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149 Cards in this Set

  • Front
  • Back
Hypertrophy
Increase in the size and function of cell - it is an adaptive response
Atrophy
Decrease in size and function of cell
Necrosis (Oncosis) vs Apoptosis
Both are cell death. In necrosis, the cell swells, usually occurs after ischemia. In apoptosis, it is a programmed cell death and the cell shrinks.
Causes of cell injury
1.    O2 deprivation: Hypoxia - is inadequate oxygenation. Ischemia - is the loss of blood supply
2.     Physical agents – radiation, burning, etc .  Chemical agents and drugs
4.     Infectious agents
5.     Immunologic reactions
6.     Genetic derangements
7. Nutritional imbalances
What are the biochemical mechanisms of cell injury?
1. ATP depletion
2. O2 & O2-derived free radicals
3. Intracellular Ca+2
4. Defects in membrane permeability
5. Irreversible mitochondrial damage. It is caused by  Ca+2, oxidative stress, activated phospholipase, FFA and ceramide.
Mitochondrial permeability transition: Leakage of cytochrom c into the cytosol
In ischemia/hypoxia, which biochemical function is affected first?
Oxidative phosphorylation in the mitochondria.
Describe the biochemical reversible changes in the cell due to ischemia or hypoxia.
-Lack of ATP production in mitochondria leads to reduced action of ATPase pump, so cell swells due to osmosis.
-More anaerobic glycolysis causes more catabolites and lowers pH of cell.
-Reduction of protein synthesis occurs as proteins detach from ER; dilation of ER occurs.
-In addition, there will be blebs and myelin figures.
In ischemia/hypoxia, what determines when irreversible cell damage occurs?
Damage to the genome and/or cellular membranes.
What are the 3 nuclear changes that can occur during irreversible cell damage in necrosis?
Karyolysis: Nucleus is lysed
Karyopyknosis: Nucleus is shrunken
Karyorrhexis: Nucleus undergoes fragmentation
What are the 3 main ways free radicals ie Reactive Oxygen Species (ROS) can cause cell injury?
1) Lipid peroxidation: ROS attack phospholipids in cell membrane
2) Oxidative modification of proteins: ROS attack disulfide bonds causing improper folding of proteins
3) DNA: ROS cause lesion or break in DNA leading to malignant transformation or cell aging
What are the cell's mechanisms to neutralize free radicals?
-Antioxidants: Vitamins A, E, C and glutathione
-Enzymes: Catalase, Superoxide dismutases, Glutathione peroxidase
-Proteins that bind iron and copper to reduce radicals being formed
How and why does reperfusion injury occur?
Blood and oxygen flow is restored after ischemia to an injured area, but the sudden onset of oxygen adds to free radical formation and damage.
Describe and give examples of the direct mechanism of chemical injury to a cell.
Chemical binds directly to a critical component within the cell. Examples are cyanide that blocks mitochondrial cytochrome oxidase and mercuric chloride that binds sulfhydryl groups on proteins resulting in a blocked ATPase or increased membrane permeability.
Describe and give examples of the indirect mechanism of chemical injury to a cell.
Usually involves Cyt P450 to convert chemical to a more toxic form. Examples are CCl4 that gets converted to CCl3- which is a damaging free radical that can cause fatty liver; also Tylenol gets converted to a toxic metabolite which can deplete the cell of GSH.
List the different morphologies of tissue necrosis
-Coagulative necrosis: Dead tissues are preserved because of denaturation of proteins. Usually caused by ischemia.
-Liquefactive necrosis: Dead cells have been digested; characteristic of bacterial infection and stroke; tissue becomes a liquid, viscous mass. The necrotic material is often creamy yellow because of the dead leukocytes.
-Gangrene: Wet is liquefactive, dry is coagulative; usually refers to a limb.
-Caseous necrosis: Typical of tuberculous infection; cheese-like.
-Fibrinoid necrosis: Immune-mediated deposition of fibrin in vessel wall causes vascular injury.
-Fat necrosis: Triglycerides broken down and combined with calcium to produce "soaps" in tissue
Describe the difference between autolysis and heterolysis in necrosis.
-Autolysis: Cell digested by its own lysosomes.
-Heterolysis: Cell digested by PMN (neutrophil) lysosome.
What are 7 causes of apoptosis?
