Section 1
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Describe Fat necrosis
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Section 1
(50 cards)
Describe Fat necrosis
a) enzymatic- acute pancreatitis & calcium saponification b) traumatic
Describe how excess of certain chemicals can damage cells
EXCESS of innocuous substances (glucose, salt, water, oxygen) or therapeutic agents (Acetaminophen, morphine) can cause cell injury and death. Of course, some things are always toxic (plutonium, other poisons).
When can cell injury be reversible?
Reversible injury can get better IF the assault abates BEFORE severe membrane damage and terminal mitochondrial dysfunction occur, or may it progress to irreversible injury and cell death.
What is dry gangrene?
Coagulative necrosis
What are some mechanisms of membrane damage?
Recall the lipid bilayer structure of cellular membranes. Mechanisms of membrane damage include: 1) Decreased phospholipid (PL) synthesis (PL needed as membrane component; dec. ATP= dec PL) 2) Increased phospholipid breakdown (inc. Phospholipase activity due to inc. Ca++), and breakdown products (act as detergent) 3) ROS, by lipid peroxidation 4) Cytoskeletal abnormalities (membrane anchors broken, e.g. by inc. protease activity due to inc. Ca++)
What happens as a result of cellular breakdown? How do we observe this?
The cellular breakdown leads to LEAKAGE of cytoplasmic contents which incites inflammation (get poetic). Under the microscope we see changes not only in necrotic cells, but also in the tissues built of them, and the results of the inflammatory response to the necrotic cells/tissue.
Describe Caseous necrosis
Cells turned to cheesy debris (Tb, fungus). Can be at the center of a granuloma. YOU CANNOT SEE THE OUTLINES OF INDIVIDUAL DEAD CELLS (that's how it differs from coagulative)
What is metaplasia?
-Metaplasia is a reversible change of one cell type to another. This may be adaptive, but comes at a cost‐ -For example, in smokers the relatively fragile glandular epithelium in the airways may be replaced by more rugged squamous epithelium, better able to resist the noxious smoky atmosphere. -But then the mucociliary elevator for removing particulate matter is lost. -The noxious smoke ingredients that cause metaplasia can also cause neoplasia.
What are the two types of hyperplasia?
Hyperplasia may be physiologic (normal) or pathologic.
How are free radicals increased?
Most ROS are a type of Free Radical. Free Radicals are increased: a) By ionizing radiation (.OH, .H) b) By metabolism of certain chemicals/poisons (CCL4 to .CCL3) c) Inflammation (Chapter2)
Describe Gangrenous necrosis
more a clinical or gross term; may be coagulative(dry) or liquefactive(wet), due to superimposed bacterial infection.
Describe coagulative necrosis.
Mummification; leaves ghostly outlines of cells that once were (infarct). Heals with a scar.
What are the most important membrane damage sites?
a) Mitochondrial‐ get decreased ATP production, ultimately necrosis b) Plasma - osmotic imbalance, fluid influx/cell swelling, loss of cell contents, dec. ATP...necrosis. c) Lysosomal‐ release of lysosomal enzymes into cell, autodigestion, necrosis.
How do ROS cause injury?
ROS cause injury by: A) Lipid Peroxidation of Membranes B) Cross‐Linking Proteins C) DNA Damage
Describe the characteristics of necrosis
-Necrosis is messy, always pathologic, and we will focus more on it than we will on the clean, often physiologic process of APOPTOSIS. -Necrosis is an everyday phenomenon reported in pathology practice. Apoptosis is not, but it is still very important‐ we'll discuss it later.
What are examples of physiologic hyperplasia?
Physiologic hyperplasia examples include the increase in cell number seen in: Hormonal hyperplasia ‐The smooth muscle cells of the pregnant uterus (concurrent with smooth muscle hypertrophy) ‐The cells of the glandular epithelium of the breast at puberty and lactation Compensatory hyperplasia ‐The thickened skin and stratum corneum of the sole of the barefoot walker ‐The regenerative liver after partial hepatectomy. (Greek myth note‐ Prometheus‐ They knew!)
What genetic disease can cause cellular injury?
a) Malformations in Down's syndrome (trisomy 21) b) Single amino acid substitution causing sickle cell anemia c) Mutations causing enzyme defects leading to deficiency of functional proteins or accumulation of damaged DNA.
What protects a cell from ROS?
-Superoxide dismutase(O2‐), catalase and glutathione peroxidase(H2O2) decompose ROS, protect cell. -Vitamins E, A, C, and beta carotene also have antioxidant activity. When ROS production exceeds removal, oxidative stress occurs.
What is a consistent feature of cell death by necrosis?
MEMBRANE DAMAGE is a consistent feature of cell death by NECROSIS. Ischemia, Microbial toxins, Complement(lytic), Physical/Chemical agents can cause membrane damage.
When are ROS produced?
1) As a normal part of cell signaling pathways (NO, others) 2) Byproduct of oxidative phosphorylation (O2‐, H2O2... mitochondria aren't perfect...) 3) During "respiratory burst" in phagosomes in WBC for killing bacteria (HOCL, ONOO‐)
Describe Liquefactive necrosis
enzymes & phagocytosis liquefy and remove dead tissue (e.g. CNS infarct, lung abscess) Leaves a fluid filled spave
Describe metaplasia of the esophagus due to gastric reflux
-Another example of metaplasia occurs in chronic reflux esophagitis due to backwash of gastric acid into the esophagus. -The normal squamous esophageal mucosa is ill‐suited to an acid milieu, and is replaced by metaplastic GASTRIC mucosa, better suited to a low pH environment. If the reflux continues, the gastric mucosa may be replace by metaplastic INTESTINAL mucosa, which is maladaptive (offers no advantage in an acid environment), and can progress to cancer. -This intestinal metaplasia is called Barrett's esophagus.
What are the main causes of cell injury?
1. Oxygen deprivation 2. Chemicals 3. Infection 4. Immune reactions 5. Genetic Defects 6. Nutrition 7. Physical Agents 8. Aging
What are the differences between reversible and irreversible injury?
Reversible injury‐ We want to know about this, because we want to help reverse injury when we can. Irreversible injury‐ Results in cell death. 2 ways to die‐ messy necrosis and clean apoptosis. More on these
What does cell damage depend on?
Ok‐ moving on to how cell and thus tissue damage occurs, focusing on submicroscopic and molecular events Cell damage depends on ‐type, duration, and severity of injury (How Bad is the injury?) ‐type, status, adaptability, and genetic makeup of injured cell (How Strong is the victim?) (e.g. hypoxia toleration‐ cardiac vs. skeletal muscle, liver cell w& w/o glycogen) -Pathways of injury are complicated‐ one insult may trigger many biochemical alterations....
What is etiology?
Etiology‐ pathologic cause; WHY a disease develops.
How can nutrition cause cell injury?
Nutrition. Starvation, vitamin deficiency are obvious; Obesity increases risk of diabetes; animal fat increases atherosclerosis and cancer risk
What happens cellularly as a result from hypoxia? What is the ultimate result?
So‐ recall that most ATP is made by oxidative phosphorylation in mitochondria. O2 is required for this. It follows that HYPOXIA will DECREASE ATP production; so will mitochondrial damage and certain poisons (cyanide). Loss of ATP leads to‐ 1) Pumps Fail‐ cell takes on Na+ and H2O, lose K+, cell swells. Also takes on Ca2+, damage ensues. 2) Lactic Acidosis, due to anaerobic glycolysis, reducing enzyme activity. 3) Ribosomal detachment, with reduction of protein synthesis. -Ultimately, ATP loss leads to irreversible membrane damage and cell necrosis.
Describe fibrinoid necrosis
pink stuff in vessel walls (vasculitis, necrotizing arteriolitis in malignant HTN)
What is an example of pathological hyperplasia?
Pathologic hyperplasia can be seen in response to excessive hormonal, growth factor, or other stimulation. ‐Endometrial hyperplasia due to disturbed estrogen/progesterone balance ‐Granulation tissue formed to repair a wound due to factors elaborated by white blood cells and connective tissue cells. ‐Benign hyperplastic polyps of the colon, shown above.
What is the difference between neoplasia and hyperplasia?
(Important to distinguish the controlled cell proliferation of HYPERPLASIA from the uncontrolled proliferation of NEOPLASIA.)
What does reversible cell injury look like?
-REVERSIBLE injury may show cellular swelling, fatty change, and mild cytoplasmic eosinophilia (redness) by light microscopy. -Also‐Cytoplasmic vacuoles, membrane blebbing/loss of microvilli, mitochondrial swelling, ER dilation (EM may be required to see these).
What is atrophy, and what are its causes?
Atrophy is cell shrinkage (and thus organ shrinkage) in response to various causes‐ 1) Disuse (in muscles due to lack of exercise) 2) Denervation (in muscles due to ALS‐ Lou Gehrig, Stephen Hawking) 3) Diminished blood supply (atherosclerosis) 4) Diminished nutrition (diet) 5) Hormonal loss (menopause) 6) Aging ("senile" atrophy)
What happens when membranes get leaky?
DAMAGE TO MEMBRANES causes LEAKS: ‐in lysosomes, with release of digestive enzymes into the cytoplasm, causing NECROSIS. ‐in plasma membranes, with release of cytoplasmic contents into the extracellular milieu, inciting INFLAMMATION.
What do injured cells look like?
-So‐ what do cell damage and death look like? First, an irreversibly injured cell, even a dead cell, may look normal because injury first occurs at the molecular/biochemical level. -Observable changes lag behind molecular injury (above). -We pathologists routinely look at cells and tissues using a light microscope‐ seems more and more like a blunt tool as molecular understanding advances, but still standard in clinical medicine.
What is wet gangrene
Coagulative+Liquefactive necrosis
What happens as a result of mitochondrial damage?
a) Abnormal (even normal) mitochondrial oxidative phosphorylation leads to ROS formation; these are CORROSIVE‐cause Necrosis/Inflammation - more in a bit. b) Mitochondrial damage can open a hole in the mitochondrial membrane (MPTP‐ The "Mitochodrial Permeability Transition Pore"opened by Bax/Bak); mitochondrial leakage leads to apoptosis, discussed later.
