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• Cell Injury and Repair
• Inflammation
• Repair, Regneration, and Fibrosis
• Immunopathology

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NORMAL -vs- ABNORMAL CELLS:

• Residual Bodies lysosomal waste vacuoles that are not excreted.
• Lipofuscin lysosomal waste material having a brown appearance.

AMYLOID: Heterogenous collection of fibrillar protein. Amyloid can be differentiated from hyaline by its Congo Red stain. Amyloid will stain red with Congo Red and Hyaline won't.

APOPTOSIS: Programmed cell death that occurs normally in development. As opposed to Necrosis.

ATROPHY: Decrease in cell size and/or number.

• OSTEOPOROSIS = Atrophy of the bone matrix.

CALCIFICATION: Deposition of calcium salts in tissue

• Dystrophic Calcification: Abnormally necrotic tissue. Occurs in previously damaged tissue, with normal Ca⁺² levels.
• Metastatic Calcification: Calcification from hyperparathyroidism ------> hypercalcemia; or from renal failure.

NECROSIS: Irreversible cell death. Necrosis has occurred if the cell membrane and nucleus are destroyed.

• Types of Necrosis:
• Caseous Necrosis: Necrosis that looks like cheese. Found in tuberculosis and some fungal diseases.
• It forms in response to intracellular pathogens such as Mycobacteria. It often is found in association with granulomas.
• Coagulation Necrosis: Sudden cut off of blood supply to an organ, particularly heart or kidney. It leads to pyknosis, karyolysis, and karyorrhexis.
• In kidney, you end up with a wedge-shaped contracted scar.
• Liquefaction Necrosis: Transformation of solid tissue into fluid.
• Sign of Necrosis:
• KARYOLYSIS: Irreversible cell death characterized by lysing of nucleus, due to action of DNAase and RNASE.
• KARYORRHEXIS: Irreversible cell death characterized by fragmentation of the nucleus.
• PYKNOSIS: Irreversible cell death characterized by condensation of the nucleus and clumping of chromatin.

DEATH: Cessation of normal body functions. Legally, brain-death, or loss of higher cortical function.

DYSPLASIA: Abnormal differentiation or maturation of tissue.

GANGRENE: Massive widespread ischemia.

• WET GANGRENE
• DRY GANGRENE: Mummification of tissue.

HEMOSIDERIN: Iron-containing pigment derived from hemoglobin.

• Hemochromatosis, Hemosiderosis: Accumulation of brown hemosiderin in liver.
• Primary Hemochromatosis: Innate metabolic defect.
• Secondary Hemochromatosis: Hemochromatosis secondary to Spherocytosis, Sickle Cell Anemia, or immune reaction to blood transfusion.
• Hemosiderin is a by product of hemolysis of blood.
• Hemosiderin is normally present, in small amounts, in some tissues.
• Prussian Blue Reaction: Hemosiderin will show up by the Prussian Blue Reaction, indicating the presence of iron inside granules.

HYALINE: MALLORY'S HYALINE: Keratin-like intracellular intermediate filaments that accumulate in liver with alcoholism. Eosinophilic.

HYDROPIC SWELLING: Reversible cell injury characterized by an influx of water and sodium chloride, and vacuolation of cytoplasm.

HYPERPLASIA: Enlargement of an organ due to increase in number of cells.

• Thyroid
• Prostate (Benign Prostatic Hyperplasia)
• Skin Warts, from Human Papilloma Virus (HPV)
• Childhood (not adult) obesity may play a role in hyperplasia.

HYPERTROPHY: Increase in size of an organ due to increased cell-size.

• Left Ventricular Hypertrophy from hypertension.
• Right Ventricular Hypertrophy originates from Left Ventricular Hypertrophy ------> Pulmonary Hypertension (Cor Pulmonale) ------> Right Ventricular Hypertrophy.

LIPOFUSCIN: Indigestible lysosomal waste-products, which accumulate in old-age. Pigment-like and rich in lipid.

LYSOSOMAL STORAGE DISEASES: Failure or incomplete digestion in lysosomes.

• VON GIERKE'S DISEASE: Glycogenosis.
• POMPE'S DISEASE: Abnormal accumulation of Glycogen in lysosomes due to acid maltase deficiency.

METAPLASIA: Change from one cell type to another.

• Lung Metaplasia: Simple Columnar ------> Squamous. Pre-cancerous.
• Barrett Esophagus: Stratified Squamous ------> Intestinal
• Myocites: Muscle ------> Bone. Ossification.

PIGMENT: Any substance that has its own color. May be endogenous or exogenous.

• Bilirubin: Brown-red; heme-byproduct
• Hemosiderin: Brown' heme-byproduct
• Lipofuscin: Brown waste-product. Brown pigment in liver can by lipofuscin or hemosiderin.
• Biliverdin: Green; oxidized bilirubin.
• Prussian Blue Test: Test for the presence of heme. Brown pigment will turn to blue with this test if heme is present.

PROGERIA: Disease characterized by early onset of aging. Has a genetic origin.

WERNER'S SYNDROME: Another aging disease, where a 25-yo man looks 80. Tight puckered skin.

• Shows symptoms that are all related to aging: cataracts, deafness, diverticulitis, hypertension, osteoarthritis.

VACUOLAR DEGENERATION: Dilation of organelles ------> accept fluid inside RER, maybe in mitochondria. Accumulation of lipid and glycogen.

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ABSCESS: Walled off, circumscribed cavity, filled with pus (Neutrophils).

Cardinal Signs of Inflammation:

• Rubor: Redness, from hyperemia (increased blood flow) and vasodilation.
• Dolor: Pain, from (1) swelling ------> stretch sensory receptors, and (2) inflammatory mediators (bradykinins)
• Calor: Heat, but only if the inflammation is in extremities, because it comes from increased blood flow to the periphery.
• Tumor: Swelling, from (1) inflammatory edema, and (2) Triple Response of Lewis
• Functio Laesa: Loss of function, from reflexional disuse due to main, and mechanical / structural necrosis and/or healing.

