SBO: PATHOLOGY ~~ INFLAMMATION AND REPAIR INFLAMMATION *** 1.

ENUMERATE THE 4 CARDINAL SIGNS OF INFLAMMATION AND GIVE THE PATHOPHYSIOLOGIC MECHANISMS INVOLVED IN EACH (mnemonic: PRISH = Pain, Redness, Immobility- loss of fxn, Swelling, Heat) a. Dolor (Pain)- results in part from the distortion of tissues caused by edema, and it also is induced by certain chemical mediators of inflammation, such as bradykinin, serotonin, and the prostaglandins. b. Calor (Heat)- results from increased blood flow through the area and is experienced only in peripheral parts of the body such as the skin. c. Rubor (Redness)- caused by the dilation of small blood vessels in the area of injury. d. Tumor (Swelling)- caused primarily by the accumulation of fluid outside the blood vessels. e. Functio laesa (Loss of fxn)- may result from pain that inhibits mobility or from severe swelling that prevents movement in the area. 2. ENUMERATE THE 3 MAJOR COMPONENTS OF THE ACUTE INFLAMMATORY RESPONSE AND DESCRIBE THE IMPORTANT EVENTS IN EACH a. Alterations in vascular caliber that lead to an increase in blood flow Transient arteriolar VASOCONSTRICTION VASODILATION ( --> hyperemia --> increase hydrostatic pressure --> edema and wheal) Slowing of circulation (increased permeability of venules and capillaries causes escape of proteins extravascularly --> increased vascularity of blood) Margination of leukocytes (slowing circulation allows leukocytes to move towards endothelium, roll over the endothelium, and then migrate through). The process of the leukocytes moving through the endothelium is known as TRANSMIGRATION b. Structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation The complement system, when activated, results in the increased removal of pathogens via opsonisation and phagocytosis. The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects. The coagulation system or clotting cascade which forms a protective protein mesh over sites of injury. The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators. c. Emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent Leukocyte localisation and recruitment to the endothelium local to the site of inflammation involving margination and adhesion to the endothelial cells: Recruitment of leukocytes is receptor-mediated. Migration across the endothelium, known as transmigration, via the process of diapedesis: Chemokine gradients stimulate the adhered leukocytes to move between endothelial cells and pass the basement membrane into the tissues. Movement of leukocytes within the tissue via chemotaxis: Leukocytes reaching the tissue interstitium bind to extracellular matrixproteins via expressed integrins and CD44 to prevent their loss from the site. Chemoattractants cause the leukocytes to move along a chemotactic gradient towards the source of inflammation. 3. DEFINE CHRONIC INFLAMMATION AND GIVE THE CAUSES Chronic inflammation- is inflammation of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist, in varying combinations. Causes: Persistent infections Immune-mediated inflammatory diseases Prolonged exposure to potentially toxic agents, either exogenous or endogenous

a. DIFFERENTIATE BETWEEN ACUTE AND CHRONIC INFLAMMATION CLINICALLY AND PATHOLOGICALLY ACUTE CHRONIC Causative agent Pathogens, injured tissues Persistent acute inflammation due to non-degradable pathogens, persistent foreign bodies, or autoimmune reactions Major cells Neutrophils, mononuclear cells Mononuclear cells (monocytes, involved (monocytes, macrophages) macrophages, lymphocytes, plasma cells), fibroblasts Primary mediators Vasoactive amines, eicosanoids IFN- and other cytokines, growth factors, reactive oxygen species, hydrolytic enzymes Onset Immediate Delayed Duration Few days Up to many months, or years Outcomes Resolution, abscess formation, Tissue destruction, fibrosis, chronic inflammation necrosis

4. ENUMERATE THE DIFFERENT TYPES OF INFLAMMATORY EXUDATE AND GIVE THE

PROTOTYPE EXAMPLES OF EACH a. Purulent or suppurative exudat es- consists of plasma with both active and dead neutrophils, fibrinogen, and necrotic parenchymal cells. This kind of exudate is consistent with more severe infections, and is commonly referred to as pus.