What are the main ROS?
Reactive Oxygen Species (ROS) include, in increasing order of reactivity (?): 1. H202 2. O2- 3. HOCL 4. ONOO- 5. OH-
What are the main targets and mechanisms of cell injury?
The Main TARGETS & MECHANISMS of cell injury are shown in the Robbins diagram above‐ 1) Mitochondria - ATP production and reactive oxygen species (ROS) generation 2) Calcium homeostasis disturbance 3) Membrane damage 4) DNA damage and Protein Misfolding
What is homeostasis?
Homeostasis‐ from Bio, remember‐ the balanced steady state of living cells. Finely tuned; biologic parameters kept within narrow range.
Describe hypertrophy. Give an example.
-Hypertension (high blood pressure) will cause work‐induced HYPERTROPHY, with increased diameter (size) of cardiac myocytes. -Hypertrophy is an adaptive mechanism employed by cells with a limited ability to divide‐ e.g., cardiac and skeletal muscle. -Hypertrophy as an adaptive mechanism has limits. In cardiac hypertrophy due to hypertension, heart cells, and thus the entire heart, increase in size. This provides a more powerful organ to pump the high pressure blood. But hypertrophy cannot progress indefinitely‐ with continued hypertensive stress, degenerative changes occur in the hypertrophic myocytes. Adaptation to stress can lead to cell injury if the stress is not relieved. -Hypertrophy is not necessarily pathologic‐ for example, the pregnant uterus increases in size both by hypertrophy and by hyperplasia of smooth muscle cells in the uterine wall. And exercise can produce beneficial hypertrophic changes in skeletal and cardiac muscle.
Describe cellular oxygen deprivation and the situations in which it occurs.
a) In pneumonia, hypoxia occurs due to inadequate oxygenation of blood in the lungs, even though blood flow through the lungs is OK. b) In CO poisoning, CO binds to hemoglobin, preventing oxygenation of blood c) In anemia, too few red cells are present, reducing oxygen carrying capacity of blood
What do irreversibly damaged cells look like?
-IRREVERSIBLE injury/NECROSIS shows Marked Cytoplasmic Eosinophilia and Nuclear changes (karyolysis, pyknosis, karyorrhexis) with Cellular Fragmentation. These changes are not as subtle as those seen in reversible injury. -EM may show membrane damage, marked mitochondrial dilation, lysosomal disruption, and myelin figures.
What is pathogenesis?
Pathogenesis‐ pathologic evolution; HOW a disease develops.
Describe the role of calcium in cell death
-Ca2+ is maintained at 10,000X LESS INSIDE the cell than outside. -ATP‐dependent Ca2+ pumps keep Ca2+ out, and mitochondria and ER sequester Ca2+ inside the cell. -If the Ca2+ pumps fail, or if mitochondria/ER release Ca2+ into the cytosol, LYTIC ENZYMES are ACTIVATED, and Phospholipase, Protease, Endonuclease, ATPase enzymes bust the place up‐ get membrane and nuclear damage contributing to necrosis. -Also‐ Increased cytosolic Ca2+ can activate apoptosis (MPTP & Caspases, later).
What is the difference between ishchemia and oxygen deprivation?
Oxygen deprivation (Hypoxia) is to be distinguished from Low Blood Supply (Ischemia). Ischemia causes hypoxia, and deprives the tissue of nutrient supply and waste removal (so its worse than hypoxia alone) Ischemia is the most common cause of hypoxia, but inadequate oxygenation or diminished oxygen carrying capacity also occur‐
What is atrophy?
-Atrophy may be thought of as a retreat to a smaller size where survival is still possible. -Protein synthesis is reduced, cellular catabolism via ubiquitin‐proteosome pathway increases, and autophagy (where the cell eats itself to survive) may occur.
What are the types of necrosis seen in practice?
Coagulative- mummification; leaves ghostly outlines of cells that once were (infarct). Liquefactive- enzymes & phagocytosis liquefy and remove dead tissue (e.g. CNS infarct, lung abscess) Gangrenous- more a clinical or gross term; may be coagulative(dry) or liquefactive(wet), due to superimposed bacterial infection. Caseous- cells turned to cheesy debris (Tb, fungus) Fat Necrosis a) enzymatic- acute pancreatitis & calcium saponification b) traumatic Fibrinoid- pink stuff in vessel walls (vasculitis, necrotizing arteriolitis in malignant HTN)
What are the main adaptations to cell stress?
The 4 main cellular adaptations to stress are: Hypertrophy‐ Increase in cell size. Hyperplasia‐ Increase in cell number. Atrophy‐ Downsizing; cell shrinkage. Metaplasia‐ Change to a more adaptive cell type (maybe) .
What can endometrial hyperplasia lead to? What is it caused by?
Cancer. Caused by sex hormone imbalance.
Section 2
(50 cards)
What environmental stresses affect aging?
-Certain environmental stresses (e.g. caloric restriction) alter signaling pathways that effect aging (e.g. inulin/CF signaling, TOR, sirloins) with improvements in DNA repair, immune system function, and protein homeostasis. More work needs to be done...
Describe fibrinolysis
1. The proenzyme plasminogen is converted by proteolysis to plasmin, the most important fibrinolytic protease. 2. Plasmin splits fibrin. 3. It is a classic teaching that factor XII to Xlla activation links the fibrinolytic system, coagulation system, complement system, and kinin system
Describe the status quo and apoptotic state of the mitochondria
-Normally Bcl-2& Bcl-xl help keep MPTP closed, keep cytochrome c inside mitochondria. -BH3 sensor activation antagonizes Bcl-2&Bcl-xl, frees Bax&Bak to open MPTP, with leakage. -Extrinsic pathway on right, shows FasLigand cross-linking Fas, activating death domain and caspases.
What is ischemia?
-Ischemia is a common cause of cell injury underlying human disease‐ Heart attack, Stroke... -Hypoxia= Low Oxygen, therefore decreased oxidative phosphorylation, decreased ATP (normally, we burn 50 to 75 kg ATP/day...) Ischemia= Low Blood Supply, therefore Hypoxia PLUS: ‐substrates for glycolysis not delivered ‐ wastes not removed -So Ischemia is worse than Hypoxia alone; Ischemia injures tissues faster and more severely than Hypoxia alone. So... O2 deprivation=Decreased ATP =ion pumps fail=cell swelling, Ca2+ influx= decreased cell function =glycolysis =glycogen depletion, lactic acidosis =decreased protein synthesis
What do apoptotic cells broadcast?
Apoptotic cells and apoptotic bodies shout "EAT ME" ; signals include: a) phosphatidylserine flips from inner to outer leaflet of plasma membrane, looks tasty to WBC b) soluble factors secreted, smell good to WBC c) adhesive glycoproteins expressed, mmmm...chewy... Phagocytosis of apoptotic so efficient that they disappear without a trace,without inciting inflammation!
What are anemic infarcts?
1. These infarcts are white or pale infarcts. 2. They are usually caused by arterial occlusions in the heart, spleen, and kidney.
What is required for the activation of the coagulation cascade?
1. Exposure to an activating substance 2. Phospholipid Surface (on platelets) 3. Calcium
How do self-reactive lymphocytes apoptose?
Apoptosis of self-reactive lymphocytes- See self, die by BOTH intrinsic and Fas death receptor pathway
How do cytotoxic T cells cause apoptosis?
Cytotoxic T cells- punch hole with perforin, inject granzyme, induce apoptosis with and without caspases....
What is autophagy?
Autophagy- lysosmal digestion of cell's own components. 1) survival mechanism during times of starvation- cell eats itself to survive (can go on so long, otherwise apoptosis supervenes) 2) clearance of misfolded proteins- digest 'em. Defective autophagy may underlie some neurodegenerative diseases.
What are examples of apoptosis?
1) Growth factor deprivation 2) DNA Damage (p53 is shepherd) 3) Misfolded proteins/ER stress 4) Self‐Reactive Lymphocytes 5) Cytotoxic T cell (granzyme/perforin)
What is thrombosis?
Pathologic formation of an intravascular blood clot
How does endothelium prevent thrombus formation?
1. Blocks subendothelial collagen 2. Produces PGI2 (opposite of TXA2) 3. Produces NO 4. Secretes heparin-like molecules, activate anti-thrombin III 5. Tissue plasminogen activator (creates plasmin, which cleaves coagulation factors and fibrin) 6. Thrombomodulin (modifies thrombin's function so that it activates protein C, which inactivates factors V and factor VIII).
What is infarction?
Infarction is necrosis resulting from ischemia caused by obstruction of the blood supply; the necrotic tissue is referred to as an infarct.
Describe the death receptor apoptosis pathway
Death Receptor (extrinsic): Ligand binds cell surface receptors (e.g. Fas, TNF-1) with a cytoplasmic "death domain". a) Cytotoxic T cells carry FasL, which will cross-link Fas on the surface of the cell about to be assassinated.. b) Crosslinking of Fas leads to activation of it's cytoplasmic "death domain", which binds adapter protein c) Which activates initiator CASPASE-8, which activates executioner CASPASES (maybe BID for intrinsic path, too). The death receptor pathway is used to eliminate self-reactive lymphocytes and targets of cytotoxic T cells.
What happens as a result of reperfusion of tissues?
With reperfusion, collateral damage ensues‐ a) Increased ROS generation occurs because: ‐O2 is now available to make ROS ‐ damaged mitochondria make more ROS ‐ restored blood flow brings WBC, which make ROS ‐ antioxidant mechanisms damaged by ischemia b) Inflammation induced by ischemia increases due to influx of WBC (ROS, Enzymes) and Plasma Proteins (Complement).
What is an embolism?
An intravascular mass that travels downstream and occludes a blood vessel
What are the steps of Primary Hemostasis?
