Section 1
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Pathological generation of radicals: inflammation
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Mar 1, 2020
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Section 1
(50 cards)
Pathological generation of radicals: inflammation
NADPH oxidase generates the superoxide ions during the oxygen dependent killing by neutrophils
What eliminates free radicals?
Antioxidants (glutathione ans vitamins C, E, A) Enzymes : -superoxide dismutase -glutathione peroxidase -catalase Metal carrier proteins: Cerroplasmin and transferrin
Low ATP disrupts key cellular functions including:
-Na/K pump: causing osmotic swelling -Ca pump: calcium build up in thee cytosol which is dangerous because it is an enzyme activator. -Aerobic Glycolysis: switch to anaerobic leading to increase in lactic acid -->low pH; which denatures proteins and precipitates DNA
Familial Mediterranean Fever
FMF is a AR gain of function defect in PMNs (neutrophils) → episodes of fever and serosal inflammation (can mimic appendicitis, arthritis, or MI) -An attack of acute inflammation with NO infection -High SAA during attacks; deposits as AA in tissues
Pathological generation of free radicals: drugs and chemicals
Liver P450 system metabolized drugs (acetaminophen) generating free radicals
Examples of apoptosis.
-endometrial shedding during menstruation -removal of cells during embryogenesis (space btw fingers) -CD8+ T cell mediated killing of virally infected cells
Coagulative Necrosis
Loss of nucleus but cell shape and organ structures are preserved by coagulation of proteins. Necrotic tissue that remains firm. -Seen in ALL tissues, except the BRAIN -Infarction is usually wedge shaped and pale; unless it is a Red Infarction (blood re-enters dead tissue).
What mediates apoptosis?
caspases that activate proteases and endonucleases Proteases break down cell cytoskeleton Endonucleases break down DNA
What is the hallmark of reversible cellular injury?
Swelling -Loss of microvilli and membrane blabbing -Swelling of RER which leads to decreased protein synthesis
Lysosomal membrane damage results in...
-High levels of hydrolytic enzymes in the cytosol, which are then activated by the high intracellular calcium.
Carbon Tetrachloride CCl4 is an organic solvent used in the dry cleaning industry. How does it cause cellular injury?
It is converted to carbon trichloride by P450 system in hepatocytes. This results in cell injury with RER swelling (impaired protein synthesis) Decreased Apoliproteins lead to fatty change in the liver.
Budd-Chiari syndrome
Hepatomegaly, ascites, and abdominal pain due to hepatic vein thrombosis. Leads to infarction of liver parenchyma. -Polycythemia vera and lupus anticoagulant are common causes.
Metastatic Calcification
High serum calcium or phosphate levels lead to deposition of Ca in normal tissues (i.e. hyperparathyroidism leading to nephrocalcinosis)
Loss of nucleus occurs via
1. Nuclear condensation (pyknosis) 2. Fragmentation (karyorrhexis) 3. Dissolution (karyolysis)
Acute Myeloid Leukemia (AML)
when the 15,17 translocation occurs, it disrupts the vitamin A (retinonic acid) receptor, which causes the cells to remain trapped in the blast phase. Treatment: -All trans-retinoid acid (which can bind to the mutated receptor)
Caseous necrosis
degeneration and death of tissue with a "cottage cheese-like" appearance combination of coagulative and liquefactive necrosis Characteristic of granulomatous inflammation due to TB or fungal infection.
Primary Amyloidosis (AL)
IgG LIGHT Chains deposit plasma cell disorder; associated with plasma cell dyscrasia -Systemic (multiple myeloma)
What is the hallmark of irreversible cellular injury?
Membrane damage
What pathologic hyperplasia does not increase the risk for cancer?
Benign Prostatic Hyperplasia
Methylglobinemia
Iron in heme is oxidized to Fe3+ (which cannot bind O2) Seen with oxidant stress (sulfa and nitrate drugs) and in newborns -Classic finding: Cyanosis and chocolate colored blood Treatment: IV Methylene Blue -Sometimes Vitamin C
Unilateral renal agenesis is an example of ...
aplasia (during embryogenesis)
Causes of Hypoxia
Ischemia, hypoxemia, and decreased O2 carrying capacity of blood
CO poisoning
CO binds to hemoglobin with an affinity 220 times that of 02. Exposures include from smoke from fires, exhaust from cars, and gas heaters. Classic finding: Cherry red skin Early sign of exposure: headache Can lead to coma and death
Myositis Ossificans
A condition in which bone forms in and replaces muscle tissue as a result of trauma (metaplasic process)
Fibrinoid necrosis
Necrotic damage to blood vessel wall -Leaking of proteins (fibrin into the wall) -Bright pink stain -Characteristic of malignant HTN or vasculitis -Can happen in Preeclampsia
Common causes of cellular injury.