ACUTE PHASE RESPONSE:

• ACUTE PHASE (HEAT-SHOCK) PROTEINS: Proteins produced early in inflammation, usually by hepatocytes.
• Interleukin-6 (IL-6): This cytokine will incite the production of these proteins.
• Types of Responses:
• Fever
• Increased tendency to sleep
• Release of neutrophils into circulation from storage
• Increased ACTH and
• Vascular changes ------> hypotension and shock

CORTICOSTEROIDS: Cortisol. Antiinflammatory properties = inhibit Cyclooxygenase-2 and blocks phospholipases in target-cell membrane.

MARGINATION: Leukocytes moving from the center of a vessel toward the periphery, in order to effect the process of recruitment.

ADHESION MOLECULES: Molecules responsible for margination and diapadesis of granulocytes into the extracellular matrix at the site of injury. They are expressed by inducible genes during the amplification phase of inflammation.

• ICAM-1: Up regulated on endothelial cell surfaces, in response to cytokine mediators. Therefore important in the process of recruiting lymphocytes to inflammatory site.
• INTEGRINS: Vital to genesis of the cellular phase of the inflammatory response. It is instrumental to cell-cell and cell-matrix interactions among migrating cells.
• In particular, they increase adherence of leucocytes to endothelial-cell lining during migration.
• SELECTINS: Lectin-like molecules that are important in the very initial reaction between leukocytes and endothelia -- in the process of margination.

DIAPEDESIS: Transmigration of leucocytes from the vasculature into the extracellular space. Involves adherence to endothelium, extension of psuedopodia between endothelial cells, and migration between endothelial cells.

NITRIC OXIDE (EDRF, Endothelium-Derived Relaxin Factor):

• It is Inducible NO-Synthase -- not Constitutive -- that is responsible for inflammatory vasodilation. Macrophages and Neutrophils will create lots of NO under the stimulation of the inducidle form of the NOS gene.

OPSONISATION: Coating a bacterium or particle in order to facilitate its phagocytosis.

• C3b is an opsonin derived from the complement system.
• Immunoglobulins opsonise many bacteria, making them more easily phagocytosed, as Neutrophils have receptors for the F_c (common) region of the Ig molecule. This extra binding region facilitates higher affinity binding for the bacterium or foreign particle.

EDEMA:

• Non-Inflammatory Edema: Swelling by excessive hydrostatic pressure (hypertension) or loss of oncotic pressure (hypoalbuminemia, gloerulonephritis, kwarshiorkor ------> ascites + peripheral edema).
• Primarily serous TRANSUDATE (specific gravity < 1.015)
• NEPHROTIC SYNDROME: Loss of albumin ------> proteinuria ------> hypoalbuminemia ------> non-inflammatory edema.
• INFLAMMATORY EDEMA: Swelling, as an inflammatory response, resulting from cytokine-mediated increased vascular permeability, and anaphylaxis.
• A dense EXUDATE of some sort can be recovered from the fluid. Specific gravity > 1.015
• Fibrinous: Containing fibrin, of a finbrinous quality.
• Purulent: Containing pus, i.e. neutrophils.
• Suppurative: Containing large numbers of neutrophils, in conjunction with liquefactive necrosis.
• Sangiunous: Containing erythrocytes
• Serous: Of a watery quality, and containing few or no cells.
• POST-CAPILLARY VENULE: These vessels are the primary targets for increased vascular permeability, via cytokines, by constricting endothelial cells.

Process of Inflammation:

• INITIATION: Ubiquitous proinflammatory enzymes are in the blood.
• Platelets produce inflammatory mediators
• Thromboxane-A₂ (TXA₂): Cleaves Prothrombin ------> Thrombin to induce clot formation.
• Plasma Proteins: Complement proenzymes, kininogen.
• First vasoconstriction occurs, then vasodilation occurs later.
• AMPLIFICATION: What happens after initiation of the inflammatory response. Characterized by:

• General properties:
• Local activation of precursors
• Autocatalytic feedback loops: Kallikrein has positive feedback on the proteolytic activation of more Factor XII.
• Expression of inducible genes for production of Cyclooxygenase-2
• Upregulate expression of CAM molecules on the surface of tissue for recruitment of leucocytes to the area
• FAILSAFE MECHANISMS: Two things are required for inducible genes to be induced. This helps to assure that the inflammatory mediators are not released until the cells have reachd the site of injury.
• Adhesion molecules must be present, an indication that the cells are out of the blood stream and have reached tissue-injury site.
• Serum is require for some of the proenzyme. Serum is only present once a clot has already occured.
• TERMINATION
• INHIBITORY MEDIATORS: IL-10 and TGF-beta have inhibitory properties.
• IL-4 and IL-5 also have antiinflammatory properties.
• Glucocorticoids in circulation are anti-inflammatory. They act by inhibiting the expression of inducible genes.

Different Forms of Inflammation: This is really a continuum.

	ACUTE	CHRONIC
Vascular Changes	Vasodilation Increased permeability	Minimal
Cellular Infiltrates	Primarily neutrophils	Mononuclear leukocytes, macrophages
Stromal Changes	Minimal Edema and separation of layers	Fibrosis, cellular proliferation, scarring.