1. Constriction of the blood vessel (neural reflex, endothelial cells have a molecule called endothelin release upon injury that will also cause a vasoconstriction) 2. vWF will bind to exposed basement membrane collagen and will act as a binding scaffold for platelets (vWF is held within endothelial Wibel-Palade body, and on platelets) 3. Platelets bind vWF via GP-Ib (Platelet Adhesion) 4. Platelet adhesion causes conformational change that allows them to dump clotting intermediaries (TXA2 and ADP) 5. ADP causes platelets to express GP IIb/IIIa 6. GP IIb/IIIa and TXA2 will be necessary for platelet aggregation via fibrinogen 7. Conformational change in the platelet membrane makes the platelet phospholipid complex available (PF3), thus contributing to the activation of the coagulation cascade, leading to the formation of thrombin.
What produces tissue factor?
Injured/activated endothelium (TF activates Factor VII)
What is Bernard Soulier Syndrome?
Lack of GpIb
What is the end product of the coagulation cascade?
Thrombin--converts fibrinogen to fibrin
How does DNA damage cause apoptosis?
2- DNA damage- p53 accumulates, stops cell cycle in G1 to allow time for DNA repair. If damage too great, p53 triggers apoptosis by intrinsic pathway. p53 mutated or absent? Then DNA damaged cells survive, may lead to neoplasia. p53 is important- it "recognizes" DNA abnormalities, "assesses" whether they can be repaired, and sends the cell to apoptotic death if irreparable DNA damage is present.
Describe the coagulation cascade
-Goal is to "Get the perfect X" Intrinsic Pathway: Subendothelial Collagen=12, 11, (skip 10 because that's our goal) 9, 8 Extrinsic Pathway: Tissue Thromboplastin=7 Common path: 5, 2, 1 (521=10)
What usually causes a pulmonary embolus?
Thromboembolus (usually DVT) that dislodges and gets stuck in the pulmonary circulation
What is the most common form of embolus?
A thrombus that dislodges (Thromboembolus)
How do misfolded proteins cause apoptosis?
Misfolded proteins- Chaperones ordinarily orchestrate proper protein folding. Misfolded proteins get ubiquitinated and dumped in the proteosome for degradation. IF misfolded proteins accumulate in the ER, they cause "unfolded protein response" which increases chaperones and decreases protein translation, reducing misfolded protein levels. If misfolded protein load too great, "ER stress" results, activating caspases and causing apoptosis. Examples- Alzheimer's, Huntington's chorea, Parkinson's dz; possibly type 2 diabetes.
Besides mitochondrial and death signal, what are other pathways of apoptosis?
3) Granzyme/Perforin- cytotoxic T cells can directly activate caspases, and also cause caspase-independent apoptosis. 4) Inflammation/Infection may also induce apoptosis.
What are hemorrhagic infarcts?
1. These infarcts are red infarcts, in which red cells ooze into the necrotic area. 2. They occur characteristically in the lung and gastrointestinal tract as the result of arterial occlusion.These sites are loose, well-vascularized tissues with redundant arterial blood supplies {in the lung, from the pulmonary and bronchial systems; in the gastrointestinal tract, from multiple anastomoses between branches of the mesenteric artery), and a hemorrhage into the infarct occurs from the nonobstructed portion of the vasculature. 3. They can also be caused by venous occlusion. This is an important contribution to infarcts associated with volvulus, incarcerated hernias, and postoperative adhesions.
Describe the extrinsic coagulation cascade
-Extrinsic pathway of coagulation is initiated by tissue factor, which activates factor VII and forms a tissue factor- factor VIla complex. The complex initiates coagulation through the activation of factor X to factor Xa (and additionally through the activation of factor IX to IXa). -Factor Xa converts prothrombin (factor II) to thrombin (factor lla). Factor Va is a cofactor required in the conversion of prothrombin to thrombin. Thrombin converts fibrinogen to fibrin. -The prothrombin-mediated cleavage of fibrinogen results in a fibrin monomer, which is polymerized and stabilized by factor XIII, thus forming the fibrin clot. -The action of the tissue factor- factor VIla complex is limited by tissue factor path- way inhibitor.
What is the most common thrombus location?
DVT
What is apoptosis?
• Cell suicide • Enzymatic autodegradation of cell contents • Packaged into membrane‐bound fragments • Fragments delicious, phagocytes eat fast • PLASMA MEMBRANE REMAINS INTACT! • NO LEAKAGE, NO INFLAMMATION! • Often normal, sometimes pathologic
What are blood vessels lined by?
Endothelial cells which sit on top of basement membrane
How do toxins damage cells?
3) Toxins act by 2 main mechanisms‐ a) Direct covalent binding to biomolecules (e.g. mercury poisoning, cancer chemotherapy) b) Metabolic conversion of inactive precursor to toxic metabolite (e.g. CCL4, Acetaminophen) CCL4 metabolised to .CCL3, causes free radical injury with membrane lipid peroxidation -Acetaminophen metabolised to NAPQI, a highly reactive quinone, conjugates sulfhydryl groups to form thiol esters
What are the physiological uses of apoptosis?
Apoptosis normally eliminates old cells, unneeded cells, potentially harmful cells: ‐ in embryogenesis, programmed cell death eliminates cells not to be used ‐ hormone‐dependent involution of endometrium during menses, of breast after weaning ‐ cell loss in proliferating cell populations to keep cell numbers constant (intestinal crypt epithelium) ‐ retirement (inflammatory cells after immune response subsides) ‐ elimination of self‐reactive lymphocytes to prevent autoimmune reactions ‐ cell death induced by cytotoxic T lymphocytes to virus‐infected cells, tumor cells
Describe the action of Protein C and endothelial involvement in its creation
-Endothelium synthesizes thrombomodulin, a cell-surface protein that binds thrombin and converts it to an activator of protein C, a vitamin K-dependent* plasma protein. -Activated protein C (APC) cleaves factors Va and VIlla, thus inhibiting coagulation. -Endothelium also synthesizes protein S, a cofactor for APC
What are the stages of fixing a vessel injury?
1. Primary Hemostasis--Platelet Plug 2. Secondary Hemostasis--Stabilization of Platelet Plug
What are mechanisms of aging?
1) DNA damage‐ most is repaired, but some damage persists and is cumulative with time. ? Role for ROS. 2) Decreased cellular replication‐ "replicative senescence"... somatic cell telomere shortening‐ lose a bit with every replication. -When telomere becomes too short, cell no longer allowed to divide‐ "cell cycle arrest". Telomerase protects germ cells and stem cells by adding a new tail after replication. Some cancer cells have telomerase. 3) Defective protein homeostasis with aging: a) Reduced protein translation b) Defective Chaperones (proper folding) c) Defective Proteosomes (destroy abnormal proteins) d) Defective Repair enzymes
Describe the effects of hypoxia on heart muscle
-Heart muscle stops contracting after 60 seconds without oxygen. If O2 restored, changes are reversible‐ Heart will tolerate 20‐30 minutes of complete ischemia; skeletal muscle 2‐3 hours before irreversible injury. -With continued O2 deprivation, Mitochondrial damage, Membrane Damage, ROS accumulation, and MASSIVE Ca2+ influx cause NECROSIS. -Extensive Necrosis can lead to organ failure and death.
Describe the mitochondrial apoptosis pathway
1) Mitochondrial (intrinsic): the usual pathway. If cytochrome C escapes from mitochondria , apoptosis ensues. Steps- a) Injury- growth factor loss, DNA damage, misfolded proteins b) sensed by BH3 proteins of the Bcl-2 family, which inhibit pro-life Bcl-2 & Bcl-xl and c) activates pro-death Bax&Bakeffectors d) which dimerize and open the mitochondrial permeability transition pore e) thru which LEAKS CYTOCHROME C and other substances f) and activates initiator CASPASE-9, forming the apoptosome complex which activates executioner CASPASES
What is the goal of secondary hemostasis?
Stabilization of the platelet plug via the coagulation cascade
Describe how thrombin formation causes positive feedback in the coagulation cascade
Thrombin production further stimulates the pathway by the activation of fac- tor XI to factor XIa and by the activation of the cofactors factor V to factor Va and factor VIII to factor VIlla.
What is the arteriolar vasoconstriction important for?
Probably important in slowing massive exsanguinating hemorrhage in major injury
How do we repair Blood Vessel damage?
Hemostasis
What is the best way to counteract ischemic injury?
-So...In ischemic injury, we want to intervene before injury is irreversible. For example, in heart attack (acute myocardial infarction) with ischemia due to coronary occlusion by blood clot, we can give thrombolytic (clot‐busting agents‐ Tissue Plasminogen Activator) therapy to restore blood flow to reversibly damaged heart muscle. BUT... there are consequences
How does growth factor deprivation cause cell death?
1- Growth factor deprivation triggers intrinsic/mitochondrial pathway, activates Bax/Bak, decreases Bcl-2/Bcl-xl
What do caspases 3, 6, and 7 do?
These executioner caspases (3,6 and 7) cleave numerous targets, leading to nuclear and cytoskeletal breakdown. FLIP, a caspase antagonist, ordinarily blocks caspases. Some viruses use a FLIP homologue to keep infected cells alive.
What does vWF travel in complex with?
Factor VIII
What are the pathologic instances of apoptosis?
Apoptosis in Pathologic conditions can be a good thing, minimizing host reaction and collateral tissue damage: ‐DNA damage‐ when DNA repair enzymes can't cope, apoptosis supervenes. Good, because accumulated mutations can lead to cancer ‐Misfolded proteins‐ lead to "ER stress" and apoptosis ‐Virus‐infected cells‐ apoptosis induced either by the virus or by immune response ‐Atrophy due to duct obstruction‐ pancreas, parotid, kidney
What is characteristics of a thrombus?
1. Lines of Zahn 2. Attach to wall vessel
What are the primary mechanisms and targets of cell injury and death?
1) Mitochondria - ATP reduction and reactive oxygen species (ROS) generation 2) Calcium homeostasis disturbance‐ ATP reduction and Enzyme Activation 3) Membrane damage‐ Havoc as above Last on the list of mechanisms/targets of cell injury, 4) DNA damage and Protein Misfolding usually results in apoptosis, not necrosis, so we'll come back to it.
Section 3
(50 cards)
What do platelet granules contain?
1. Procoagulants* -VIII, V, ADP and Ca2+ 2. Inflammation -Histamine, Serotonin, Epinephrine 3. Repair -PGDF, TGFB
What are the lipid soluble vitamins?