1) inflammation 2) nutritional deficiency or excess 3) hypoxia 4) trauma 5) genetic mutations
reperfusion injury
Return of blood to ischemic tissues causes oxygen derived free radicals, further damaging tissues Rising troponins after reperfusion of infarcted myocardial tissue
Ischemia arises with...
-Decreased arterial perfusion -Decreased venous drainage (Budd Chiari Syndrome) -Shock
Amyloidosis
abnoromal protiens that are folded into beta sheets deposit in the ECM-->damaging tissues -Congo red staining and apple green birefringence under polarized light.
Hypoxemia arises with...
1. High altitude - decreased Patm, leading to decreased PAO2 - no change in the Aa gradient 2. Hypoventilation: increased PACO2; decreased PAO2 - no change in the gradient 3. Diffusion defect: PAO2 not able to push as much O2 into the blood due to thicker diffusion barrier - leads to more shunt - INCREASE GRADIENT 4. V/Q mismatch: - circulation problem, oxygenated air does not reach the blood - INCREASE GRADIENT
Liquifactive necrosis
Enzymatic lysis of cell and proteins Characteristic of: -Brain infarction (enzymes from microglial cells) -Pancreatitis (enzymes from pancreas) -Abscess (enzymes from neutrophils)
Streak ovary in Turner syndrome is an example of...
hypoplasia (during embryogenesis)
What tissues undergo only hypertrophy and not hyperplasia?
Permanent tissues -Cardiac muscle -Neurons -Skeletal muscle
decreased oxygen carrying capacity
-Anemia (Normal SaO2) -CO poisoning (Decreased SaO2) -Methylglobinemia (Decreased SaO2)
What metaplasia carries no increased risk for cancer?
Apocrine metaplasia of the breast
Pathological generation of radicals: metals
Fe generates hydroxyl free radicals via the fenton reaction (copper and iron)
Extrinsic receptor-ligand pathway of apoptosis
1) FAS-ligand binds FAS death receptor/CD95 on cell activating caspases (Ex. negative selection of thymocytes) OR 2) TNF binds TNF receptor on target cell >> caspase activation
How does decrease in cell size occur during atrophy?
Via ubiquitin-proteasome degradation of the cytoskeleton and autophagy of cellular components (via hydrolase in lysosomes)
Secondary amyloidosis (AA)
- due to deposition of AA amyloid from SAA (acute-phase reactant) - assoiciated with chronic inflammatory conditions such as rheumatoid arthritis, IBD, spondyloarthropathy, protracted infection, and familial mediterranean fever -Systemic
Gangrenous necrosis
Coagulative necrosis that resembles mummified tissue -Lower limb and GI tract -if superimposed infection happens, liquefactive necrosis occurs and you get wet gangrene.
Dystrophic calcification
Calcium deposits on dead tissues (fatty acids) in the setting of normal serum calcium and phosphate. The necrotic tissue is a nidus for calcification Ex) psmomma bodies
Intrinsic (mitochondrial) pathway of apoptosis
Damage -> inactivation of Bcl2 (normally stabilizes mito membrane) -> mito membrane damage -> leakage of cytC -> caspases activated Initial damage can be caused by cellular injury, DNA damage or decreased hormone stimulation
Pathological generation of radicals: ionizing radiation
Water is hydrolyzed to hydroxyl free radical
Plasma membrane damage results in...
-cytosolic enzymes leaking into the serum (troponin; AST/ALT) -additional calcium entering the cell
Keratomalacia
Due to vitamin A deficiency -night blindness -The thin squamous lining of the conjunctiva undergoes metaplasia into stratified squamous epithelium.
Mitochondrial membrane damage results in...