• Acute: Common to find purulence (Neutrophils)
• Subacute or Chronic-Active: Intermediate between acute and chronic.
• Chronic: Find a lot of mononuclear leukocytes (macrophages), and associated with Granulomas.
• DISTRIBUTION
• Focal: Centered around a single source, such as a localized pathogen, local injury, or foreign body.
• Multifocal: Cetered around multiple single sources.
• SECONDARY SYPHILLUS presents with multifocal dermatitis.
• Diffuse:

COMPLEMENT:

• Classical Pathway: Requires antibodies to activate.
• Will produce anaphylatoxins C3a, C4a, C5a.
• C4a is only produced by the classical pathway.
• Leads to formation of the MEMBRANE ATTACK COMPLEX: C5b,6,7,8,9 form a lipid-soluble macroprotein that permeabalizes the bacterial membrane ------> rapid bacterial cell lysis.
• Alternative Pathway: Does not require antibody to activate.
• Will produce anaphylatoxins C3a, C5a.
• Endotoxin triggers the alternative pathway but not the classical pathway. Endotoxin is released by gram-neg bacteria.
• Anaphylatoxin:
• Examples of compounds:
• C3a:
• C4a:
• C5a: Very important inflammatory mediator. The most important iniator of acute inflammatory response.
• Anaphylactic Properties: Vasodilation and increased permeability.
• Chemotactic Properties: Attract PMN's to the site of infection.
• Effects:
• Inducement of smooth muscle contraction.
• Increased vascular permeability.
• Degranulation of mast cells and basophils (IgE mediated)
• C3b: An Opsonin that binds to bacteria, making them easier targets for phagocytosis by macrophages and neutrophils.

HISTAMINE:Vasoactive amine that increases vascular permeability. There are two histamine receptors.

• H1-Receptor: More important in the induction of increased vascular permeability, by inducing contraction of post-capillary venule endothelial cells.
• H2-Receptor: Found in stomach, and promotes secretion of acid in stomach.

EICOSANOIDS: Derivatives of Arachidonic Acid

• PROSTANOIDS: These metabolites are products of Cyclooxygenase.
• PROSTAGLANDINS: Have a wide variety of pro-inflammatory effects. PGH₂ is the main one.
• THROMBOXANES: TXA₂ is produced in quantity by platelets, and is vasoconstrictive and causes platelet aggregation. TXA₂ is derived from cyclooxygenase.
• SERUM: Once you form an initial clot, that releases additional inflammatory medikators that further accelerate the process; sort of a positive feedback effect.
• EFFECTS: Causes the formation of clots, and is a potent vasoconstrictor.
• CYCLOOXYGENASE (PGH-SYNTHASE): Enzyme creates the prostanoids. It has two isoforms:
• PGHS-1: Constitutive PGH-Synthase is critical for low-level production of prostaglandins to maintain homeostasis, such as maintaining gastric lining.
• PGHS-2: Inducible PGH-Synthase: Found in high concentration in leucocytes, allowing them to produce large amounts of prostanoids at the site of infection, once initiation has occured.
• ASPIRIN irreversibly inhibits Cyclooxygenase-2 (PGH-2), this inhibiting production of prostaglandins (anti-inflammatory), and thromboxanes (anti-inflammatory, blood thinning).
• Indomethacin is another drug with similar properties -- inhibit cyclooxygenase.
• PROSTACYCLIN, PGI₂: It is a powerful vasodilator; it antagonizes, inhibits, and opposes the effects of TXA₂. An overbalance of TXA₂ will result in platelet aggregation and inflammation.
• It aids in the dissolution of clots by opposing the action of TXA₂.
• HETE's: Some of them are chemotactic for neutrophils and eosinophils.
• LUEKOTRIENES: Formed by Lipoxygenases, and having a wide range of pro-inflammatory properties.
• Leukotrienes, LTB4, LTC4, LTD4, LTE4 are slow-reacting substances of anaphylaxis.
• LTB4 is also a potent chemotactic factor for neutrophils.
• These are important in Type-1 Hypersensitivity reactions.

CYTOKINES: Local factors having a variety of function, and released by Lymphocytes (Lymphokines), and Granulocytes (Interleukins).

• Colony Stimulating Factors (CSF's): Have a growth effect on leucocytes. Releasesd by macrophages and lymphocytes.
• NETWORK: Cytokines have overlapping, redundant effects, and generally a deficiency of one does not ruin the entire system.
• INTERFERONS:
• alpha,beta-INTERFERON (Type 1): Best known for antiviral properties. The alpha-beta receptor is ubiquitous on all cell types.
• gamma-INTERFERON (Type 2): Has a separate receptor, integral to the inflammatory response.
• Promotes formation of giant cells in granulomatous infection.
• Interferon-gamma and ENDOTOXIN synergize to make huge amounts of Inducible NO-Synthase ------> systemic anaphylaxis.

HORMONES:

• AUTOCOIDS: Hormones that act on the same cell from they are secreted. An example is PGE2.
• SEROTONIN: Vasoactive amine, with vasodilatory effects, released by several cells, particular platelets.

LYMPHOCYTES: Are found prevelant in chronic inflammatory states.

• B-CELLS: They bear immunoglobulins on their surface.
• PLASMA CELLS: Mature B-Cells, with clockface nucleus, that secrete IgG antibodies. Their presence is associated with chronic infection.
• T-CELLS:
• Lymphocytosis: Increase in total number of lymphocytes.
• Lymphopenic: Deficient in lymphocytes; lymphopenia.

MONONUCLEAR LEUKOCYTE: Macrophages and Monocytes.

• Macrophages have a wide variety of effects:
• Antigen presentation to T_H cells.
• Sacvenging and degradation of dead tissue and effete cells.
• Activation of host defense against enemies.
• Precursors to epithelioid and giant cells in granulomatous inflammation.
• Monokine: A cytokine produced by a monocyte.

OXYGEN-INDEPENDENT DEFENSES: Released by both PMN's and mononuclear leucocytes.