• Four-A, D, E, K; are Fat-soluble
What are the types of radiation?
• Non-ionizing (UV); can move atoms in a molecule or cause vibration but is insufficient to displace electrons from atoms. • Ionizing (X-rays, Gamma rays/knife, Alpha particles-2 protons and 2 neutrons, and Beta particles-electrons); energy to remove tightly bound electrons.
What are the causes of malnutrition?
- Poverty - Ignorance - Chronic alcoholism - Acute illnesses - Chronic illnesses - Self-imposed dietary restriction(s) - Drugs, therapies, malabsorption
Compare and contrast primary and secondary malnutrition
• Primary malnutrition - One or all are missing • Secondary (conditional) malnutrition - Intake is good - Malabsorption, impaired utilization/storage, excess losses, or increased requirements
Which coagulation cascade intermediaries are NOT serine proteases?
1. V and VIII are glycoproteins 2. XIII is a transglutaminase
Describe severe primary protein malnutrion
• Severe PRIMARY protein -energy malnutrition - Serious and lethal • Two protein components (body) - SOMATIC-proteins in skeletal muscle - VISCERAL-proteins in visceral organs (e.g. liver) • Most common victims of protein-energy malnutrition are children.
What determines ROS damage? What does it cause?
- Rate and removal = damage determination - Lipid peroxidation of membranes - Cross-linking and other changes in proteins - DNA damage (single-strand DNA "breaks")
Describe the intrinsic clotting pathway
1. Factor XII is activated by negative charged molecules--mainly sub endothelial collagen. 2. Factor XII and prekallikrein activate one another by using HMWK as a cofactor 3. Factor XII activates Factor IX 4. Factor IX works with its cofactor (Factor VIII), calcium, and PF3 (on platelets) to activate factor X
What is prothrombin?
Factor II
Which coagulation cascade intermediates are Vitamin K dependent?
II, VII, IX, X
What are the acute and chronic effects of alcohol?
• Acute effects-toxicity and stupor/coma/death • Chronic effects-most often seen and profound - Liver - Gastrointestinal tract - Nerves - Vitamins/Nutrients - Heart - Malignancies
Diagram the effects of lead concentration on the body
What is toxicology?
• The science of poisons - Distribution, effects, mechanisms of action of toxic agents
What is KWASHIORKOR?
- Protein deprivation is RELATIVELY greater than the reduction in total calories. - LOSS OF VISCERAL PROTEIN • Liver is affected and albumin is markedly decreased - EDEMA - Loss of weight (overall) is masked by edema - Multiple other lesions » Fatty liver » Skin disease » Hair changes » Immune defects
What is Marasmus?
- Weight level falls to 60% of normal for sex, height, and age. - Protein AND total calories are reduced. - LOSS OF MUSCLE MASS (SOMATIC) • Adaptive (provides the body with amino acids as a source of energy where no intake of energy is occurring) - Visceral Protein Compartment-Spared - Serum albumin-normal - Fat stores-depleted
What is antithrombin III?
Inhibits activity of thrombin, IX, X, XI, and XII -Requires heparin-like molecules to be active (on intact endothelium) -Acts with heparin the drug -Antithrombin III is consumed through activity
Describe the toxic effects of Lead. What are the its sources?
1. Air, food, pica 2. Paints, gasoline, mines, foundries, batteries, spray paints 3. Flaking "old" paint- 1 sq. cm=175 ug lead • Children-blood brain barrier and brain damage • Absorbed lead-bones (competes with Ca++) - 80-85% bones (20-30 year half-life) - 5-10% blood (diagnostic levels; tests from blood) - 5-10% soft tissues
Describe the action of Factor X
Activated Factor X, along with its cofactor (Factor V), Calcium, and PF3 (on platelets) activate prothrombin, in order to form thrombin.
What are xenobiotics?
Xenobiotics-exogenous chemicals in the environment. Absorbed by: inhalation, ingestion, or skin contact.
What are the measurements of radiation?
• Curie (disintegrations per second-radionuclide) • Gray (Gy)-energy absorbed by a target tissue • Sievert (Sv)-Absorbed x Biologic effectiveness
What does Thrombin do?
-Activates Fibrinogen to Fibrin -Activates Factor XI (positive feedback) -Aggregates platelets -Acted on by thrombomodulin (away from injury) can activate Protein C, and along with protein S it cleaves Factors V and VIII (The cofactors of coagulation) -Activates Cofactors!!! Factors XIII and V!!!!***
What is environmental pathology?
• Encompasses outdoor, indoor, and occupational settings in which we (humans) live and work. • Eat, breathe, food and water, toxic agents • Personal environment (habits-smoking, etc.). • With AGE comes exposure • With BAD habits comes exposure • DNA damage, repair, and tumor formation or tissue damage
How is the intrinsic pathway evaluated?
PTT (Activated partial thromboplastin time)
Diagram the metabolism of alcohol
What cross links fibrin?
Factor XIII
Diagram the coagulation cascade
What are the interactions between lead and nervous tissue?
• Neurologic tissues-most resistant • High levels of lead for prolonged periods of time can even affect the neurologic tissues - Central effects-Children-Low IQ • Sensory, motor, intellectual, and psychological impairments - Peripheral effects-Adults-neuropathies
What is Fibrinogen?
Factor I
What happens to toxins in the body?
Toxins-metabolized (detoxification); beware of toxic metabolites (e.g. Acetaminophen, ETOH)
How is the extrinsic pathway evaluated?
PT (prothrombin time)
What are environmental diseases?
• Disorders caused by exposure to chemical or physical agents in the ambient, workplace, and personal environments, including diseases of nutritional origin. • What DO you do? and What DON'T you do?
What is the major system for detoxifying xenobiotics?
• Cytochrome P-450 system-major system for catalyzing reactions (activate or detoxify) - Both detoxification and activation CAN produce Reactive Oxygen Species-oxygen-derived free radicals
What factors into environmental exposure?
- Pollutants producing multiplicative effects - Age - Genetic predisposition - Different tissue sensitivities of exposed persons
Describe the epidemiology of alcohol
• 50% of adults in the Western world drink alcohol - 5-10%=chronic alcoholism - Binges are also a form of alcoholism • Absorbed-stomach and small intestine (unaltered) • Most-metabolized-cyP450,Alcohol dehydrogenase, and catalase
What is Glanzmann thrombocytopenia?
Lack of GpIIb/IIIa
Describe the effects of tobacco. What toxic substances does it contain, and what are their effects?
• Most common exogenous cause of human cancers (90% of lung cancers). • Most preventable cause of human death. 1. Tar, polycyclic aromatic hydrocarbons, benzopyrene, nitrosamines=carcinogenesis 2. Carbon monoxide=impaired oxygen transport 3. Nicotine=tumor promotion; addiction
Describe the metabolic effects of alcohol
1. Alcohol oxidation=decrease in Nicotinamide adenine dinucleotide (NAD+). Required for fatty acid oxidation in the liver (Fat accumulation in the liver). 2. Acetaldehyde-toxic effects 3. CYP2E1 metabolism of ETOH=Reactive oxygen species 4. Liver-Main site of chronic injury
How is plasminogen inhibited?
-Plasminogen activation blocked by plasmin activation inhibitor (PAI) -Free plasmin is inactivated by alpha2-antiplasmin
Besides PT and PTT, how is the coagulation cascade measured?
Fibrinogen amount
What is Factor IV?
Calcium Ion
What are some organic toxins?
Organics-solvents, polycyclic hydrocarbons (combustion of gas and coal); organochlorines (DDT, PCBs, Dioxin, etc.); Bisphenol (synthesis of polycarbonate food and water containers)
Describe the extrinsic clotting pathway
1. Tissue Factor secreted by activated endothelial cells activates Factor VII 2. Factor VII along with TF and PF3 (on platelets) and calcium activate Factor X 3. Factor VII also activates Factor IX (Real in vivo start to the coagulation cascade!!!)
What is the fibrinolytic system? Describe its mediators and mechanism.
-Digets unnecessary clots -Plasminogen is the major component, incorporated into blood clots during formation. Anticoagulant when activated -Activation to plasmin (Factor XII, and Tissue Plasminogen Activator, urokinase, streptokinase)
What diseases are caused by tobacco?
• Most common diseases=emphysema, chronic bronchitis, and lung cancer. • Many other organs affected- (e.g. atherosclerosis, among many others) • Passive smoke and disease(s) • Multiplicative effects = alcohol
What are the effects of radiation exposure?
- Rate of delivery - Field size - Cell proliferation - Hypoxia - Vascular damage - DNA damage
Describe drugs/solvents
Drugs/Solvents-lipophilic (penetrate cell membranes and gain entrance)
Diagram the phases of xenobiotic elimination
What are ROS sources?
- ROS-Sources - Mitochondrial respiration - Phagocytes
What are the effects of lead on bone?
Impaired Remodeling Of Calcified Cartilage= Interference With Normal remodeling
Section 4
(50 cards)
How do viruses cause disease?
- Major determinant of tropism is viral receptors on host cells Cause disease by: • Direct cytopathic effects • Antiviral immune response • Transformation of cells into tumor cells
Diagram the classes of human pathogens
What area of the brain controls feeding?
The Central Arcuate Nucleus of the Hypothalamus
What are biofilms?
-Biofilms = layer of extracelluar polysaccharides secreted by bacteria -Aids in adherence to tissues or devices and immune and drug evasion. -Important in endocarditis, artificial joint infections, and respiratory infections in CF pts
What neurons within the central arcuate nucleus activate weight gain?
-NPY (Neuropeptide Y) -AgRP
What are the effects of Vitamin A toxicity?
- Short or long-term excesses of vitamin A may produce toxic effects • ACUTE-Headache, dizziness, vomiting, stupor, blurred vision • CHRONIC-weight loss, anorexia, nausea, vomiting, bone and joint pain (Retinoic acid stimulates osteoclast production and activity; fractures are common) - Synthetic retinoids (skin disease) are not associated with these complications
What do T cell deficient patients suffer from?
T‐cell deficiencies - intracellular organisms such as viruses and some parasites
What are the main healthcare acquired diseases?