1) Programmed destruction of cells during embrogenesis and metamorphosis
2) Hormone-dependent involution in adults. Ex: endometrium during menstrual cycle.
3) Cell death in tumors
4) Death of immune cells, T and B, when antigen or bacteria are eliminated.
5) Pathologic atrophy of hormone-dependent tissues. Ex: Prostatic atrophy after castration.
6) Pathologic atrophy of parenchyma of organs after duct obstruction. Ex: Kidneys in hydronephrosis – stone or BPH cause backup
7) Councilman bodies in viral hepatitis
What is the morphology of cell apoptosis?
Cell shrinkage, Chromatin condensation, Blebs and apoptotic bodies, Phagocytosis of apoptotic cells or bodies.
What is the name of the protease family that is activated in apoptosis?
Caspases. They can be activated by cytochrome c that is released by the mitochondria or by a signal transduction pathway initiated by TNF or Fas receptors.
Hyperplasia
An adaptation that increases the number of cells and the volume in an organ or tissue
What are the two types of physiological hyperplasia?
1. Hormonal H, female breast at puberty, and pregnant uterus
2. Compensatory H, after partial hepatectomy
What causes pathological hyperplasia?
Pathologic hyperplasia is caused by excessive hormonal stimulation or the effects of growth factors in the target cells
Give 2 examples of physiological hypertrophy and 1 example of pathological hypertrophy.
Physiologic, induced by hormones: uterus at pregnancy, breast during lactation
Physiologic, induced by heavy work: skeletal muscle
Pathologic, induced by chronic hemodynamic overload: hypertension, faulty valves
Give 4 examples of physiological atrophy and 5 examples of pathological atrophy of cells.
Physiologic Atrophy,
1) uterus after parturition
2) thyroglossal duct atrophy
3) aging
4) menopause
Pathologic Atrophy:
1) Immobilization of a limb,
2) Loss of innervation,
3) Diminished blood supply,
4) Malnutrition: marasmus,
5) Loss of endocrine stimulation: ie castration
Give 3 examples of cell metaplasia.
1. Epithelial (squamous) metaplasia: columnar to squamous in chronic smokers
2. Metaplasia from squamous to columnar type: Barrett esophagitis
3. Connective tissue metaplasia: myositis ossificans
Name 6 cytoskeletal abnormalities.
1. Defects in cell locomotion (damage leukocyte migration)
2. Defects in accumulation of material or phagocytosis
3. Chediak-Higashi Syndrome: decreased fusion of lysosomes with phagosomes in WBC, impairment of phagocytosis of bacteria
4. Defect in sperm motility (sterility)
5. Immobilization of cilia of Respiratory T
6. Alzheimer’s disease - neurofibrillary tangles inside neurons
What are 5 intracellular accumulations?
Lipids, proteins, cholesterol, glycogen and pigments.
What is the name for abnormal accumulation of triglycerides within parenchymal cells?
Steatosis (fatty change)
What are some causes of steatosis within parenchymal cells?
Toxins, protein, alcohol, CCl4; diabetes mellitus, obesity, anoxia
What is the difference in appearance between steatosis in the liver and the heart?
Liver: Clear vacuoles; liver is enlarged, yellow, soft, greasy.
Heart: bands of yellowed myocardium alternating with bands of darker red-brown, uninvolved myocardium.
Name 5 manifestations of cholesterol accumulation.
1. Atherosclerosis: Atherosclerotic plaque - smooth muscle cells; macrophages, foamy cells, lipid vacuoles.
2. Xanthomes: clusters of foamy cells in subepithelial connective tissue of skin, tendons
3. Xanthelasma: clusters of foamy macrophages on the eyelids
4. Inflammation and necrosis: foamy macrophages.
5. Cholesterolosis: accumulation of foamy macrophages in the lamina propria of gall bladder.
What are xanthomes?
Clusters of foamy cells (due to cholesterol) in subepithelial connective tissue of skin, tendons.
What is xanthelasma?
Clusters of foamy macrophages (due to cholesterol) on the eyelids
What is cholesterolosis?
Accumulation of foamy macrophages (due to cholesterol) in the lamina propria of gall bladder
What are 3 causes of protein accumulation in cells?