• Bactericidal Permeability Increasing Protein (BPI): Cationic protein. It strongly increases the permeability of bacterial cell walls.
• It is contained in the primary granules of Neutrophils.
• Major Basic Protein: Found in the lysosomes of Eosinophils.
• Defensins: Found in the primary granules of Neutrophils. Defensins can kill fungi and viruses as well as bacteria.
• Lactoferrin: Chelate iron, to starve aerobic bacteria. Found in secondary granules in neutrophils.

GRANULOCYTES:

• BASOPHIL: Least common of the granulocytes. Horseshoe nucleus.
• Similar in structure and function to Mast Cells, but having a different cell lineage.
• Have lots of IgE-Receptors and thus partake in allergic response.
• Release lots of vasoactive mediators: histamine, PAF, Leukotrienes
• NEUTROPHIL:
• Morphology / Life-Cycle:
• Tripartite nucleus. Also known as Polymorphonuclear Leucocyte (PMN), because of the morphology of its nucleus.
• Neutrophils are fully mature when released into circulation, but can be further stimulated by cytokines and growth factors at sites of inflammation.
• Termed a professional phagocyte, for havingt extraordinary phagocytic properties.
• LEFT SHIFT: Test; an increase in the number of immature neutrophils in circulation, indicating that the bone marrow is having trouble meeting the demand for neutrophils.
• Degenerative Left Shift: A decrease in the absolute number of neutrophils; bad news.
• Leukemoid Reaction: Change in the leukogram, which can immitate leukemia without actually being it.
• Neutropenia: Deficiency of neutrophils.
• Neutrophilia: An absolute increase in the number of neutrophils.
• EOSINOPHIL:
• Also sometimes known as a PMN, because of the morphology of its nucleus.
• Particularly present in (1) allergice reactions, and (2) parasitic infections.
• Eosinophil Catioinic Protein: Unique basic protein that is toxic to certain parasites.
• Eosinophilia: The condition of having an excess number of eosinophils in the blood.

KALLIKREIN-KININ SYSTEM: Activation system in acute inflammation leading to production of bradykinin.

• Bradykinin:
• Potent vasodilator.
• Pain producing stimulus.
• Potent smooth muscle contraction.
• Kallikrein: Has potential to cleave C5 ------> C5a, which is a potent chemotaxic agent.
• Hageman Factor (Factor XII):
• It causes the conversion of Pre-Kallikrein to Kallikrein. (formation of bradykinin)
• It causes the conversion of Plasminogen to Plasmin. (clot lysis)

CHEDIAK-HIGASHI SYNDROME: Inability to form phagolysosomes, due to inability for lysosomes to fuse with phagosomes inside phagocytic cells.

• Deficiency of Cathepsin-G in lysosomes.

CHEMOTACTIC FACTORS: Factors that induce chemotaxis. Chemotaxis is the process of a leucocyte sensing a minute difference in concentration gradient between the front and back of cell, and thereby directing its movement toward the source of the gradient.

• SOURCES:
• N-Formyl Peptides in bacteria are chemotactic for neutrophils.
• C5a is chemotactic for neutrophils.
• Eosinophil Chemotactic Factor (ECF) is chemotactic for eosinophils and is commonly found in anaphylactic allergic reactions.
• TGF-beta is chemotactic for fibroblasts and macrophages, and promotes collagen synthesis.
• Leukotriene-B4 (LTB4) is chemotactic.
• PRIMING occurs as the leukocytes follow the chemotactic gradient. They are metabolically getting ready for the site of infection.
• EFFECTS of CHEMOTACTIC AGENTS:
• They increase the number and affinity of Fc receptors on neutrophils, and move them to the front of the cell, in order to promote Ab-dependent opsonisation.
• They mobilize granules to the front of the cell.
• Enhanced motitlity
• Enhanced oxidative metabolism (priming)
• Exression of inducible genes
• Increased phagocytosis mediators
• Indirect profinflammatory mediators.
• RECRUITMENT: During this process we develop turbulent blood flow and have hemoconcentration as cells migrate to the area.

GRANULOMATOUS INFLAMMATION: Chronic inflammation, occuring after the acute-phase response.

• EPITHELIOID CELL: Derived from macrophages, uniquely found in chronic granulomatous inflammation. All granulomas have epithelioid cells.
• GIANT CELL: Commonly found in granulomas, but not required. They are derived from the fusion (syncitium) of several macrophages.
• Interferon-gamma and Interleukin-4 (IL-4): Both of these cytokines promote the formation of giant cells from macrophages. These cytokines are produced at the site of the lesion.
• FOREIGN BODY GIANT CELL: Giant cell containing foreign particles, often visible.
• LANGHANS GIANT CELL: Giant cell having characteristic horseshoe configuration of its multiple nuclei.
• Two-types of Granulomas:
• FOREIGN-BODY GRANULOMA: Granulomas formed in response to indigestable materials.
• ALLERGIC (IMMUNE) GRANULOMA: Formed in Type-IV Delayed hypersensitivity reactions.
• CHRONIC GRANULOMATOUS DISEASE: Deficiency of NADPH-Oxidase ------> leucocyte cannot create superoxide anion and thus cannot kill bacteria. Bacteria are phagocytosed but not killed.
• Failure to kill these bacteria leads to chronic, and finally, granulomatous inflammation.
• SARCOIDOSIS: Chronic granulomatous disease, of unknown cause, characterized by non-caseating granulomas, i.e. granulomas without a center of caseous necrosis.
• GRANULOMA STRUCTURE:
• CENTER: Caseous Necrosis center, in the case of a Casseating Granuloma, as in Tuberculosis.
• INNER LAYER: Epithelioid Cells + Multinucleated Giant Cells -- specialized macrophages.
• MIDDLE LATER: Lymphocytes are found next, in immune granulomas.
• OUTER LAYER: Predominantly fibroblasts.

GRANULATION TISSUE: Tissue that is in the process of healing, and having nothing to do with an inflammatory granuloma or granulomatous infection.