• Health care‐acquired diseases (Nosocomial) - 1.7 million pts/yr in USA • VRE/MRSA • WASH YOUR HANDS!!!!!!!
What is the largest cause of vitamin overdose?
Most chance for toxicity/overdose - Exogenous ingestion of just one vitamin - E.G. vitamin A toxicity (fat-soluble; stores)
What is an example of a super antigen?
• Staph TSS
What can cause immunocompromise?
- Infection (HIV/AIDS) - Drugs (steroids, immunosuppressives, chemo) - Malignancy (leukemia)
How does a high fat low fiber diet impact cancer?
• Bacteria, bulk, carcinogens/promoters • Colon carcinoma
What are the urinary tract defenses?
• Flushing of urine • Physical barrier of mucosa • Low ph of vagina • Anatomy (women uti's 10x more than men because of shorter urethra) - Urinary tract is almost always invaded from the exterior via the urethra
What hormones do adipose cells secrete?
-Leptin -Adiponectin -ESTRONE (Obese women, peripheral estrogen)
What is the GMS Stain used for?
Aspergillus
What are the respiratory tract defenses?
• Mucus and cilia (related to size of particles, less than 5um travel directly to alveoli) • Alveolar macrophages - Microbes that cause infection in lungs develop mechanisms to overcome the above defenses
What is the Kinyoun stain used for?
Nocardia
What happens as a result of vitamin A deficiency?
- Night blindness (vitamin A is part of rhodopsin) - Specialized epithelium • Metaplasia, keratinization • Eye • Respiratory System - Immune deficiency
What are the functions of Vitamin A?
- Normal vision in reduced light - Specialized epithelial cells (mucus-secreting) - Enhance immunity to infections
When is the number of adipocytes within the body determined?
By adolescence
What is the Geimsa stain used for?
Malaria
How do bacteria cause disease?
- Damage depends on three (virulence) factors: 1) Ability to adhere to host cells - Adhesins 2) Invade cells and tissues 3) Deliver toxins - Endo and exotoxin
What is quorum sensing?
Quorum sensing = specific genes (i.e. virulence genes) are expressed when concentration of bacteria gets high enough
Describe bacterial pathogenicity genes
- Genes for virulence factors are often found in clusters called pathogenicity islands - Sometimes pathogenicity genes are conferred by plasmids or bacteriophages
Diagram the techniques of ID pathology
Give examples of how diet can impact disease
- Hypertension and Na+ - Dietary fiber and colon diverticulosis and cancer - Caloric restriction (fasting) and increased lifespan - Garlic and heart disease(Not your Mom's Twilight)
What are the GI immune defenses?
- Stomachacid - Mucus - Lyticenzymes - Mucosal peptides called defensins - Normalflora - Secretory IgA -Most infections caused by weakened local defenses or when organisms develop ways to overcome defenses
What does Leptin do?
Reduce food intake/Increase energy expenditure
Describe a microbe that causes symptoms distal to the primary point of infection
Polio initially infects GI tract, but major manifestations in anterior horn cells of spinal cord
What do antibody deficient patients suffer from?
• Pts with antibody deficiencies (i.e. X‐linked a gammaglobulinemia) - predominantly bacterial and some viral infections
Give examples of how diet can impact cancer
- Exogenous Carcinogens - Endogenous synthesis of carcinogens from dietary components - Lack of protective factors
Give an example of bacterial signaling-based exotoxins
Cholera results in disregulation of adenylate cyclase
What parts of our diet protect against cancer?
• Vitamin C, E, Beta-carotenes, Selenium and antioxidant (protective) properties
What is immunohistochemical stain used for (usually)?
H. pylori, CMV
Give examples of bacterial enzyme-based exotoxins
• S. aureus exfoliative toxins separate keratinocytes from dermis
What do complement deficient patients suffer from?
Complement deficiencies - S. pneumo, H. influenzae. N. meningitidis
What does Ghrelin do?
-Secreted by stomach -Stimulates appetite -Only afferent component of weight management that stimulates feeding
What is the Mucicarmine stain used for?
cryptococcus
Describe Vitamin A
• Retinol, retinal, retinoic acid • Liver, fish, eggs, milk, butter • Carrots, squash, spinach • B-carotene-most important carotenoid • Fat-soluble
What are the endogenous diet causes of cancer?
Endogenous carcinogen- e.g. nitrosamines/amides • Gastric carcinoma (sodium nitrite-Nitrite/preservatives) • Nitrates (from foods; metabolized)
What are the skin immune defenses?
- Physical barrier - Low ph and fatty acids inhibit growth • Most infection caused by break in barrier
What does Peptide YY do?
-Secreted by ileum/colon -Signals satiety
Describe the impact of diet on disease
• Over, under-nutrition and deficiencies aside • Diet COMPOSITION (even in the absence of any of the above) may make a significant contribution to the causation and progression of a number of diseases. • Cholesterol; 75% inherited/25 % diet • Fats (saturated >>> unsaturated); lessening saturated fats • Oils (safflower, corn, and fish)
What is endotoxin?
- LPS, component of outer membrane of gram neg bacteria - Recognized by immune system • Activates protective immunity • Also involved in septic shock, ARDS, DIC (too many cytokines)
What is the best source of vitamins?
• Best source is Native food - Body knows what it needs and takes it - Pills DO NOT replace good dietary habits
What are exogenous diet causes of cancer?
Exogenous carcinogen- e.g. aflatoxin • Many others-saccharin, aspartame
What is the PAS stain used for?
acanthamoeba keratitis
What neurons within the central arcuate nucleus activate weight loss?
-POMC Neurons -CART Neurons
What does Insulin do?
-Secreted by pancreas. Decreases blood sugar. -Continual secretion can burn out pancreas (Type II DM)
What is an example of a neurotoxin?
• C. botulinum and C. tetani
Section 5
(50 cards)
Describe chronic inflammation and scarring
• Exhibited by many infections - May lead to complete healing or extensive scarring • Almost any inflammatory response, if severe enough and sufficient duration may result in chronic inflammation and scarring
Describe Granulomatous Inflammation
• Inflammatory infiltrate composed predominantly of histiocytes (tissue macrophages) • Most commonly associated with mycobacterial and fungal infections, sometimes with parasites or viruses
What is innate immunity?
• Innate immunity-natural/native. Cells and proteins always present and poised to fight. - Epithelium-Skin, GI tract, Respiratory tract - Phagocytic leukocytes-Neutrophils, monocytes/macrophages, NK cells, complement cascade proteins • PREVENT and CONTROL
What do neutrophil deficient patients suffer from?
Neutrophil function - S. aureus, some gram neg bacteria, some fungi
What is tissue necrosis?
• Organism produces tissue death so rapidly that inflammatory cells don't have time to accumulate. • May be caused by Clostridium perfringens, herpes (encephalitis), entamoeba histolytica
What is Transthyretin?
(TTR) 1. Normal serum protein that binds and transports thyroxin and retinol 2. Mutations alter structure and folding -Prone to aggregation -Resistant to proteolysis -Mutant lysozyme 3. Familial amyloid polyneuropathy 4. Senile systemic amyloidosis (heart, among others)
Describe B2m Amyloidosis
• B-2 microglobulin-MHC class I molecules and AB2m (similar to Beta 2 microglobulin) - Builds up in serum of patients with renal disease - Not efficiently filtered through dialysis membranes
What are the immune cells of the body?
- Lymphocytes • B cells • T cells - Antigen-presenting cells • Dendritic cells and Follicular Dendritic Cells • Macrophages - Effector cells • NK cells • Plasma Cells • CD4 or CD 8 cells • Macrophages
Describe systemic amyloidosis
• Systemic - Primary-Monoclonal protein (AL) - Secondary-Chronic inflammatory Condition (AA)
What are the types of hypersensitivity reactions?
• Type I-Immediate hypersensitivity (Allergy) IgE, Immediate hypersensitivity • Type II-Antibody-Mediated Disease • Type III-Immune Complex Disease • Type IV-T-cell Mediated Disease
Where can amyloids occur within the body?
• Amyloid may be systemic (generalized) or localized (single organ)
What are the types of localized amyloidosis?
- Senile Cerebral-AB amyloid - Endocrine-Calcitonin
What processes usually percent disorders like amyloidosis?
• Misfolded proteins-normally degraded intracellularly (proteasomes) or extracellularly by macrophages • These mechanisms fail in amyloidosis • Excess production of proteins that are prone to misfolding - Normal proteins that fold improperly - Mutant proteins that are prone to misfolding
What organs are effected by secondary amyloidosis?
- Kidneys, Liver, Spleen, Lymph Nodes, Adrenals, Thyroid
What are the categories of bioterror?
•A - Highest risk - Readily transmitted or disseminated, highmortality rate •B - Moderate risk •C - Emerging pathogens with potential for high mortality and morbidity
What does an acid fast stain look like?
What is AA?
AA (amyloid-associated) fibril- - Serum precursor (SAA) protein synthesized in the liver (influence of IL-6 and IL-1) - Long-standing inflammation or inflammatory conditions - Accumulation • Abnormal monocyte-derived enzymes • Genetically determined structural abnormality in the SAA molecule itself
Describe the maturation of an adaptive immune response
• Capture by Dendritic Cells • Naïve T cells proliferate - Cytokines (DCs, Macrophages, Lymphocytes) - T 4 cells (Subtypes) • TH1 • TH2 • TH17
Describe primary amyloidosis
- Usually systemic and AL - Bence-Jones proteins (serum and urine) - Primary (no other associated disease) - Primary (Plasma-cell derived) - A type of systemic amyloidosis
What does purulent inflammation look like?
Describe Reactive Systemic Amyloidosis
- Secondary to an associated inflammatory condition - Chronic inflammation - Tuberculosis, Bronchiectasis, Chronic osteomyelitis - Autoimmune disease (RA, Inflammatory bowel disease) - A type of systemic amyloidosis
What does Wegner's granulomatomas look like?
What is adaptive immunity?
• Adaptive Immunity-acquired or specific; normally silent. - Lymphocytes and their products. - Synonymous with immune system or immune response. • HUMORAL- antibodies (produced by B cells) - Extracellular organisms-blood, secretions, tissues • CELL-MEDIATED- T cells - Intracellular organisms
What does granulomatas inflammation look like?