-loss of ETC (so giving oxygen wouldn't help) -cytochrome c leaking into cytosol (apoptosis)
Free radicals cause cellular injury via
Peroxidation of lips and oxidation of DNA (aging and cancer)
Cytotoxic CD8+ T cell-mediated pathway of apoptosis
Perforin secreted CD8+ T cell to create pores in the target cell. Granzymes enter theses pores and activate caspases -Ex) killing of virus infected cells
What transfers electrons to oxygen in the oxidative phosphorylation pathway?
Cytochrome c oxidase (complex IV)
Fat necrosis occurs with...
Trauma (breast) or pancreatitis damage to peripancreatic fat
Section 2
(50 cards)
How are B cells activated?
1. Antigen binding surface IgM or IgD, causing maturation of IgM or IgD secreting plasma cells. 2. B cell antigen presentation to CD4+ via MHC II. CD40 receptor on B cells bind CD40L on T cell (2nd signal) Helper T cell secretes IL-4 and IL-5
Hageman factor (factor XII)
Inactive proinflammatory protein produced in liver Activated on exposure to sub-endothelial or tissue collagen Activates: -Coagulation and fibrinolytic systems -Complement -Kinin system
CD8+ activation
TCR binds MHC I IL-2 provides second activation signal Kill via 1. Perforin and granzyme release 2. Expression of FasL which binds Fas on target cells, activating apoptosis
Dialysis associated amyloidosis
Beta2-microglobulin deposits in joints. When on dialysis, B2-microglobin is not filtered well and builds up in the blood
Arachidonic Acid Metabolites
Arachidonic Acid released from cell membrane by phospholipase A2 and then acted upon by COX or 5-lipoxygenase creating prostoglandins, prostocyclines, thromboxanes(COX) and leukotrienes(5-lipoxygenase)
What are mast cells activated by?
Tissue trauma C3a and C5a Cross-linking of membranous IgE by antigen
PGI2, PGD2, PGE2 mediate?
mediate vasodilation and increased vascular permeability come from the COX pathway
what is the defining characteristic of a granuloma?
Epithelioid histiocytes
Pain (dolor)
PGE2 and bradykinin Sensitize nerve endings
What does PGE2 mediate?
pain, fever
Leukocyte Adhesion Deficiency
Results from loss of CD18. This leads to inability to synthesize integrins and thus lekocytes can't get out of blood stream. Manifestations: recurrent infections without pus formation, delayed detachment of the umbilical cord and increased circulating neutrophils
What do the Wiebel Palade bodies make?
VonWillebrand factor and P-selectin
What molecules attract and activates neutrophils?
IL-8 LTB4 C5a bacterial products Th-17
Chediak-Higashi syndrome
Autosomal recessive protein trafficking defect Can't "railroad" the phagosome to the lysosome; impaired phagolysosome formation -Increased pyogenic infections - Neutropenia (because you can't pull the two cells apart during division) - Giant granules (because you can't distribute the Golgi products and they fuse) - Defective primary hemostasis (because of abnormal dense granules in platelets) - Albinism (melanocytes can't distribute pigment to keratinocytes) - Peripheral neuropathy
Caseating granuloma
TB (AFB) or fungal infection (GMS stain)
Non-insulin Dependent Diabetes Mellitus Amyloidosis (Type II DM)
Amylin (derived from insulin) deposits in the islets of the pancreas
Non-caseating granulomas
Foreign material, Crohn's disease, Sarcoidosis, Berrylium exposure, cat scratch disease (stellate shaped granulomas in the neck)
Where does vasodilation occur?
arteriole
Opsonins
IgG and C3b
Neutrophil arrival and function: Second step is __________.
Rolling Selectins on vasoendothelium P-selectins: Weibel Palade bodies E-selectins: IL-1 and TNF Selectins bind sialyl Lewis X on leukocytes GlyCAM-1(CD34) on endothelium binds L-selectin
Redness (rubor) and warmth (calor)
due to vasodilation -Mediated by HISTAMINE, PGs, and bradykinin
mediators of acute inflammation
1. TLRs 2. arachidonic acid metabolites 3. mast cells 4. complement 5. Hageman factor (XII)
Clinical finding of Systemic Amyloidosis
systemic deposits → Renal (nephrotic syndrome) Heart (restrictive cardiomyopathy, arrhythmia), Tongue enlargement, malabsorption, and hepatosplenomegaly Diagnosis requires tissue biopsy (abdominal fat or rectum) Damaged organ must be transplanted; amyloid cannot be removed
What characterizes chronic inflammation?
lymphocytes and plasma cells
Neutrophil arrival and function: First step is __________.