b. Fibrinous exudates-

is composed mainly of fibrinogen and fibrin. It is characteristic of rheumatic carditis, but is seen in all severe injuries such as strep throat and bacterial pneumonia. Fibrinous inflammation is often difficult to resolve due to the fact that blood vessels grow into the exudate and fill the space that was occupied by fibrin. Often, large amounts of antibiotics are necessary for resolution.

c. Catarrhal exudates- is seen in

the nose and throat and is characterized by a high content of mucus.

d. Serous exudate

(sometimes classified as serous transudate)- is usually seen in mild inflammation, with little protein content. Its consistency resembles that of serum, and can usually be seen in certain disease states like tuberculosis. e. Malignant (or cancerous)pleural effusion is effusion where cancer cells are present. It is usually classified as exudate.

** 1. DEFINE INFLAMMATION Inflammation- (Latin, inflammare, to set on fire) is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process. 2. ENUMERATE THE MOST LIKELY MEDIATORS OF THE INFLAMMATORY EVENTS AND GIVE THE ROLE THAT EACH PLAY IN THE DIFFERENT INFLAMMATORY EVENTS MEDIATOR PRINCIPAL SOURCES ACTIONS CELL-DERIVED Histamine Mast cells, basophils, platelets Vasodilation, increased vascular permeability, endothelial activation Serotonin Platelets Vasodilation, increased vascular permeability Prostaglandins Mast cells, leukocytes Vasodilation, pain, fever Leukotrienes Mast cells, leukocytes Increased vascular permeability, chemotaxis, leukocyte adhesion and activation Platelet-activating factor Leukocytes, mast cells Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst Reactive oxygen species Leukocytes Killing of microbes, tissue damage Nitric oxide Endothelium, macrophages Vascular smooth muscle relaxation, killing of microbes Cytokines (TNF, IL-1) Macrophages, endothelial cells, Local endothelial activation mast cells (expression of adhesion molecules),

Chemokines Complement products (C5a, C3a, C4a) Kinins Proteases activated during coagulation

Leukocytes, activated macrophages PLASMA PROTEINDERIVED Plasma (produced in liver)

fever/pain/anorexia/hypotension, decreased vascular resistance (shock) Chemotaxis, leukocyte activation Leukocyte chemotaxis and activation, vasodilation (mast cell stimulation); Increased vascular permeability, smooth muscle contraction, vasodilation, pain; Endothelial activation, leukocyte recruitment

3. GIVE THE BASIC CELLULAR COMPONENTS OF THE INFLAMMATORY RESPONSE AND

IDENTIFY THE PRINCIPAL ROLE THAT EACH PLAY CELL TYPE FUNCTIONS MEDIATORS PMN Phagocytosis of infectious agents ROS, cationic peptides, eicosanoids, proteases (elastase, cathepsinG, PR-3, and uPA) M activation through phagocytosis Amplify inflammatory response TNF- , IL-1 , IL-6 Stimulate repair response VEGF, IL-8 M Phagocytosis of PMN and fragments of tissue degradation Amplify inflammatory response TNF- , IL-1 , and IL-6 Anti-inflammatory function IL-10, TGF- 1 Stimulate repair response: angiogenesis, PDGF, VEGF, bFGF, TGF- , and TGFfibroplasia Fibrolysis t-PA, uPA, u-PAR, and PAI-1/-2 MC Control vascular permeability Histamine Control influx of PMN Chymase, tryptase Regulate tissue remodeling T cell; Th1/Th2 T cells Regulate tissue remodeling CD40 ligand; IL-2, TNF- / IL-4, -5,-10