What are the types of host responses to infection?
1. Suppurative (Purulent) 2. Mononuclear and Granulomatous 3. Cytopathic/cytoproliferative reaction 4. Tissue necrosis 5. Chronic inflammation and scarring
Describe Delayed Type Hypersensitivity Reactions
Delayed‐Type Hypersensitivity TH 1‐Interferon Gamma Prolonged DTH reactions= Granulomatous inflammation
Describe Familial Amyloidotic neuropathy
• Transthyretin • Peripheral and Autonomic nerves
How was the term "amyloidosis" coined?
• Abundant charged sugar groups in the absorbed proteins gives the deposits staining characteristics that were once thought to resemble starch (amylose) • So, these are called AMYLOID because they were "like" starch. • The name has entrenched itself despite the realization that the deposits are unrelated to starch. They are protein(s).
Describe endocrine amyloidosis
Endocrine amyloid - Calcitonin-Medullary carcinoma of thyroid
How are host responses to infections complicated?
• Typically not seen in a vacuum - I.E. AIDS patient with CMV inclusions and pneumocystis • Similar changes may also be seen in setting of physical or chemical injury or inflammatory conditions (i.e. vasculitis)
Describe the Cytopathic/Cytoproliferative Reaction
• Usually sparse inflammation • Cells develop inclusions, die, become architecturally abnormal and/or replicate • Usually done by viruses
What are the types of hereditary amyloidosis?
AA/Transthyretin
Describe Senile systemic amyloidosis
• Transthyretin • Systemic; Dominant involvement of the heart
What does a GMS stain look like?
What is the acid fast stain for?
For mycobacteria or nocardia (modified)
Describe the pathogenesis of amyloidosis
• A disorder of protein misfolding • More than 20 different proteins can aggregate to form fibrils with the appearance of amyloid • Non-branching fibrils (7.5 to 10 nm) • Beta-pleated sheet polypeptide chains • Congo Red stain produces congophilia (red stain) • Birefringence is seen with polarized light • Dichromatism (apple-green color) is seen with polarized light
What are the types of systemic amyloidosis?
AL/AA/B2
Summarize the causes and effects of amyloidosis
- An example (especially AL type) of immune system disorder (dys- or un-regulated/neoplastic immunoglobulin production) - Immune system dysfunction (B2-microglobulin) - Hyper-immune system function (chronic inflammatory response) - WITH CLINICAL SEQUELAE
Clinically compare and contrast AA and AL
• AA-control the underlying condition • AL-multiple myeloma-poorer prognosis - Reduce the burden of malignant cells
What are the types of localized amyloidosis?
AB/Endocrine
What is AL?
AL (amyloid light chain) protein - Immunoglobulin light chains - Monoclonal Plasma cell (or B cell) disorders - Lambda light chains more frequently
What is AB amyloid?
AB amyloid- - Cerebral lesions of Alzheimer disease - Core plaques - Blood vessels - Derived from trans-membrane glycoprotein • Amyloid precursor protein (APP)
Describe the clinical course of amyloidosis
• Non-specific symptoms • Poor prognosis; Short survival (1- 3 years) • Resorption of protein is RARE. • Tissue injury and impair function by causing pressure on cells and tissues. • It does not evoke an inflammatory response.
What organs are effected by primary amyloidosis?
- Heart, GI tract, Respiratory Tract, Peripheral Nerves, Skin, and Tongue
Describe the essential morphology and histology of amyloidosis
• Amyloid deposition is always - EXTRACELLULAR - Begins BETWEEN CELLS
Summarize what amyloidosis is.
• Associated with a number of inherited and inflammatory and neoplastic disorders • Extracellular deposits of fibrillar proteins • Tissue damage and functional compromise. • Produced by the aggregation of misfolded proteins or protein fragments. • Bind a variety of proteoglycans and glycosaminoglycans
What does a GMS stain do?
Will stain fungal organisms black
What do CMV and HPV cytopathic reactions look like?
Describe Familial Mediterranean fever
• Inflammation (serosal surfaces) • AA protein • Armenian, Sephardic Jewish, Arabic origins
Describe the suppurative host response.
• Response to acute tissue injury composed predominantly of neutrophils • Pus = neutrophils and liquefied, necrotic tissue • Usually due to bacteria
Section 6
(50 cards)
Describe acute cellular graft rejection
• Acute (Cellular)-First months; CD 4 and CD 8 cells; HLA differences
Describe acute humoral graft rejection
• Acute (Humoral)-Vasculitis; necrotizing vasculitis.
What is abnormal blood flow?
• Any loss of normal laminar blood flow - Turbulence causes activation of coagulation and injures endothelium - Stasis allows activation of platelets in contact with vascular wall, and slows washout of activated coagulation factors and entry of anticoagulants
What type of immune disorder is Graves Disease?
Type II Hypersensitivity
What is edema?
• Edema is the accumulation of interstitial fluid within tissues - Edema fluid accumulating within body cavities is called pleural effusion (hydrothorax), pericardial effusion (hydropericardium) or peritoneal effusion (ascites)
What is anasarca?
- Anasarca is severe, generalized edema with profound swelling and effusions
Describe Hashimoto's Thyroiditis
Hypothyroidism -Autoantigen recognition of thyroid tissue. T cell infiltration and destruction of the thyroid gland. -Thyroid gland becomes enlarged due to lymphoid cell infiltration (white and yellow as opposed to red, glandular hyperplasia)
When should inherited hyper coagulability be considered?
Inherited hypercoagulability should be considered in young patients (<50 y.o.) with repeated thrombosis, family history
What type of immune disorder is Hashimoto's Thyroiditis?
Type IV hypersensitivity with some autoantibody involvement (some type II)
What are Permanent Cells
Cannot divide (or it's nearly impossible for them to) -Neurons
How are tissue grafts rejected?
• Rejection of allografts-response mainly to MHC molecules • Direct recognition • Indirect recognition
Describe the development of a Th1 response
- IL-12=TH1 cells • IFN gamma-by TH1 cells=More TH1 cells • Potent macrophage stimulator
What are emboli?
• An embolus is a solid, liquid or gaseous mass that is carried by the blood to a site distant from its origin - Emboli lodge in vessels too small to allow further passage - Systemic emboli cause ischemic necrosis (infarction) of downstream tissues - Pulmonary emboli cause hypoxia, hypotension, right heart failure and sudden death
Describe edema caused by Lymphatic obstruction
• Neoplastic • Postsurgical • Post irradiation • Inflammation
Draw out the mechanisms of edema
Describe T cell mediated hypersensitivity
DTH - CD4 cytokine release (with damage) - Granulomatous inflammation • CD4+ cells drive the macrophage/monocyte accumulation - T-cell mediated cytotoxicity • CD8+ cells; perforin-granzyme system; death of targeted cells
Describe edema caused by increased hydrostatic pressure.
Impaired venous return -Congestive heart failure -Constrictive pericarditis -Ascites -Venous obstruction or compression Arteriolar Dilation -Neurohumoral dysregulation -Heat
What is Virchow's Triad?
• Virchow's Triad - Endothelial injury - Abnormal blood flow: stasis or turbulence - Hypercoagulability of the blood -these are implicated in thrombosis
What are the possible fates of thrombi?
• Propagation - increase in size • Embolization-dislodges and goes elsewhere in the vasculature • Dissolution - plasmin‐induced proteolysis and disappearance - Tends to occur in younger and smaller thrombi • Organization and recanalization - ingrowth of fibroblasts, endothelial cells, smooth muscle cells, with growth of capillary channels and eventual restoration of the lumen
Describe hyperacute graft rejection
• Hyperacute-Minutes/Hours; pre-formed anti- donor antibodies; vascular thrombosis.
Describe Graves Disease
-Autoantibody forms for TSH receptor, and leads to constitutive secretion of T3/T4. Hyperthyroidism. -Hyperplasia of thyroid glandular tissue (red histologically)
Describe edema caused by Inflammation
1. Acute inflammation 2. Chronic inflammation 3. Angiogenesis
Describe the types of immunological tolerance
• Tolerance (fundamental property of immune system) • Central Tolerance-apoptosis or switching to non-self reactive receptors. • Peripheral Tolerance-inactivation, suppression, or apoptosis
Describe the clinical significance of hemorrhage
• Depends on the volume of blood lost, and rate of bleeding - Rapid loss of up to 20% of blood volume can be tolerated by a healthy adult - Slower loss of greater volumes can also be well tolerated - Site of hemorrhage is important: hemorrhage into an enclosed space like the skull can be fatal - Chronic external bleeding can cause iron deficiency; internal bleeding does not
What are the physiological causes of edema?
1. Increased hydrostatic pressure 2. Reduced plasma osmotic pressure 3. Lymphatic obstruction 4. Sodium retention 5. Inflammation
Describe edema caused by Sodium retention
-Excessive salt intake with renal insufficiency -Increased tubular reabsorption of sodium 1. Renal hypoperfusion 2. Increased renin‐angiotensin
Describe the development of a Th17 response
IL-1, IL-6, IL-23=Th17 effector cells • TH17-promotes neutrophils and monocytes- inflammation
What is congestion?
• Congestion is a passive process resulting from impaired outflow of venous blood - Can occur systemically, as in cardiac failure - Can occur locally due to isolated venous obstruction • Congested tissues have an abnormal blue‐red color • Long‐standing congestion can cause inadequate tissue oxygenation and cell death
Describe endothelial injury
• Any endothelial injury will result in loss of thromboresistence - Need not be ulcerated or physically disrupted • Can be caused by hypertension, turbulence, bacterial toxins, radiation, metabolic abnormalities (homocystinemia, hypercholesterolemia), toxins in cigarette smoke, others
What happens when self-tolerance fails?
• Failure of self-tolerance- - Susceptibility genes - Infections or tissue alterations • Systemic Lupus Erythematosus
What is the status quo of hemodynamics?
• The health of cells and tissues depends on normal microvascular circulation • In the microcirculation, hydrostatic and osmotic pressure are in near balance, so there is little net movement of fluid from intravascular to extracellular space • Hemostasis prevents loss of blood from hemorrhage
What are Stabile Cells?
