets (generating bleeding disorders).
Defects in microbicidal activity. An example is chronic granulomatous disease which renders patients susceptible to recurrent bacterial infection. Results from inherited defects in the genes encoding several components of NADPH oxidase.
Clinically, the most frequent cause of leukocyte defect is bone marrow suppression, leading to reduced production of leukocytes. - Describe the steps involved in the isolation and destruction of an infectious agent by polymorphonuclear leukocytes (neutrophils).
- Through chemotaxis, the neutrophils are attracted to the site of injury. Upon arrival, they recognize and attach to the cause of insult through via mannose and scavenger receptors. Phagocytosis is enhanced when microbes are opsonized by specific proteins for which neutrophils express high-affinity receptors. The next step is the engulfment of particles which leads to the creation of a phagosome; this fuses with the lysosome leaving a phagolysosome. Through the use of ROI’s, lysozymes, defensins or other enzymes (ie-elastase) the microbes are destroyed
- What are the potential patterns of acute infection
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Serous, marked by outpouring of fluid that can lead to separation of cells and tissue layers;
Fibrinous, occurs when fibrinous exudates lead to the ingrowth of fibroblasts leading to scarring;
Suppurative, presence of large amounts of purulent exudates consisting of neutrophils, necrotic cells, and edema fluid;
Ulcers, produced by the sloughing of inflammatory or necrotic tissue - What cells are involved in acute inflammation
- PMNs, mast cells, platelets, macrophages, endothelial cells
- What are the potential outcomes of acute inflammation
- Complete resolution, healing by connective tissue replacement (fibrosis), or progression to chronic inflammation
- What are the systemic effects of acute inflammation
- Increased pulse and bp, decreased sweating (due to redirection of blood flow to minimize heat loss through the skin), shivering, chills, anorexia, somnolence, and malaise. The excessive release of cytokines can lead to liver injury, heart failure and loss of perfusion pressure, resulting in hemodynamic shock.
- What causes chronic inflammation
- Persistent infections, prolonged exposure to potentially toxic agents (either exogenous or endogenous), or through autoimmunity.
- How is chronic inflammation characterized
- By the processes of active inflammation, tissue destruction, and attempts at repair proceeding concurrently. Macrophages bind and activate T-lymphocytes which then release IFN-gamma which, in turn, activates macrophages.
- What three things are seen histologically in chronic inflammation
- Infiltration with mononuclear cells, tissue destruction, and attempts at healing by connective tissue replacement of damaged tissue.
- What cells are involved in chronic inflammation
- Lymphocytes, plasma cells, macrophages, and activated fibroblasts
- What are the possible outcomes of chronic inflammation
- Resolution, scar formation, and death. The systemic effects are similar to those in acute infection.
- What is granulomatous infection
- Can be diffuse or local and is a distinctive pattern of chronic inflammatory reaction characterized by focal accumulations of activated macrophages, which often develop an epithelioid appearance. A great example is tuberculosis. The macrophages accumulate around the infection and sometimes fuse to form giant cells which, along with epithelioid cells, serve to encompass and wall-off the foreign material. The cells involved are macrophages and the outcome is a granuloma, within the center of which the foreign material can often be identified.