Keratinocyte proliferation, differentiation, FGF-7, FGF-10, and IGF-1, hyaluronan synthesis in Kc bFGF, basic fibroblast growth factor; M , monocyte/macrophage; MC, mast cell; PMN, polymorphonuclear leukocyte; ROS, reactive oxygen species; uPA, urokinase-type plasminogen activator 4. DESCRIBE THE ROLE OF THE LYMPH NODES, LYMPHATICS AND THE MONONUCLEAR PHAGOCYTE SYSTEM IN THE INFLAMMATORY RESPONSE Lymph nodes and lymphatics: Filters and polices the extravascular fluids. Lymphatics normally drain the small amount of extravascular fluid that has seeped out of capillaries. Lymph flow is increased and helps drain edema fluid that accumulates due to increased vascular permeability. Lymphatic vessels, like blood vessels, proliferate during inflammatory reactions to handle the increased load. Mononuclear phagocyte system: sometimes called reticuloendothelial system, consists of closely related cells of bone marrow origin, including blood monocytes and tissue macrophages. The products of activated macrophages 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. Activation of macrophages results in increased levels of lysosomal enzymes and reactive oxygen and nitrogen species, and production of cytokines, growth factors, and other mediators of inflammation.

In short-lived inflammation, if the irritant is eliminated, macrophages eventually disappear (either dying off or making their way into the lymphatics and lymph nodes). In chronic inflammation, macrophage accumulation persists, as a result of continuous recruitment from the circulation and local proliferation at the site of inflammation. 5. DEFINE GRANULOMATOUS INFLAMMATION Granulomatous Inflammation- a form of proliferative inflammation characterized by the formation of granulomas. a. GIVE THE CHARACTERISTIC HISTOLOGIC FEATURES Microscopic aggregation of macrophages that are transformed into epithelium-like cells, surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells. b. ENUMERATE AT LEAST 5 GRANULOMATOUS DISEASES DISEASE CAUSE TISSUE REACTION Tuberculosis Mycobacterium Caseating granuloma (tubercle): focus of activated tuberculosis macrophages (epithelioid cells), rimmed by fibroblasts, lymphocytes, histiocytes, occasional Langhans giant cells; central necrosis with amorphous granular debris; acid-fast bacilli Leprosy Mycobacterium leprae Acid-fast bacilli in macrophages; noncaseating granulomas Syphilis Treponema pallidum Gumma: microscopic to grossly visible lesion, enclosing wall of histiocytes; plasma cell infiltrate; central cells necrotic without loss of cellular outline Cat-scratch Gram-negative Rounded or stellate granuloma containing central granular disease bacillus debris and recognizable neutrophils; giant cells uncommon Sarcoidosis Unknown etiology Noncaseating granulomas with abundant activated macrophages Crohn disease Immune reaction Occasional noncaseating granulomas in the wall of the (inflammatory against intestinal intestine, with dense chronic inflammatory infiltrate bowel disease) bacteria, self-antigens

6. DESCRIBE THE CHANGES IN WHITE CELL POPULATION EVOKED BY THE DIFFERENT INFLAMMATORY CONDITIONS INCLUDING THE EXCEPTIONS TO THE RULES. WHAT IS LEUKEMOID REACTION? Leukemoid Reaction- describes an elevated white blood cell count, or leukocytosis, that is a physiologic response to stress or infection. The leukocyte count usually climbs to 15,000 or 20,000 cells/L, but sometimes it may reach extraordinarily high levels of 40,000 to 100,000 cells/L. Leukocytosis occurs initially because of accelerated release of cells from the bone marrow postmitotic reserve pool (caused by cytokines, including TNF and IL-1) and is therefore associated with a rise in the number of more immature neutrophils in the blood (shift to the left). Prolonged infection also induces proliferation of precursors in the bone marrow, caused by increased production of colony-stimulating factors. Most bacterial infections induce an increase in the blood neutrophil count, called neutrophilia. Viral infections, such as infectious mononucleosis, mumps, and German measles, cause an absolute increase in the number of lymphocytes (lymphocytosis). In bronchial asthma, allergy, and parasitic infestations, there is an increase in the absolute number of eosinophils, creating an eosinophilia. Certain infections (typhoid fever and infections caused by some viruses, rickettsiae, and certain protozoa) are associated with a decreased number of circulating white cells (leukopenia). REPAIR ** 1. IDENTIFY THE TWO DISTINCT PROCESSES INVOLVED IN REPAIR