HAGEMAN / FIBRINOLYTIC SYSTEM: Activating system for amplifying the inflammatory response. Hageman Factor (XII) creates fibrin from fibrinogen, which yields plasmin to break down fibrin to fibrin-split products, which have inflammatory properties and are diagnostic of inflammatory infections.

• Elevated Fibrinogen levels indicate that an infection is present.
• You can also measure that Erythrocyte Sediminentation Rate (ESR) as a non-specific indicatory of infection.

PLATELETS: The most ubiquitous source of proinflammatory mediators.

• In particuilar, they are a source of Vasoconstrictive, clot-forming Thromboxane A₂ (TxA₂).

PLATELET ACTIVATING FACTOR (PAF): Lipid, not stored in granules; extremely vasoactive inflammatory intermediate.

• It is mobilized from the cell membrane of many different cells, and produced by the action of Phospholipase A₂.
• EFFECTS:
• Activates platelets to synthesize TXA₂ (hence the name!)
• Causes strong vascular smooth muscle contraction and increased permeability via inducing synthesis of Inducible NO-Synthase in vascular endothelium.
• Strongly chemotactic.
• Causes luekocyte aggregation, adhesion, and priming -- i.e. it stimulates them to synthesize oxygenated intermediates.
• PAF is 100x to 1000x more potent than Histamine in its vasoactivity.

CONSOLIDATION: Especially in lung, conversion of an inflamed tissue into a dense and firm tissue.

• Gray Hepatization: Late consolidation of the lung, developing firmness. The inflammatory process has continued long enough for hyperemia to subside, leaving primarily leukocytes.
• Red Hepatization: Early consolidation, characterized by firmness and redness from hyperemia. Inflammatory process is in acute phase.

OXYGEN-DEPENDENT BACTERIOCIDE: Reactions involving oxidative radicals and requiring oxidative metabolism.

• Antioxidants inhibit the formation of oxidative radicals, or aid in breaking them down.

• Glutathione Peroxidase
• Vitamin-E
• Superoxide Dismutase
• Catalase

FRUSTRATED PHAGOCYTOSIS: Occurs when leukocytes cannot completely engulf a cell because the cell is too large. So, instead they exocytose their digestive enzymes to the surrounding tissue, resulting in autoinflammatory tissue injury.

PRURITUS: Itching; non-inflammatory. Note spelling.

PYROGEN: Fever-forming. Endogenous pyrogens include:

• Interleukin 1 (IL-1)
• Tumor Necrosis Factor, TNF-alpha

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CELL TYPES and Regenerative Ability:

• LABILE CELLS: Cells with a short lifespan that constantly proliferate: skin, gut, hematopoetic cells.
• PERMANENT CELLS: Cells that cannot regenerate once they are destroyed. A destroyed cell will form a scar. Brain, Heart.
• STABLE CELLS: Cells that are in G₀ of the cell-cycle and don't normally divide, but can be induced to divide quickly upon injury. These cells have good regenerative capacity. Liver, Renal proximal convoluted tubule.
• ACUTE TUBULAR NECROSIS occurs with O₂-deprivation in O2-hungry renal tubules. As long as the basement membrane is intact, the tubule cells will regenerate.
• Oliguric Phase: Little urine output during necrosis -- kidney shuts down.
• Polyuric Phase: Lots of output during healing process. Kidney functions but the proximal tubules are busy regenerating, thus reabsorption is very low.

Surgical Wounds:

• PRIMARY INTENTION: Letting a surgical wound heal without a big scar, where the wound has neatly apposed edges.
• SECONDARY INTENTION: Letting a surgical wound heal and leave a big scar, called granulating in from the bottom up, with edges that are not neatly apposed.
• This is necessary in appendectomies and abdominal surgeries in general, in order to assure that the wound doesn't later burst open.

PYELONEPHRITIS: Pus in the collecting tubules. You get a urine cast of PMN's resembling the shape of the tubules.

• If you only partially treat it, you can get chronic pyelonephritis as a result.

EXTRACELLULAR MATRIX: The materials over which cells migrate and travel during development and wound-healing. It contains five primary parts

• COLLAGEN: There are four types of Collagen we need to know. Collagen is synthesized and secreted by fibroblasts.
• TYPE I COLLAGEN: Skin,, bone, and tendon.
• TYPE II COLLAGEN: Cartilege.
• TYPE III COLLAGEN: Aorta, uterus, and GI smooth muscle. Reticular collagen.
• TYPE IV COLLAGEN: Basement membranes, exclusively.
• Scleroderma is proliferation of collagen.
• BASEMENT MEMBRANE: Made of Type IV Collagen.
• Synthesized by basal cells of epithelia.
• FNXN: Filtration in the kidney. Basement membrane contains heparin sulfate, which is negatively charged, to guide filtration and keep out big negatively charged proteins like albumin.
• FIBRONECTIN: It has several specific binding sites, and generally functions as a guide, to allow cells to migrate through the matrix.
• Binding sites:
• Collagen binding site
• Fibrinogen binding site
• Proteoglycan binding sites
• Binding sites for various bacteria.
• Wound Healing: Fibronectin plays an important cross-linking function.
• ELASTIC FIBERS: Pliable structures like arteries and uterus.
• Similar to collagen (containing Pro and Lys), but contains almost no hydroxyylated structures.
• Marfan Syndrome is a defect in elastic fibers.
• PROTEOGLYCANS:

INTEGRINS: Transmembrane proteins that interact with the ECM. They may act as a communication link between intracellular environment and extracellular matrix. Via integrins, the ECM can modify cell behavior.