1. Reabsorption droplets in proximal renal tubules. Filtered protein that is reabsorbed by epithelial cells of PRT throughout pinocytosis. Phagolysosomes appear pink hyaline droplets within cytoplasm.
2. Ig in plasma cells: eosinophilic inclusions called Russell bodies.
3. Alpha 1- antitrypsin (AAT) in liver cells: In AAT deficiency, the enzyme accumulates in ER in the form of eosinophilic inclusions. (AAT's function is to inhibit proteases)
What is the main cause of glycogen accumulation in cells?
Genetic diseases called glycogenosis or glycogen storage diseases.
What is lipofuscin?
Lipofuscin = lipochrome = aging pigment
1. It is a lipoprotein derived through lipid peroxidation of polyunsaturated lipids
2. It doesn’t injure the cell and cell function.
3. It is seen in liver, heart of aging persons, or patients with cancer or cachexia (brown atrophy).
Where is melanin produced?
Melanin is produced in melanocytes.
What is the name of the disorder that causes accumulation of homogentisic acid in the cell?
Alkaptonuria. (Also called Ochronosis. It is an autosomal recessive disorder in which there is a lack of homogentisic oxidase, an enzyme that converts homogentisic acid to methylacetoacetic acid in the tyrosine degradation pathway)
What are 3 causes of accumulation of hemosiderin (iron storage protein) in the cells?
(1) Local: common bruise - area red-blue -- green (biliverdin) -- red (bilirubin) -- golden yellow (hemosiderin);
(2) Systemic: hemosiderosis is caused: Iron in diet, impaired utilization of iron, hemolytic anemias, transfusions. Hemosiderin doesn’t damage the cells or their function.
(3) Hemochromatosis - extreme accumulation of iron; causes heart failure, diabetes mellitus, liver fibrosis, skin pigmentation – can be inherited or acquired
Where does bilirubin come from and in what organs does it mostly accumulate?
It's the last product in the metabolism of heme group of hemoglobin, accumulation most evident in liver and kidney.
What are the causes of jaundice (accumulation of bilirubin)?
1) Prehepatic - with hemolytic anemias 2) Hepatic - hepatitis
3) Posthepatic - obstruction of intra or extrahepatic bile ducts
In pathological calcification, what condition would cause the calcemia level to be normal?
Dystrophic calcification where Ca2+ is deposited in dead tissue. This can cause atheromas, damaged heart valves, tuberculus lymph nodes.
In pathological calcification, what condition would cause the calcemia level to be high (hypercalcemia)?
Metastatic calcification where Ca2+ is deposited in vital tissue.
What are the causes of metastatic calcification? (Name 6)
(1) hypercalciemes in hyperparathyroidism,
(2) Vitamin D intoxication,
(3) systemic sarcoidosis,
(4) Milk-Alkali Syndrome,
(5) Hyperthyroidism,
(6) Idiopathic hypercalcemia of infancy, bone tumors, advanced renal failure
What pathological conditions can metastatic calcification cause?
Respiratory deficits and nephrocalcinosis
In what conditions can extracellular hyaline be observed?
1. Old scars.
2. Walls of arteries in kidney in hypertension & diabetes mellitus.
3. Amyloid (protein).
What is the definition of inflammation?
Inflammation is the reaction of the blood vessels, leading to the accumulation of fluid and leukocytes in the extravascular tissues
What is the first cell type to respond in an inflammatory response?
Mast cell.
What are the differences between acute and chronic inflammation?
1. Acute inflammation:
a. Rapid onset, short duration (min/hours/days)
b. Accumulation of fluids and plasma proteins (edema)
c. Accumulation of neutrophils
2. Chronic inflammation
a. Slower onset, longer duration
b. Accumulation of macrophages and lymphocytes
c. Proliferation of blood vessels, fibrosis, tissue necrosis.
What are the 4 (sometimes 5) symptoms of acute inflammation?
Rubor (redness), tumor (swelling), color (heat), dolor (pain) and functio laesa (loss of function)
What vascular changes occur in acute inflammation?
a. Vasodilation of arterioles and opening of new capillary bed
b. Increased blood flow (heat, redness)
c. Increased permeability of microvasculature and outpouring of protein rich fluid into interstitial tissues
d. Increased viscosity of blood and stasis - coagulation
e. Leukocytic margination and migration towards the injured area
Which leukocyte is most prevalent in acute inflammation?