Don't usually divide, but can enter cell cycle if necessary. Scars can form with continued destruction. -Liver, Thyroid
Describe SLE
Lupus - Multi-system disorder - Protean Manifestations - Predominantly Immune Complex Deposition (Type III disease) - Some Autoantibodies (Type II disease)- Antiphospholipid Syndromes
Describe the different types of pulmonary thromboemboli
• Most PE (60 - 80%) are small and clinically silent • Embolism to small peripheral vessels causes pulmonary infarcts • Embolism to medium sized arteries causes pulmonary hemorrhage but not infarction - Due to dual circulation • Large PE can cause sudden death • Multiple emboli over time can cause pulmonary hypertension and right heart failure
What are the types of hemorrhage?
• Petechiae are minute (1 - 2mm) hemorrhages in skin, mucosa or serosal surfaces - Related to low platelet count, platelet dysfunction or loss of vascular wall support • Purpura are larger (3 - 5mm) hemorrhages - Caused by the same things are petechiae, trauma, vascular inflammation • Ecchymoses are larger (1 - 2cm) subcutaneous hematomas ("bruises") - Causes by trauma, coagulation disorders
Describe cardiac thrombi
• Thrombi in the heart chambers or aorta are called mural thrombi • Thrombi on heart valves are called vegetations, and may be related to infective endocartitis or non‐bacterial thrombotic endocarditis • Venous thrombi are common, with 90% occurring in leg veins. • Distinction of thrombi from postmortem clots is important to Pathologists
Describe chronic graft rejection
• Chronic- - Cellular-T cells and their cytokines - Humoral-Antibody-mediated
Describe the arterial and venous thrombi
• Arterial and cardiac thrombi arise at sites of endothelial injury or turbulence • Venous thrombi arise at sites of stasis • Both propagate in the direction of the heart - The propagating portion is prone to break off and embolize • Thrombi can have alternating lighter and darker layers called lines of Zahn
What is a unique symptom of Grave's Disease? Why is it caused?
Exopthalamos -GAG's are deposited in orbital soft tissue -Sympathetic stimulation of levator palpebrae muscle
What are Labile Cells?
Rapid Turnover, constantly dividing. -Mucosal cells
What is hemorrhage?
• Hemorrhage is the extravasation of blood from blood vessels • Hemorrhage may be external, or - Accumulate in tissues (hematoma) or - In body cavities (hemothorax, hemopericardium, hemoperitoneum, hemarthrosis)
What are the clinical aspects of thrombi?
• Thrombi are a major cause of morbidity and mortality - Cause obstruction of blood flow - May give rise to emboli • Deep venous thrombosis in leg veins is common, and 50% are asymptomatic • Give rise to pulmonary emboli
Describe edema caused by Reduced plasma osmotic pressure
• Protein losing glomerulopathies • Liver cirrhosis • Malnutrition • Protein losing enteropathy
What is a pulmonary thromboembolism?
• Causes 200,000 deaths per year in the US • More than 95% of PE arise from deep leg veins proximal to the popliteal fossa • The size of the embolus determines where it lodges - Large embolus at the bifurcation of the right and left pulmonary arteries is called a saddle embolus - Small emboli will pass to the periphery of the lung - A patient who has had one PE is at risk for more
What is hyper coagulability? What are the types?
• Any alteration in the hemostatic mechanism that predisposes a patient to thrombosis - Primary (inherited) hypercoagulability • Factor V Leiden, prothrombin 20210A, deficiencies of protein C, protein S, AT‐III, others - Secondary (acquired) hypercoagulability • Age, obesity, smoking, inactivity, cancers
What is hemostasis?
• Procoagulant and anticoagulant forces are in balance in a normal individual. - Dominance of anticoagulant forces results in hemorrhage - Dominance of procoagulant forces results in thrombosis • Hemostasis is discussed in greater detail in the accompanying web based exercise.
What are two of the receptors used in HIV (according to this class)
CXCR4-T cells CCRT-macrophages (CCR5--Macrophages and T cell, followed by a switch to CXCR4--T cells)
Compare and contrast Hyperemia and Congestion
• Hyperemia and congestion both refer to an increase in blood within the tissues - Hyperemia is an active process resulting from increased blood inflow - Congestion is a passive process resulting from decreased blood outflow
What is hyperemia?
• Hyperemia is an active process resulting from arteriolar dilation and increased blood flow - Occurs at sites of inflammation or infection - Occurs in exercising skeletal muscle • Hyperemic tissues are redder than normal due to increased oxygenated blood, and are warm to touch
Describe the types of graft rejection (antibody VS T cell mediated)
• T cell-mediated rejection-Acute and Chronic (Cellular) • Antibody mediated rejection-Hyperacute or Chronic (Humoral)
Section 7
(50 cards)
Describe the complement cascade
What's an infarction?
• An infarct is an area of ischemic necrosis caused by interruption of the blood supply - Infarction is the process by which an infarct is made • Most infarcts are caused by arterial thrombosis or arterial embolism - Less common causes include vasospasm, atherosclerosis or extrinsic compression of an artery • All infarcts may be bland or septic
What are the minor cell-derived mediators of acute inflammation?
ROS NO Lysosomal enzymes
How do leukocytes act after driving at the site of inflammation?
Once at the site, leukocytes activate Phagocytosis Intracellular destruction Extracellular destruction Mediators
What are the types of chemical regulation of inflammation?
1. Cell derived -Intracellualr granules 2. Plasma Protein Derived -Circulating in active form
What does suppurative inflammation look like?
What does C5a do?
○ Starts formation of MAC ○ Mimics C3a ○ Activates lipoxygenase ○ Activates and chemoattracts leukocytes
What factors affect infarct development?
• Anatomy of the vascular supply - Dual vascular supply is protective • Rate of occlusion • Tissue vulnerability to ischemia • Hypoxemia
Describe Chediak Higashi syndrome
Defective organelle trafficking Impaired phagocytosis, signaling Severely immunocompromised
What is a red infarct?
• Red (hemorrhagic) infarcts occur: - With veinous occlusion, as in torsion - In loose tissues where blood can collect - In tissues with dual circulation (lung, small bowel) - In congested tissues - Where blood flow is reestablished after infarction
How do leukocytes carry-out extracellular destruction?
Extracellular destruction ○ Secrete lysosomal contents NET Fibrillar extensions from neutrophils with antimicrobial chemicals
What is Hageman factor, and what does it do?
Hageman factor (Factor XII) Activates kinins Activates clotting Activates fibrinolysis Activates complement
What does fibrinous inflammation look like?
What does C3b do?
○ Cleaves C5 ○ Opsonizes material for phagocytosis
Diagram the signaling recognition routes for acute inflammation initiation
What is inflammation?
-Host process to eliminate a cause of injury and the resultant damage, and to begin repair -Can be a damaging process itself -Complex series of interactions
What is a white infarct
White (anemic) infarcts occur in solid organs with end arterial circulation, and in dense tissue
How do leukocytes destroy engulfed material?
○ Lysosome joins, becomes phagolysosome Phagocyte oxidase creates ROS Myeloperoxidase
Describe inflammatory cell adhesion
Integrins on leukocyte surface activate Tight binding, halt cells Binding causes cytoskeletal changes
Describe Systemic Thromboembolism
• Most (80%) arise from intracardiac mural thrombi - Others from aortic aneurysms, ulcerated atherosclerotic plaques, cardiac valvular vegetations - 10 - 15% unknown origin • Common embolization sites are lower extremities (75%), CNS (20%), intestines, kidneys, spleen
What are the overall goals of inflammation?
Five R's Recognition Recruitment Removal Regulation Repair
What are the derivative of arachidonic acid?
Bound in membrane Released by phospholipases Metabolized into eicosanoids ○ Cyclooxygenase: prostaglandins, thromboxanes ○ Lipoxygenase: leukotrienes and lipoxins
What are the vasoactive amines?
Histamine ○ Major source: Mast Cells ○ In response to: trauma, complement, cytokines, ○ Effect: vasodilation, increased permeability Serotonin ○ Major source: platelets ○ In response to: platelet aggregation ○ Effect: vasoconstriction
What are the types of shock?
- Cardiogenic shock: ↓ cardiac output due to pump failure - Hypovolemic shock: ↓ cardiac output due to pump failure - Septic shock
What are the cardinal signs of inflammation?
Rubor Calor Tumor Dolor Functio laesa
What are the messengers of chronic inflammation?
Chronic inflammation ○ IFN-gamma ○ IL-12
What are the possible outcomes of acute inflammation?
Resolution (activate repair pathways) Chronic inflammation Scarring
What are the triggers of acute inflammation?
Acute inflammation: triggers Infection Trauma Tissue necrosis Foreign bodies Immune reactions
Describe inflammatory cell migration
Chemotaxis following foreign materials, chemokines, complement Bind receptors, change cytoskeleton
What are the stages of shock?
Stages of shock: nonprogressive, progressive and irreversible
Describe inflammatory cell transmigration
Chemokines in the tissue attract cells Collagenases break through vessel (diapedesis)
Describe LAD 1 and LAD 2 deficiency
-Lazy Leukocyte Leukocyte adhesion deficiency Impaired migration, defective phagocytosis
What are the main types of cell-derived inflammatory mediators?
1. Vasoactive amines 2. Arachidonic acid
Describe the vascular changes associated with acute inflammation
Get blood (and cells) to the area ○ Vasodilation ○ Increased permeability ○ Adhesion activation
Describe the control of inflammation
Tightly controlled Cellular feedback loops Chemical inhibitors
Diagram the aspects of inflammation and their time of onset
Diagram the pathways of eicosanoid synthesis
Diagram leukocyte rolling and migration
What are the cellular events of acute inflammation?
Get cells to the area, start the attack ○ Migration-related molecules ○ Activating cytokines
What are the major messengers of acute inflammation?
○ IL-1,IL-6,TNF Source: macrophages, endothelial cells, mast cells Effect: activate endothelial cells - Increase adhesion, secrete more cytokines - Cause acute phase response ○ Chemokines CXC type attracts and activates neutrophils CC type attracts macrophages
What are the mediators of immune cell attack?