CYTOKINES:

• MDGF, MACROPHAGE-DERIVED GROWTH FACTOR:
• PDGF, PLATELET-DERIVED GROWTH FACTOR: Secreted by platelets, induces proliferation of fibroblasts, microglia, and smooth muscle.
• May also serve as a chemotactic agent for inflammatory cells.
• EGF, EPIDERMAL GROWTH FACTOR: Induces proliferation of epithelia; essential for wound-healing.
• Most cells have EGF-receptors. A kinase is activated as secondary messenger once EGF binds.
• EGF also has pre-cancerous properties, if the EGF-receptor pathway is unregulated.
• FGF, FIBROBLAST GROWTH FACTOR: Promotes the growth of fibroblasts, endothelial cells, and smooth muscle.
• It is also probably present in the process of angiogenesis.
• TGF, TRANSFORMING GROWTH FACTOR beta:

ANGIOGENESIS: Formation of new vasculature following injury. Occurs during formation of granulation tissue. FGF is a cytokine that is thought to induce angiogenesis.

• Bartonollosis and Bacillary Angiomatosis are two infectious processes that involve angio-genesis.
• Angiogenesis also occurs during some cancerous processes.

GRANULATION TISSUE: The initial response to a wound, early part of scar formation. Proliferation of fibroblasts and blood vessels. It may or may not include inflammatory cells.

• CALLUS: A type of granulation tissue that consists of bone or cartilege.
• KELOID: Hypertrophic or exhuberant scar, often occuring in black people. If you excise a keloid, it will grow back.
• Normal scarn mature from Type-III (early) to Type-I (mature) collagen. Keloids remain as immature Type-III collagen.
• CICATRIX: Scar. Lots of fibroblasts, some with nucleoli (metabolically active). A little hemosiderin pigment is present.

HEALING: A response to tissue injury, and attempt to maintain homeostasis.

• CONTRACTURE: Exhuberant, overactive contractile stage of wound-healing. This can result in a deformed scar.

• Dupuytren's Contracture is idiopathic contracture of the palmar aponeurosis.

• DEHISCENCE: The bursting of a wound. Failure of tensile strength of scar.
• Abdominal wounds are the most subject to dehiscence, thus surgeons let abdominal wounds heal by secondary intent.
• Abdominal dehiscence can be provoked by coughing, vomiting, wound infection, or poor nutrition during the healing period.
• THREE STAGES to wound healing:
• INITIAL RESPONSE: Initial cellular response to injury
• Neutrophils: They are the first line of defense. They are chemotactically attracted to injury site by tissue factors. They arrive within hours.
• Macrophages engulf the neutrophil debris, within days.
• Fibroblasts finally arrive to begin the process of repair.
• CONTRACTION: Bring the wound edges closer together.
• Myofibroblasts: Looks like fibroblast but has contractile elements. Works in contraction of wound.
• REPAIR: Secrete extracellular matrix (fibroblasts) and lay down a scar.
• Proteoglycans are the first substances to be laid down, followed by formation of collagen.
• REGENERATION: Regenerate epithelial tissues.
• It occurs in liver and skin, as long as basement membranes are still intact. If basement membranes are gone, then a scar (in the case of skin) or micronodules (in the case of liver) will form instead.
• Factor that influence wound-healing:
• Overall Nutrition: Proteins deficiencies and vitamin deficiencies (esp. Scurvy since Vit-C is required for collagen formation)
• Obesity ------> poor vascularity ------> poor wound healing.
• Age
• Race: Blacks at higher risk of forming keloids.
• Complication in wound healing:
• Dehiscence, or ulceration of the scar.
• Infection, malnutrition, and hypoxia (poor vascularity) all increase the risk of dehiscence.

CIRRHOSIS: Result of a chronically damaged liver. Histologically it a combination of regenerated liver cells interspersed with fibrosis.

• MICRONODULAR CIRRHOSIS: Alcoholic Cirrhosis. Alcohol killsliver cells globally and destroys basement membranes. With BM's destroyed, when the liver tries to regenerate, it has no scaffolding on which to grow, and the result is formation of a bunch of micronodules, instead of uniform liver tissue.
• Fibrosis runs from Portal Triad to Protal Triad, and works its way inward.
• HEPATOMA: Hepatocellular Carcinoma. Liver tumor occurs more prevelantly in cirrhotic livers. Why?
• Because the hepatocytes are constantly proliferating, thus increasing likelihood of malignancy.
• Concurrent infection with Hepatitis-B or C in alcoholism is extremely common.
• MACRNODULAR CIRRHOSIS: Chronic Active Hepatitis. Nodules form similar to micronodular cirrhosis, except that injury spreads outward from focal points in the liver -- i.e. from points of viral infection. The response to this focal injury is formation of nodules which appear as macronodules.
• FATTY LIVER: Reversible damage due to alcohol.
• Alcoholic hyaline is visible with fatty liver.

CARDIAC DISEASE:

• CARDIAC TAMPONADE: Blood in the pericardial sac, which can happen after an MI, at the time of maximal healing during formation of a scar in the myocardial muscle. Rare and instantly fatal.
• Can happen about six days post-MI, during the late phase of healing when Macrophages are cleaning up debris.
• The ventricular septum can also burst, leading to hypoxia and shock
• Reperfusion Injury by oxidative radicals is a risk after 4 hours post-MI.