Marginalization due to vasodilation in POST CAPILLARY VENULES. cells migrate from center to periphery
CD14
TLR4 co-receptor on macrophages that recognizes LPS (a PAMP)
Alzheimer's disease
A-beta amyloid derived from B-APP deposits in the brain forming amyloid plaques -Gene for APP on chromosome 21; early onset in those with Down syndrome
CD4+ activation
1. TCR binds MHC II on APC 2. CD28 binds B7 on APC Th1: secretes IFN-gamma Th2: secretes IL-4, IL-5, IL-6, IL-13
Toll-like receptors (TLRs)
transmembrane protein of immune cells (macrophages and dendritic) that recognizes pathogens (PAMPs)and activates an immune response directed against those pathogens
Neutrophil arrival and function: Sixth step is __________.
Destruction of Phagocytosis material via oxidative burst in the phagolysosome
Medullary carcinoma of the thyroid
calcitonin (produced by the tumor cells) deposits within the tumor See tumor cells in amyloid background on histology
What does TLR activation result in?
up regulation of NF-KB (transcription factor for immune mediators)
Myeloperoxidase deficiency
Phagocytic cells may show an oxidative burst but be unable to produce hypochlorous acid; as a result, the phagocytes' ability to kill the microbes is compromised. Usually asymptomatic, but a patient is at increased risk for Candidasis
Swelling (tumor)
exudation of fluid (edema) Mediated by histamine and tissue damage
Neutrophil arrival and function: Third step is __________.
Adhesion. Integrin on leukocytes adhere to cell adhesion protein on the endothelium. ICAM-1(CD54) binds CD11/18 integrins(LFA-1, Mac-1) VCAM-1(CD106) binds VLA-4 integrin -Integrin upregulated by C5a and LTB4 -CAPs unregulated by TNF and IL-1
Senile cardiac amyloidosis
NON-MUTATED Serum Transthyretin Deposits in the Heart Asymptomatic >80 years old
What dose selectins bind on Leukocytes?
sialyl Lewis X; cause rolling
LTB4, LTC4, LTD4, LTE4 mediate?
bronchospasm, vasoconstriction and increased vascular permeability (pericyte contracts to put space between cells)
Fever
Pyrogens (LPS on bacteria) stimulate release of TNF and IL-1 which increase COX activity in perivascular cells in the hypothalamus. Increased PGE2 changes the temperature set point.
kinin system
system activated by Hageman factor as part of the inflammatory response; Kinin cleaves high molecular weight kinin (HMWK) to produce bradykinin.
Familial amyloid cardiomyopathy
Mutated serum transthyretin deposits in the heart, leading to restrictive cardiomyopathy; may also see a polyneuropathy.
Histamine causes?
vasodilation of arterioles and increased vascular permeability
Where does increased vascular permeability occur?
post capillary venule
Granuloma formation
1. macrophages process and present the antigen via MHCII to CD4 helper cells 2. Interaction leads macrophages to secrete IL-12, inducing the helper T cells to differentiate into the Th1 subtype 3. Th1 then secrete IFN-y 4. IFN-y causes the macrophages to differentiate into epithelioid histiocytes
Autoimmune Lymphoproliferative Syndrome (ALPS)
Genetic condition that leads to autoimmunity due to peripheral tolerance of T and B cells: defect in Fas (CD95) Cause: -thrombocytopenia, anemia, LAD, lymphoma, heptosplenomegaly
What causes chronic inflammation?
1. persistent infection 2. infection virus, mycobacteria, parasites, fungi 3. autoimmune disease 4. foreign material 5. cancer
What does bradykinin mediate?
pain, increased vascular permeability, vasodilation
Neutrophil arrival and function: Fourth step is __________.
Transmigration and Chemotaxis across post capillary VENULES Travel between epithelial cells/Diapedesis: PECAM-1 (CD31) binds PECAM-1 (CD31)
Neutrophil arrival and function: Fifth step is __________.
Phagocytosis. Enhanced by C3b and IgG Pseudopods extend from leukocyte to for phagosome, which is internalized and fused with the lysosome to produce a phagolysosome.
How do you screen for CGD?
Nitroblue tetrazolium test
Section 3
(37 cards)