Neutrophils. (In chronic inflammation, it's more lymphocytes and macrophages)
What are the sequential events for the neutrophils to go from the blood to the site of injury?
1) Margination (neutrophils are pushed from central axis to the periphery)
2) Rolling (due to activation of selectin adhesion molecules on the surface of neutrophils and endothelial cells, neutrophils loosely bind and roll)
3) Adhesion
4) Transmigration (diapedesis)
5) Chemotaxis
6) Phagocytosis
What components act as chemoattractants for the neutrophils?
Bacterial products, Components of complement (C5a), products of lypoxygenase pathway (LTB4), Cytokines (IL-8 which are produced by macrophages).
Why don't infections heal as well in people with diabetes mellitus?
In Diabetes Mellitus the wall is thicker due to glycosylated molecules sticking to walls so it’s harder for WBC’s to go through, thus infected wounds don’t heal.
How does a phagocyte recognize the microbe to attack it?
In the injured area, bacteria are coated by opsonins. Opsonized bacteria are recognized by WBCs. Opsonins - Fc fragment of IgG, C3b of complement
What is involved in the engulfing stage of phagocytosis?
Microbe is engulfed into a phagosome. Phagosome fuses with lysosome to form phagolysosome and digest the foreign particle
What O2-dependent mechanisms are used in our lysosomes to kill the bacteria and what enyzmes/reactions are needed to form them?
a. Superoxide (O2" ): In the membrane of neutrophil NADPH oxidase produces O2“
b. Hydrogen peroxide (H2O2): H2O2 is produced within the phagolysosome:
c. Hypochlorous acid (HOCl): major component, catalyzed by myeloperoxidase (MPO)
d. Hydroxil radical (OH ): Faber-Weiss Reaction (Cu+2); Fenton Reaction (Fe+2)
What non-oxidative methods are used in our cells to kill microbes?
a. Lysosomal hydrolases of WBCs – this is most important method
b. Cationic proteins in primary granules of neutrophils that kill gram-negative bacteria
c. Defensins - Cationic proteins that kill bacteria, fungi, viruses
d. Lactoferrin - iron-chelating protein; sequesters iron
e. Lysosyme - kills gram-positive bacteria
f. Bactericidal proteins of Eosinophils - kill parasites.
Tissue often becomes damaged during acute inflammation. Describe 4 ways in which this can happen.
1) Regurgitation during Feeding - damaging ROS leaks from the phagocyte and damages nearby cells
2) Frustrated phagocytosis – antibody/antigen complex goes against basement membrane and phagocytes try to eat but they damage the membrane. (Ex: Goodpasture Syndrome where the glomerulus and alveoli are damaged
3) Surface phagocytosis – bacteria is pushed to tissue surface and phagocytes eat, damaging tissue
4) Cytotoxic Release – Phagocytes try to devour something like uric acid and get dissolved themselves, releasing damaging components.
What types of cells release histamine?
The sources are mast cells, basophils, platelets
What triggers the release of histamine?
Physical injury, binding of Ab to mast cells, anaphylatoxins (C3a, C5a), histamine releasing proteins derived from leukocytes, neuropeptides (substance P), cytokines (IL-1, IL-8)
What complement components are considered anaphylatoxins?
C3a and C5a
What main action does histamine have in the body?
Histamine release causes increased permeability of postcapillary venules
In acute inflammation, what releases serotonin?
Platelets
What triggers the release of serotonin?
Platelet aggregation, Platelet Activating Factor (PAF)
What is the action of serotonin?
Increase vascular permeability
What are the three pathways to activate the complement system?
1) Classical pathway - stimulated by antigen/antibody complex (IgG or IgM)
2) Alternative pathway - C3b binds directly to microbe polysaccharide
3) Lectin pathway - activated by mannose-binding lectin
What is the significance of C5 through C9 of the complement system?
C5 - C9 make up the MAC - membrane attack complex - that destroys the membrane of the bacteria.
Which complement protein acts as an opsonin?
C3b
What is the name of the disorder that causes a person to have blood in the urine in the am due to DAF (decay accelerated factor) not being expressed?
Paroxysmal nocturnal hemoglobinuria. Every night the complement system gets activated due to respiratory acidosis (this is normal). In these people, however, they can't turn it off easily.