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HYPERSENSITIVITY:

• TYPE-I: IMMEDIATE. Mediated by IgE molecules binding to Fc-receptors on Mast Cells and Basophils.
• Examples:
• Hay Fever, allergic rhinitis, penicillin anaphylaxis.
• SENSITIZATION: Initial formation of the IgE. Prior exposure to the allergen is required for an allergic reaction to happen later.
• ANAPHYLAXIS: Anaphylaxis can occur by two separate processes -- either Mast Cell degranulation or complement-derived Anaphylatoxins. The result is the same but the mechanisms are different.
• MAST-CELL DEGRANULATION occurs in an allergic response in results in release of the following:
• Histamine has several effects:
• Intense bronchial smooth muscle contraction
• Increased vascular permeability
• Increased secretion by nasal, bronchial, and gastric glands.
• Proteases, Heparin
• Eosinophil and Neutrophil Chemotactic Factors (ECF, NCF): Eosinophilia is a common sign of a Type-I allergic reaction.
• Membrane Derived Metabolites: PGD2, LTB4, PAF are also released in Mast Cell activation, although they weren't in granules. Prostaglandins and Leukotrienes are derived from Arachidonic acid, and PAF is not. All of them cause bronchospasm and increased vascular permeability.
• TYPE-II: ANTIBODY-DEPENDENT CYTOTOXIC. A reaction of soluble IgG, IgM antibody with membrane-bound antigen (usually autoantigen)
• COMPLEMENT: IgG and IgM and activate Complement via Fc receptors on endothelial cells. Complement is then activated via Classical (antibody-dependent) pathway. Complement effects:
• Cell Lysis through MAC. This accounts for hemolysis in certain kinds of hemolytic anemias.
• OPSONIZATION via C3b which acts as an opsonin: phagocytic cells express C3b-receptors and can thus bind to targets. This also occurs in certain autoimmune hemolytic anemias.
• Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): Natural Killer Cells, as well as macrophages and some PMN's have Fc-receptors and can thus attack IgG-coated target cells and lyse them. This process occurs without phagocytosis.
• This may play a role in Hasimoto's Thyroiditis.
• TYPE-III: IMMUNE-COMPLEX. Accumulation of immune-complexes, formed by soluble antibody and soluble antigen.
• SERUM SICKNESS: Horse or bovine serum can be injected into human's as an antidote to bee venom or snak bites. The foreign serum will then induce formation of immune-complexes, which elicit symptoms 6 to 8 days later.
• SYMPTOMS: Fever, arthralgia, vasculitis, acute glomerulonephritis.
• ARTHUS REACTION: Experimental vasculitis, in which a localized injury is produced by immune complexes. Immune-complexes accumulate on vessel walls which activated complement ------> vascular enodthelial lesions.
• Fibrin will accumulate in vessel-walls which will result in a fibrinoid necrosis in the area. Fibrinoid Necrosis of vascular walls is common in all Type-III diseases.
• PPD TB SKIN TEST is also an example of a delayed hypersensitivity reaction.
• TYPE-IV: DELAYED. Antibody-independent, cell-mediated response of T_C cells against antigen. Reaction is generally 24 to 72 hours after allergen exposure.
• T-CELL Mediation: T-Cells recognize the antigen directly and release lymphokines in response to it.
• Immature CD4 cells mature and proliferate in response to antigen presented by macrophages or B-Cells. Mature T_H1 cells then release cytokines:
• IL-2 stimulates growth of more T_H cells in an autocrine fashion.
• IFN-gamma powerfully activates Macrophages, which can then further go onto activate fibroblasts via TGF-beta.
• Cytotoxic Cells recognize antigens directly, and proliferate in response to it.
• Natural Killer (NK) cells can also proliferate in Type-IV responses. They have Fc receptors and respond primarily to membrane glycoproteins, virus-infected cells, or tumor cells.
• Type-IV (Cell-Mediated) defense is very important in battling against intracellular parasites such as mycobacteria (tuberculosis), and it often results in the formation of granulomas, as the activated Macrophages form Epithelioid cells.

THEORIES OF AUTOIMMUNITY: Autoimmune diseases have multiple etiologies.

• Sequestered Antigens: Freeing of sequestered antigens. Examples = anterior chamber of eye (lens), testis.
• Abnormal T-Cell Function; lack of supressor T-Cells. This theory has the most evidence supporting it.
• Polyclonal B-Cell Activation
• Biological Mimicry, as in Rheumatic Heart Diseases, in which antibodies against streptococcal antigens cross-react with myocardium.

HYPERSENSITIVITY / AUTOIMMUNE DISEASES: Most auto-immune diseases, for unknown reasons, occur predominantly in woman, sometimes by a margin of 10:1 or greater.