Repair- when the healing takes place by proliferation of connective tissue elements resulting in fibrosis and scarring. Processes: Granulation tissue formation- hallmark of tissue repair 1. Phase of inflammation 2. Phase of clearance 3. Phase of in growth of granulation tissue Contraction of wounds- contraction helps to close the wound by decreasing the gap between its dermal edges and by reducing the wound surface area. Hence, it is an important feature in healing by secondary union. 2. GIVE THE TWO ESSENTIAL FEATURES OF GRANULATION TISSUE Pink, soft, granular appearance on the surface of wounds Histologic feature is the presence of new small blood vessels (angiogenesis) and the proliferation of fibroblasts 3. ENUMERATE THE MOST IMPORTANT DIFFERENCES BETWEEN THE TWO TYPES OF WOUND HEALING a. Healing by first intention aka. primary wound healing or primary closure Describes a wound closed by approximation of wound margins or by placement of a graft or flap, or wounds created and closed in the operating room. Best choice for clean, fresh wounds in well-vascularized areas Indications include recent (<24h old), clean wounds where viable tissue is tension-free and approximation and eversion of skin edges is achievable. Wound is treated with irrigation and dbribement and the tissue margins are approximated using simple methods or with sutures, grafts or flaps. Wound is treated within 24 h following injury, prior to development of granulation tissue. Final appearance of scar depends on: initial injury, amount of contamination and ischemia, as well as method and accuracy of wound closure, however they are often the fastest and most cosmetically pleasing method of healing. b. Healing by second intention aka. secondary wound healing or spontaneous healing Describes a wound left open and allowed to close by epithelialization and contraction. Commonly used in the management of contaminated or infected wounds. Wound is left open to heal without surgical intervention. Indicated in infected or severely contaminated wounds. Unlike primary wounds, approximation of wound margins occurs via reepithelialization and wound contraction by myofibroblasts. Presence of granulation tissue. Complications include late wound contracture and hypertrophic scarring c. Healing by third intention aka. tertiary wound healing or delayed primary closure Useful for managing wounds that are too heavily contaminated for primary closure but appear clean and well vascularized after 4-5 days of open observation. Over this time, the inflammatory process has reduced the bacterial concentration of the wound to allow safe closure. Subsequent repair of a wound initially left open or not previously treated. Indicated for infected or unhealthy wounds with high bacterial content, wounds with a long time lapse since injury, or wounds with a severe crush component with significant tissue devitalization. Often used for infected wounds where bacterial count contraindicates primary closure and the inflammatory process can be left to dbribe the wound. Wound edges are approximated within 3-4 days and tensile strength develops as with primary closure. d. Partial Thickness Wounds Wound is superficial, not penetrating the entire dermis. Type of healing seen with 1st degree burns and abrasions. Healing occurs mainly by epithelialization from remaining dermal elements.

Less contraction than secondary healing in full-thickness wounds Minimal collagen production and scar formation.

4. ENUMERATE THE DIFFERENT SYSTEMIC AND LOCAL FACTORS THAT MODIFY THE INFLAMMATORY REPARATIVE RESPONSE AND GIVE THE CLINICAL SETTINGS OR SITUATIONS THAT EXEMPLIFY EACH OF THE DIFFERENT FACTORS Systemic factors: Nutrition Eg: Protein starvation - impairs Vitamin C - defective collagen Zinc deficiency delays - administration restores Hematologic Derangements Eg: reduction in number of circulating neutrophils AS WELL AS defects in leukocyte chemotaxis AND pahgocytosis will yield more bacterial infection. (these infections slow the healing process) Diabetes Mellitus Eg: impaired vascularity diminished neutrophil chemotaxis decreased phagocytic activity Hormones Eg: adrenal steroids have a depressant effect on inflammatory and reparative reactions Local factors: Infection (retards growth) Vascularity (must be adequate for inflammation and repair) Foreign Bodies (ie sutures.. retard via irritation) Location of Injury (must contain stable and labile cells) 5. DIFFERENTIATE BETWEEN RESOLUTION AND ORGANIZATION AND GIVE THE CLINICAL SIGNIFICANCE OF EACH Resolution- subsiding of a pathologic state, such as the reduction of inflammation or the softening and disappearance of swelling. Organization- process in which fibrin coagulum is transformed into vascularized connective tissue by ingrowth of fibroblasts and capillaries katemendoza2014