Name the disorder: C1 inhibitor is not expressed, so stress and trauma provoke edema in skin (not pitting) in face, chest, abdomen, extremities, & GI.
Hereditary angioneurotic edema
What is the first factor that is in both the kinin cascade and clotting cascade?
Factor XII (Hageman factor)
What does kallikrein do?
Kallikrein activates high-molecular-weight kininogen to bradykinin in the kinin cascade; activates factor XII to XIIa; activates complement C5 to C5a.
What action does bradykinin have?
Bradykinin increases vascular permeability, contraction of smooth muscle, dilation of blood vessels and causes pain.
What converts plasminogen to plasmin in the kinin cascade?
Fibrinolytic system.
What inhibits bradykinin?
Bradykinin is inhibited by kininase and ACE of lungs
What does thrombin do?
Converts fibrinogen to fibrin.
What does plasmin do that links the kinin/clotting cascade to inflammation?
It converts C3 to C3a and also converts fibrin to fibrin-split products which have permeability-inducing properties.
What are the two main pathways off of the arachidonic acid pathway?
Cyclooxygenase and 5-lipoxygenase
What are the main products from lipoxygenase pathway and what actions do they have?
(1) Leukotriene B4 (LTB4): chemotactic and activator of WBC
(2) Leukotrienes LTC4, LTD4 , LTE4: vasoconstriction, bronchospasm, vascular permeability
What are the main products from cyclooxygenase pathway and what actions do they have?
(1) Prostacyclin (PGI2) causes: vasodilation, vascular permeability, chemotactic effects of mediators
(2) Thromboxane A2 (TxA2): vasconstriction, platelet aggregation
(3) PGD2, PGE2, PGF2: vasodilation, edema, pain and fever (PGE2)
What is PAF and where is it produced?
PAF (platelet activating factor) is a bioactive phospholipid-derived mediator. It is produced by: platelets, basophils (mast cells), neutrophils, monocyte/macrophages, endothelial cells
What are the two major cytokines in inflammation and where are they produced?
IL-1 and TNF-alpha. They are produced by macrophages, lymphocytes (TNF-beta or lymphotoxin), other cells
What stimulates production of IL-1 and TNF-alpha?
Their production is stimulated by: endotoxin, immune complexes, toxins, physical injury
What are the main functions of cytokines and chemokines?
1. endothelial activation (adhesion molecules and chemical mediators)
2. aggregation and neutrophils priming (TNF)
3. releasing of proteolytic enzymes from mesenchymal cells causing tissue damage
4. inducing of systemic acute-phase responses: fever, decrease appetite, increase sleep, neutrophilia, septic shock, hypotension, acidosis, increase heart rate
What produces NO and what are its main roles in inflammation?
Produced by endothelial cells, macrophages, some neurons. It : reduces leukocyte recruitment, NO and reactive O2 species form multiple antimicrobial metabolites that damage microbial DNA proteins and lipids.
What does Substance P do?
Transmission of pain, regulation of B/P, stimulation of secretion by immune and endocrine cells, increase vascular permeability.
What are the 7 outcomes of acute inflammation?
1) Chronic inflammation
2) Resolution - occurs w/ mild injury to cells that have the capacity to enter the cell cycle Ex: 1st degree burn
3) Abscess - Ex: Lung abscesses in bronchopneumonia
4) Fibrosis - Occurs w/ extensive injury or damage to permanent cells Ex: 3rd degree burns
5) Sinus – an abscess is opened in a cavity
6) Ulcer - loss of surface epithelium
7) Fistula - abnormal communication between two organs; Ex: Crohns disease causes many fistulas
Definition of chronic inflammation
Chronic inflammation is inflammation of prolonged duration in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously
What are 3 factors that would predispose someone to have chronic inflammation?
1. Persistent infection (tubercle bacilli, Treponema pallidum - syphilus, certain fungi, leprosy)
2. Prolonged exposure to potentially toxic agents (silica, coal dust), or plasma lipid in atherosclerosis
3. Autoimmunity: rheumatoid arthritis, lupus erythematosus
What are 3 histological features of chronic inflammation?
1. Presence of mononuclear cells: macrophages, lymphocytes, plasma cells
2. Tissue destruction
3. Healing by fibrosis
During acute inflammation macrophages disappear. Describe how or why they have a continual presence in chronic inflammation.