• ASTHMA: Can be caused by a Type-I Hypersensitivity to exogenous allergens in the respiratory tract.
• CHARCOT-LEYDEN CRYSTALS: Eosinophilic granules found in the mucus; diagnostic of asthma.
• HASHIMOTO'S THYROIDITIS: A combination of Type-II (organ-specific) and Type-IV (cell-mediated) auto-immune disease.
• PATHOGENESIS: Type-II ADCC against thyroglobulin, and against thyroid peroxidase (microsomal bodies).
• SYMPTOMS: Goiter, due to inflammatory infiltrates in the thyroid.
• HASHITOXICOSIS: Severe hyperthyroidism, found in this disease.
• OTHER DISEASES: Many other autoimmune diseases are commonly associated with Thyroiditis: SLE, Rheumatoid Arthritis, Sjogrens, Addison's, IDDM.
• GRAVE'S DISEASE: Type-II autoimmune attack against TSH-receptors in the thyroid gland, resulting in overactivation of them ------> Hyperthryoidism.
• This is a disease where an auto-antibody acts as an Agonist.
• MYASTHENIA GRAVIS: Type-II autoimmune attack against Nicotinic Acetylcholine receptors ------> block Ach-receptors ------> Fatigueable Weakness.
• This is a disease where an auto-antibody acts as an Antagonist.
• GOODPASTURE'S SYNDROME: Type-II Autoimmune attack against Collagen-IV basement membrane components.
• SYMPTOMS: In Goodpasture's, the auto-antibodies attack primarily the Glomerular Basement Membrane and Pulmonary basement membrane ------> Renal Failure (Glomerulonephritis) and Pulmonary disfunction.
• Classic dual symptoms are therefore hemoptysis and renal failure.
• DIAGNOSIS: Immunofluorescence shows a linear array of immunofluorescence, as antibodies bind to basement membrane.
• SYSTEMIC LUPUS ERYTHEMATOSUS (SLE): Type-III Hypersensitivity in which immune complexes are formed against nuclear components in any lysed cells. This is the most common systemic auto-immune disease.
• Anti-Nuclear Antibodies, ANA, Anti-dsDNAare the most common autoantibodies, but there are others.
• SYMPTOMS:
• Butterfly Malar Rash is very common.
• Vasculitis
• Glomerulonephritis
• Polyarthralgia is the most common complaint. Synovitis also occurs.
• Heart-problems can occur but are less common: Pericarditis, and non-bacterial vegetations on valve leaflets called Libbman-Saks Endocarditis.
• SUN EXPOSURE makes the symptoms worse, as DNA is exposed to antibodies in the bloodstream.
• DIAGNOSIS:
• BAND-TEST: Look for immunofluorescence at the dermal-epidermal junction upon skin biopsy.
• Immunofluorescence of Anti-dsDNA Antibodies is diagnostic of SLE.
• Labs: Hemolytuic anemia, thrombocytopenia (low platelet count), leukopenia.
• PEMPHIGUS VULGARIS: Large, easily erupted bullae on mucous membranes.
• DIAGNOSIS:
• Immunofluroescence shows a netline pattern of autoantibodies. Compare to Goodpasture's, which is linear.
• Take a skin biopsy and look for antibodies (IgG), but it must be from a newly evolved lesion, otherwise it could be explained by infection.
• Progressive denudation of skin will lead to infections.
• They are very similar to burn patients in their needs and risks.
• SJOGREN SYNDROME: Also predominantly Type-III Autoimmune disorder characterized by sicca (dry eyes) and xerostomia (dry mouth). Second most common connective tissue disorder, after SLE.
• Rheumatoid Factor is commonly found, whether or not they have Rhrumatoid Arthritis.
• Associated with a 4-fold increased risk for malignant lymphoma.
• SCLERODERMA: Connective Tissue autoimmune disease characterized by excessive collagen deposition in skin and internal organs.
• Etiology is associated with chromosomal abnormalities (breaks, translocations).
• Most organ systems are involved, with generalized collagen deposition and scleritis found throughout.
• SYMPTOMS:
• Raynaud's phenomenon is often found early on.
• Exertional dyspnea is found due to pulmonary interstitial fibrosis.
• Polyarthralgias.
• POLYMYOSITIS / DERMATOMYOSITIS: Autoimmunity against skeletal muscle and skin. In men, it is often associated with an underlying visceral cancer.
• WEGENER'S GRANULOMATOUS VASCULITIS: Small-vessel vasculitis; common to also find glomerulonephritis. Probably Type-IV reaction.
• Saddle-shaped nose, with damage to the nasal septum.
• Lung granulomas.
• RHEUMATOID ARTHRITIS: Antibody against the Fc portion of IgG, forming an immune complex which is then termed Rheumatoid Factor.
• CONTACT DERMATITIS: Type-IV delayed hypersensitivity. Poison Ivy.

IMMUNE DEFICIENCY DISEASES: Most congential immunodeficiency diseases are X-linked and thus occur only in males.

• CONGENITAL X-LINKED HYPOGAMMAGLOBULINEMIA (XLA) (BRUTON'S DISEASE): Caused by a defect in the early-mature B-Cells. Pre-B Cells are detected but cannot mature.
• Age: Infantile
• COMMON VARIABLE IMMUNODEFICIENCY: Hypogammaglobulinemia (deficient IgG). Pt presents with pyogenic infection.
• Age: Adult, 30 years.
• SELECTIVE IGA DEFICIENCY: Most common of immunodeficiencies. B-Cell count is normal, but IgA is not synthesized or secreted. Could be a problem with class-switching or with the secretory pathway.
• Symptoms: Recurrent or opportunistic GI-tract and respiratory infections.
• DIGEORGE SYNDROME: Congenital malformation of 3^rd and 4^th Brachial Pouches, resulting in no formation of Thymus.
• Patient will present with severe hypocalcemia due to hypoparathyroidism (Parathyroid does not form normally).
• SEVERE COMBINED IMMUNODEFICIENCY (SCID): Absence of both T and B-Cells. Onset at 6 months.
• Adenosine Deaminase Deficiency is usually the cause in autosomal-recessive SCID (there is also an X-linked form). Deficiency of ADA leads to accumulation of deoxyadenosine and its derivatives (e.g., deoxy-ATP), which are toxic to immature lymphocytes.
• CHRONIC MUCOCUTANEOUS CANDIDIASIS: Specific immunodeficiency against Candida fungi and nothing else. Strange...
• WISCOTT-ALDRICH SYNDROME: Rare X-linked, cause unknown. It is a complete failure to produce antibodies against polysaccharides.
• ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS): Infection of CD4 cells by HIV retrovirus.
• Common Complications: Opportunistic infections. Of course this list is not complete.
• Persistent Generalized Lymphadenopathy: Common early symptom. Persistent enlargement of lymph nodes with no apparent cause.
• Kaposi Sarcoma is a common skin cancer that occurs all over the body in AIDS and rapidly metastasizes.
• Pneumocystis Carinii is an opportunistic pathogen that frequently causes pneumonia in immunocompromised patients.
• Cytomegalovirus
• Toxoplasmosis occurs in the brain where it forms lesions that are evident on MRI. Toxoplasmosis occurs in normal people, too, but it doesn't form the lesion because our immunity can quickly wipe it out.
• Candida infections.
• gp120 is the name of the viral-coat protein, which recognizes CD4 receptors on T_H cells in order to gain entry into the cells.

AGGRETOPE: Association of a peptide epitope with Type-I MHC complex. It can then react with CD8 cytotoxic cells.

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