○ Cytokine secretion ○ Arachidonic acid metabolites Amplifies the inflammatory response Starts counteraction
Describe chronic granulomatous disease
Phagocyte oxidase defect Cannot kill engulfed bacteria
Describe leukocyte phagocytosis
Phagocytosis ○ Receptors find target -TLR, Inflammasome -Receptors for opsonins - IgG, complement C3 ○ Pseudopods engulf
What are the pattern recognition receptors for inflammation?
TLR: toll-like receptor ○ Recognizes microbial patterns, activates inflammation Inflammasome ○ Recognizes products of dead cells, activates inflammation
What does ulceration look like?
What are other types of emboli?
• Fat embolism • Bone marrow embolism • Amniotic fluid embolism • Air embolism
Describe the mechanisms of inflammatory vascular changes
1. Vessels dilate -Increased caliber=increased flow 2. Endothelial cells contract -Shriveled cells=gaps for cells to escape -Immediate/briefly due to bradykinin, histamine -Sustained due to TNF and IL-1. 3. Also transcytosis, leakage due to injury 4. Increased lymph drainage -Can lead to lymphangitis
What is shock?
• Systemic hypo perfusion of tissues - Caused by diminished cardiac output or decreased effective blood volume - Causes tissue hypoxia, with cellular dysfunction and death
What does C3a do?
C3a ○ Vascular permeability ○ Vasclular dilation (triggers mast cells)
Describe inflammatory cell rolling
Margination and rolling Flow changes push WBC's to periphery Cytokines (histamine, IL-1, TNF) induce selectins on endothelial surface
Section 8
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Diagram second intention wound healing
Compare and contrast regeneration and scarring
Regeneration: ○ Labile tissues -Skin, intestines, liver ○ Remaining cells and stem cells proliferate and replace lost cells Scarring: ○ Permanent tissues -Heart, brain ○ If unable to regenerate, undergoes fibrosis ○ Provides structural stability, not function
Describe the genetic basis of cancer.
• Genetic disorder‐ DNA mutations acquired spontaneously or by environmental insults; minority germline mutations (hereditary) - Genetic changes cause dysregulation of cell growth, survival, senescence, programmed cell death, etc. - Survival advantage of tumor cells, dominate cell populationclonality i.e., progeny of one cell
How does angiogenesis occur in instances of tissue damage and scar formation?
Hypoxia = VEGF from tissues VEGF causes NO production (vasodilation) VEGF causes endothelial migration Vessels form and organize -interact with MMP in ECM
What are the steps of scar formation?
Angiogenesis -Granulation tissue Migration and proliferation of connective tissue cells Maturation/organization
What is the function of the ECM?
Functions as a fluid reservoir Regulates growth and differentiation Scaffolding for repair
What is cancer?
Cell growth dysregulation
What is a tumor? What type are there?
• Tumor=neoplasm - Benign - Malignant
What are the acute phase proteins?
CRP, fibrinogen, serum amyloid May act as opsonins Give clues to inflammatory state (ESR, CRP)
Describe the collagens and elastics of the ECM
They offer structure, strength 1. Collagen: fibrillar: types I, II, III, V -Cross-linked, strong, vitamin C dependent 2. Collagen: non-fibrillar: type IV -Less strong, makes basement membrane
What are the exceptions to the "oma" benign tumor rule?
- Exceptions to -oma meaning benign: Lymphoma, mesothelioma, melanoma, seminoma -All are MALIGNANT!
What are the pathways of macrophage activation?
Classical ○ Microbial products, foreign substances, IFN Causes increase in lysosomes, cytokines If persistent, can become giant cells Alternative ○ Activated by non-IFN cytokines (IL4, IL13) Causes increase in repair-related growth factors
Diagram first intention wound healing
What are the components of the ECM?
1. Fibrous collagens and elastins 2. Proteoglycan gels 3. Adhesive glycoproteins
Describe benign tumors and their nomenclature.
• Innocent • Remain localized • Patient generally survives • Named by suffix -oma added to cell type of origin - e.g., chondroma, lipoma, fibroma, adenoma, papilloma
Describe the non-neutrophil granulocytes of inflammation
Eosinophils ○ Allergy, parasites Mast cells
What is granulomatas inflammation? Give examples.
Distinctive chronic inflammatory pattern Aggregates of macrophages with lymphs ○ Infection: TB, syphilis, Leprosy ○ Autoimmune conditions: Crohn disease ○ Diseases: CGD ○ Sarcoid
What are the subtypes of granulomas?
Caseating ○ Hypoxia and inflammatory injury cause central necrosis ○ Prototype is TB Non caseating ○ Sarcoid, Crohn, exposures
Describe G protein coupled growth factor receptors
Largest family of membrane receptors ○ Chemokines, many others Binding of receptor causes G-protein/cAMP interaction
What are the hallmarks of cancer*???
1. Autonomous growth, unregulated by physiologic cues 2. Lack of response to growth inhibitory signals 3. Evasion of cell death 4. Limitless replicative potential 5. Angiogenesis 6. Invasion of local tissue and spread to distant sites 7. Ability to evade immune system
Describe how Hageman Factor acts on clotting
Activates clotting ○ Factor Xa Increases vascular permeability Forms thrombin - activates and attracts leukocytes - Increases permeability - Activates complement
Describe macrophages and their function
1. Circulate as monocytes At site of injury, reach tissue and transform to macrophages 2. Functions Phagocytosis Secrete cytokines (IL-1, TNF) Antigen presentation/Interaction with T-cells Initiate repair processes
Describe the role of B and T cells in inflammation
T and B cells recruited to sites Same mechanisms as for all leukocytes B cells become plasma cells T cells secrete cytokines, direct process
What are the functions of growth factors?
Stimulate survival and proliferation Prevent apoptosis Promote migration, differentiation
What happens during leukocytosis?
○ Leukemoid reaction, left shift ○ Bacteria: more PMN, Virus: more lymph
Describe how Hageman Factor activates fibrinolysis
Plasminogen-->plasmin Breaks down clot (fibrin products increase vascular permeability) Activates complement
Describe malignant tumors and the basis of their nomenclature.
• Cancer=malignant • Invade and destroy adjacent structures • Spread to distant sites (metastasize) • Nomenclature depends on tissue of origin
What factors affect tissue repair?
Infection (most important cause of delay) Nutrition Steroids Mechanical variables/wound location Poor perfusion Foreign bodies
What are the types of growth factors?
1. Receptors with intrinsic kinase activity 2. G-protein receptors 3. Receptors without intrinsic enzyme activity
Describe growth receptors that lack intrinsic kinase activity
Numerous cytokines Binding of receptor causes change in protein that allows interaction with JAK protein
Diagram Type I and Type II Macrophages
Describe the high control which exists over inflammatory mediators.
1. Kininase 2. Antioxidant scavengers 3. Rapid degradation (lipoxygenase path) 4. Complement regulatory proteins - C1 inhibitor (Inhibit C1q) - DAF (Dissociate C2b4b) - Factor H (Dissociate Alternative Pathway) 5. Macrophage secretion of IL-10
What are the two types of repair?
1. Regeneration 2. Scarring
Describe second intention wound healing
○ Larger wound ○ Larger clot ○ More intense inflammation ○ More wound to fill ○ Wound contraction required ○ Scar strength 10% at 1 week 80% by 3 months
Describe fever induction
○ Pyrogens activate cyclooxygenase ○ Increased prostaglandins elevates temp set point in hypothalamus ○ Shift blood flow centrally to prevent heat loss -Causes increased BP and HR
What are the effects of the acute phase cytokines?
1. Fever 2. Leukocytosis 3. Acute Phase Protein Production
Describe first intention wound healing
First intention ○ Small wounds ○ Regenerative repair ○ 24 hours: neutrophils ○ 48 hours: epithelial growth ○ 3 days: macrophages ○ 5 days: neovascularization ○ Weeks: collagen remodeling
What are the types of chronic inflammation, and what is it?
Persistent inflammation, injury and repair 1. Persistent infection ○ TB, syphilis, viruses 2. Hypersensitivity reactions ○ Autoimmune, environmental allergens 3. Exposure ○ Silica
Describe the proteoglycan gels of the ECM
Resilience, lubrication, reservoir ○ Heparan sulfate, hyaluronic acid
Describe how Hageman factor activates kinins
Activates kinins ○ HMWK-->bradykinin Vasodilation, bronchocontriction, pain
Describe growth Receptors with intrinsic kinase activity
EGF, VEGF Binding of receptor causes phosphorylation and lead to cell proliferation
What is the impact of the ECM on tissue repair?
Regeneration can only take place if the ECM framework is mostly intact. If not, scarring and fibrosis are the path
Describe the adhesive glycoproteins of the ECM
Connects matrix to itself and to cells ○ Fibronectin, laminin, integrins
Describe the steps of connective tissue organization in scar formation
1. Migration and proliferation of fibroblasts PDGF, TGF-B produced by inflammatory cells 2. Deposition of ECM proteins Fibroblasts begin producing growth factors such as TGF-B Promotes collagen synthesis and has anti-inflammatory effects 3. Organization Degradation of collagen by matrix metalloproteinases
What is the nomenclature for mesenchymal neoplasias?
• Mesenchymal: sarcoma (liposarcoma, chondrosarcoma) - From blood or hematopoetic elements: leukemia or lymphoma
What are the components of the ECM?
○ Interstitial Matrix -Gel formed by mesenchymal cells ○ Basement membrane -Junction between epithelium and mesenchyme - Formed by both cells
What cause the acute phase response?
IL-1,IL-6,TNF Cause acute phase response
What are stem cells, and what are their types?
1. Self-renewing, asymmetrically replicating 2. Two major types Embryonic stem cells: ○ Truly pluripotent Adult stem cells ○ More differentiated along a tissue line
What are the hallmarks of chronic inflammation?
Predominantly mononuclear cells (macrophages, lymphocytes) Neutrophils may still be present
What is neoplasia?
• Neoplasia: new growth; autonomous, increase growth regardless of local environment
Section 9
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