(1) Continuous recruitment of monocytes from circulation.
(2) Local proliferation of macrophages (atheromatous plaque).
(3) Immobilization of macrophages: - macrophage inhibitory factor, oxidized lipids.
What are macrophages called in the:
CNS
Liver
Lung
Bone
CNS: Microglia
Liver: Kupffer cells
Lung: Alveolar macrophages
Bone: Osteoclasts
How do macrophages contribute to fibrosis?
Through FGF (fibroblast growth factor), they recruit fibroblasts and stimulate angiogenesis; they also contribute to collagen formation
How do macrophages contribute to tissue damage?
Toxic oxygen metabolites, AA metabolites, NO, neutrophil chemotactic factors, proteases, coagulation
Besides macrophages, what other cells are commonly seen in chronic inflammation?
1. Lymphocytes (IFN-gamma attracts and activates macrophages)
2. Plasma cells produce antibodies against the antigen
3. Mast cells participate in acute and chronic inflammation
4. Eosinophils are characteristic of immune responses mediated by IgE and parasites
What are the interactions between lymphocytes and macrophages in chronic inflammation?
IFN-gamma from T-cells attracts and activates macrophages. Macrophages activate T-cells by presenting antigens and through cytokines like IL-12.
What are some examples of granulomatous inflammation?
TB, sarcoidosis, cat-scratch disease, lymphogranuloma inguinale, leprosy, syphilis, mycotic infections, Crohns, etc
What cells are involved in granulomas?
1. Epitheloid cells - macrophages with pale cytoplasm that resemble epithelial cells. Epitheloid cell collections form the granulomas
2. Lymphocytes surround the epithelial cells
3. Multinucleated giant cells - macrophages fused together to form a giant cell
4. Langhans giant cell - multinucleated giant cell where the nuclei are arranged in a horseshoe pattern
5. Foreign body giant cell - multinucleated giant cell with an undigested foreign particle inside
6. Other cells: - eosinophils, fibroblasts may be associated with granulomas
When inflammation becomes systemic, how do IL-1 and TNF-alpha promote fever?
They act as endogenous pyrogens:. 1) IL-1 stimulates prostaglandins in hypothalamic thermoregulatory center
2) TNF-alpha: direct action in hypothalamus; stimulates the release of IL-1 from macrophages
In systemic inflammation, what is the mechanism(s) that cause leukocytosis?
a. Macrophages release (IL-1, TNF-alpha) cytokines - accelerated release of neutrophils from bone marrow
b. Macrophages and T Lymphocytes produce colony-stimulating factors - induce proliferation of bone marrow precursors
What is a leukemoid reaction and how can it be differentiated from Leukemia?
Very high leukocyte count, but no anemia, no thrombocytopenia, and LAP (leukocyte alkaline phosphatase) test shows high
Match the infection with the condition:
Bacterial infection, viral infection, parasite infection;
Neutrophilia, Lymphcytosis, Eosinophilia
- Bacterial infections induce neutrophilia
- Viral infections induce lymphocytosis
- Parasitic infestation induces eosinophilia
What's the difference between transudate and exudate?
- Transudate - edema fluid with decreased protein (<3g/dl) content (sg < 1.015) – usually with disease of the heart or liver
- Exudate - edema fluid with increased protein (>3g/dl) content (sg > 1.015)
Describe the difference between the morphological patterns of inflammation: Serous, Serosanguinous, Fibrinous, Purulent, Suppurative
-Serous exudate (effusion) - exudate with less inflammatory cells Ex: burn blisters
-Serosanguinous exudate - serous exudate with RBCs
-Fibrinous exudate - exudate with fibrin, because of activation of coagulation system
-Purulent exudate - exudate with prominent cellular components
-Suppurative inflammation - purulent exudate and liquefactive necrosis
What are the signs of APR (acute phase response) - a regulated physiologic reaction associated with inflammatory conditions?
- fever
- leukocytosis
- decreased appetite
- altered sleep
- changes in the plasma levels of acute phase proteins APP
Which organ up-regulates the manufacture of acute-phase proteins through IL-6 receptor?
The liver.
What are some examples of acute-phase proteins?
C-reactive protein, alpha 1 - Antitrypsin, Haptoglobin, Ceruloplasmin, Fibrinogen, alpha 2 – Macroglobulins
What can accelerated erythrocyte sedimentation rate (ESR) be used to monitor?
Accelerated erythrocyte sedimentation rate (ESR) is a qualitative index used clinically to monitor inflammatory disease
What 2 processes are involved in tissue repair?
1. Regeneration or replacement of injured cells by cells of the same type
2. Fibrosis or replacement by connective tissue, which leaves a permanent scar.
In terms of cell proliferation, how are cells classified (3 types)?
1. Labile cells (> 1.5% are in the state of proliferation) - epithelial cells, hemopoietic cells, stem cells are cells that have an unlimited capacity to proliferate.
2. Stable cells (< 1.5% are in proliferation) - Parenchymal cells of liver, pancreas, kidneys, Fibroblasts, smooth muscle cells, chondrocytes, osteocytes, Endothelial cells
3. Permanent cells (no proliferation) – Neurons, Skeletal muscle cells, Cardiac cells
What are protooncogenes?
Protooncogenes are genes involved in normal growth control pathways. They are stimulated by growth factors to induce cell proliferation
What 3 types of cell surface receptors are involved with the control of cell proliferation?
1. Receptors with intrinsic kinase activity. (Growth Factors use this)
2. Receptors without intrinsic catalytic activity (cytokine receptor superfamily)
3. G protein-linked receptors. (Hormones typically use these)
Name 5 signal transducing pathways in the cell.
1. Mitogen-activated protein kinase pathway (MAP kinase pathway).
2. Phosphoinositide-3-kinase (PI3) pathway
3. Inositol-lipid (IP3) pathway
4. cAMP pathway.
5. JAK/STAT pathway
What do the growth factors EGF and TGF-alpha control?
Proliferation of epithelial cells, fibroblasts, hepatic cells
What produces the growth factor PDGF and what does it control?
1. It is present in platelets (granules), macrophages, endothelial cells, smooth muscle cells, tumor cells
2. It causes migration and proliferation of fibroblasts, smooth muscle cells, and monocytes.
What does the growth factor FGF control?
(1) Angiogenesis (bFGF)
(2) Wound repair: FGF increases migration of macrophages, fibroblasts, epithelial cells in damaged tissues.
(3) Development of skeletal muscle and lung maturation
(4) Hematopoiesis: Development of specific lineages of blood cells; development of bone marrow stroma
What does the growth factor VEGF control?
1. Promote angiogenesis and vasculogenesis
2. Induces specific lymphatic endothelial proliferation and hyperphasia of lymphatic vasculature
What does the growth factor TGF-beta (Tranforming Growth Factor) control?
1. TGF-beta 1 is produced by platelets, endothelial cells, lymphocytes, macrophages.
2. In low concentrations, TGF-beta induces production of PDGF that is mitogenic.
3. TGF-beta stimulates fibroblast chemotaxis, and production of collagen and fibronectin.
4. It blocks protease inhibitors
5. TGF-beta favors fibrogenesis
What are the functions of the ECM (extra-cellular matrix)?
1. ECM proteins sequester H2O to provide turgor to soft tissues, minerals to provide rigidity to skeletal tissues.
2. ECM provides a medium for cells to adheres, migrate, and proliferate.
What are the 3 groups of macromolecules that form the ECM?
1. Fibrous structural proteins: collagen and elastin.
2. Adhesive glycoproteins: fibronectin and laminin
3. A gel of proteoglycans and hyaluronans.
What are the 4 steps in the process of fibrosis?
1. Angiogenesis
2. Migration and proliferation of fibroblasts
3. Deposition of ECM
4. Remodeling
What is the difference between angiogenesis and vasculogenesis?
Angiogenesis is the process of neovascularization, in which preexisting vessels send out capillary sprouts to produce new blood vessels. Vasculogenesis is the process of creating new vessels during the embryonic stage.
What is the most important growth factor in inducing angiogenesis?
VEGF
What stimulates the production of VEGF?
VEGF expression is stimulated by TGF- alpha, PDGF, TGF-beta, tissue hypoxia
In fibrosis, migration of fibroblasts occurs, triggered by TGF-beta, PDGF, EGF, FGF, and cytokines IL-1, TNF-alpha. What secretes these and which is the most important in the migration of fibroblasts?
Platelets and macrophages secrete the above factors. TNF-beta is the most important.
During angiogenesis promoted by VEGF, what else is occurring?
There is increased vascular permeability and deposition of fibrinogen and fibronectin in the injured area.
What is the timeframe for deposition of collagen by fibroblasts?
Fibroblasts in the injured area start the deposition of collagen in 3-5 days and continue for several weeks.
Definition of tissue remodeling.
It is the replacement of granulation tissue with a scar. Tissue remodeling is a result of ECM synthesis and degradation.
What is granulation tissue?
It is the combination of new small blood vessels and fibroblasts that form in an injured area in the first few days.
What are metalloproteinases and what is their purpose?
They are Zn-dependent proteinases that degrade collagen, granulation tissue and other ECM proteins to clear the way for stronger collagen to be laid down.
What are the different types of metalloproteinases and what do they do?
1. Interstitial collagenases - cleave collagen I, II, III.
2. Gelatinases - cleave amorphous collagen and fibronectin.
3. Stromelysins - cleave laminin, proteoglycans, fibronectin, amorphous collagen.
4. Membrane-bound matrix metalloproteinases
What activates and what inhibits metalloproteinases?
Metalloproteinases are activated by plasmin and HOCl and are inhibited by tissue inhibitors of metalloproteinases (TIMP), produced by mesenchymal cells.
What is "healing by first intention" and "healing by second intention"?
This refers to the type of wound. A clean, surgical cut would be healing by first intention, whereas a wound that creates large defects would be healing by second intention. The 2nd would take longer to heal and would have much more granulation tissue.
What occurs in the first 24 hours after a wound?
- Formation of blood clot
- Appearance of neutrophils
- Epithelial cells migrate toward center of clot to begin laying down basement membrane
What occurs in 3 to 7 days after a wound?
- Neutrophils are replaced by macrophages
- Migration of fibroblasts
- Formation of granulation tissue which is a combination of new vessels (angiogenesis) and fibroblasts
Why should people who have had a heart attack or a major injury not move much during the first week?
Granulation tissue is quite weak; it only has about 10% of the strength of the original ECM, so movement after an injury should be limited until the granulation tissue is replaced by stronger collagen.
T/F: Wound contraction usually occurs in healing by first intention.
False. Wound contraction is usually seen healing by second intention (large surface wounds).
What are 4 local factors that can affect wound healing?
1. Infection – if abscess is formed, it needs to be drained
2. Mechanic factors, motion
3. Foreign bodies: unnecessary sutures, fragmented steel, glass, bone; body will react by forming an abscess
4. Size, location, and wound type: small injuries and those located in vascularized areas heal faster
What are 4 systemic factors that can affect wound healing?
1. Nutrition: Vitamin C deficiency, zinc helps in remodeling
2. Metabolic status: Diabetes Mellitus
3. Circulatory status: Arteriosclerosis, varicose veins – causes ulcers in skin
4. Hormones: Glucocorticoids have anti-inflammatory effect and inhibit collagen synthesis.
What is wound dehiscence?
Wound dehiscence is a deficient scar formation, is common after abdominal surgery and due to increased abdominal pressure. There’s so much inflammation that there’s opening of the wound.
In what diseases do ulcerations usually occur?
Ulcerations occur in individuals with atherosclerotic vascular disease, or diabetic peripheral neuropathy.
T/F: By the third month, wound strength is 70-80% of tensile strength of unwounded skin, and remains the same for life.
True
T/F: Keloid is an excessive, hypertrophic scar and is formed based on an individual's predisposition.
True.
T/F: Excessive amount of granular tissue, protruding above the level of skin, without epithelialization is called aggressive fibromatoses.
False. Aggressive fibromatoses is a low grade tumor, usually with bad burns. Excessive amount of granular tissue, protruding above the level of skin, without epithelialization is called exuberant granulation.
Mercuric chloride and cyanide poisoning are 2 examples of chemical injury by direct binding to organelles. Describe what effect these two compounds have on cells.
1. Mercuric chloride poisoning: mercury binds sulfhydryl groups of proteins blocking ATPase pump, or increase membrane permeability
2. Cyanide blocks mitochondrial cytochrome oxidase