Pathoma Ch 1-2 Flashcards

1
Q

Hyperplasia vs Hypertrophy with mechanisms

3 tissues that can only undergo hypertrophy

A

Hyperplasia: increase in cell number from STEM cells

Hypertrophy: increase in cell size from gene activation a, protein synthesis, and production of organelles.

  1. cardiac cells
  2. skeletal muscle cells
  3. nerves
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2
Q

Two ways that atrophy can occur

A
  1. Decrease in cell number via apoptosis
  2. Decrease in cell size via:
    a. Ubiquitin-proteosome degredation (intermediate filaments are tagged and destroyed by proteosomes)
    b. autophagy (vacuoles fuse with lysosomes whose hydrolytic enzymes breakdown cellular components)
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3
Q

Metaplasia (what is it, mechanism, example)

A
  • change in stress leading to change in cell type
  • occurs via reprogramming of stem cells, which then produce the new cell type
  • is REVERSIBLE

Metaplasia –> Dysplasia –> Cancer if persistent stress

ex: Barrett esophagus, Vitamin A deficiency (columnar cells of conjunctiva –> keratinizing squamous cells), Myositis Ossificans

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4
Q

Dysplasia

Aplasia

Hypoplasia

A

Dysplasia: disordered cell growth. Proliferation of precancerous cells. Ex: cervical intraepithelial neoplasia (CIN). Arise from longstanding hyperplasia or metaplasia

Aplasia: failure of cell production during embryogenesis (unilateral renal agensis)

Hypoplasia: decrease in cell production during embryogenesis (steak ovary in Turner Syndrome)

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5
Q

Ischemia and 3 types of it

A

decreased blood flow through an organ

  1. Decrease arterial profusion (atherosclerosis)
  2. Decrease venous drainage (budd chiari syndrome –> caused by polycythemia vera, which is increased RBC due to overproduction)
  3. Shock: generalized hypotension resulting in poor tissue perfusion
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6
Q

Hypoxemia, what is it and what are 4 examples

A

low partial pressure of oxygen in the blood (PaO2<60)

  1. High altitude (decreased PAO2)
  2. Hypoventilation (increased PACO2 –> decreased PA02)
  3. Diffusion defect (thicker diffusion barrier like in interstitial pulmonary fibrosis)
  4. V/Q mismatch: blood bypass oxygenated lung (right to left shunt) or oxygenated air cannot reach blood (atelectasis)
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7
Q

Methemoglobinemia

A

Fe2+ carries oxygen.

Fe2+ –> Fe3+ in methemoglobinemia, cannot bind oxygen. PaO2 normal, SaO2 decreased

-seen with odidant stress (sulfa and nitrate drugs)

Presentation: cyanosis with chocolate colored blood

Tx: Methylene blue (converts Fe3+ –> Fe2+)

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8
Q

3 problems associated with low ATP

A
  1. Na/K pump cannot run, resulting in increased Na in cell leading to increased H20 in cell.
  2. Ca pump not work, resulting in increased Ca in cytosol
  3. Aerobic glycolysis –> anaerobic glycolysis –> production of lactic acid
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9
Q

Early vs late stage cellular injury from hypoxia

A

Early: hallmark is Cellular Swelling (reverisble)

results in loss of microvilli and blebbing, swelling of RER leading to loss of protein synthesis

Late: hallmark is membrane damage (irreversible)

  1. plasma membrane damage (troponin leak out)
  2. Mitochondrial membrane damage (cytochrome C leak out)
  3. Lysosome membrane damage (hydrolytic enzymes leak out, activated by Ca2+)
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10
Q

6 types of necrosis with mechanisms and examples of each

A
  1. Coagulative Necrosis: remains FIRM. ischemic infarction of any organ EXCEPT BRAIN. wedged shaped. Seen 1-3 days post MI
  2. Liquefactive Nectrosis: Brain (via microglial cells), Abscess (enzymes of neutrophils), Pancreatitis (enzymes of pancreas autodigest)
  3. Gangrenous necrosis: coagulative necrosis that resembles mummified tissue. ischemia of lower limb and GI
  4. Caseous necrosis: soft and friable, combo of liquefactive and coagulative. Seen in TB/Fungal where granulomas form
  5. Fat necrosis: chalky white due to Ca deposition. Trauma of fat –> saponification
  6. Fibrinoid Necrosis: damage to blood vessel wall. Bright pink staining (fibrin). Malignant hypertension and vasculitis
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11
Q

Activation of capsases (which are responsible for mediating apoptosis via activation of proteases and endonucleases)

3 ways

A
  1. Intrinsic mitochondrial pathway: inactivation of Bcl2 allows cytochrome C to leak from mito matrix
  2. Extrinsic receptor ligand: FAS binds FAS death receptor (CD95) to activate capsase
  3. Cytotoxic CD8+: Perforins create pores, Granzymes enter pores and activate capsaes
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12
Q

3 types of free radicals and how do they cause cellular injury (2)

A
  1. O2- (superoxide)
  2. H2O2 (hydrogen peroxide)
  3. OH (hydroxyl radical) **the most damaging**

cause injury via

  1. peroxidation of lipids
  2. oxidation of DNA and proteins
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13
Q

Elimination of free radicals via 3 mechanisms in body

A
  1. antioxidants (glutathione, Vitamin A,C,E)
  2. Enzymes:
    - superoxide dismutase for O2 –> H2O2
    - glutathione peroxidase for OH
    - catalase (in peroxisomes) for H2O2
  3. Metal carrier proteins (transferrin and ceruplasmin)
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14
Q

Carbon tetrachloride (CCl4)

A

solvent used in dry cleaning industry

-converted to CCl3, results in cell injury with swelling of RER and results in decreased apolipoprotein –> fatty change in liver

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15
Q
A
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16
Q

Mediators that attract nutrophils

A
  1. leukotriene b4 (LTB4 is a neutrophil chemotactic agent. Neutrophils arrive B4 others)
  2. IL-8
  3. C5A
  4. Bacterial products
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17
Q

2 reasons that you get acute inflammation

(neutrophils + edema)

A
  1. In response to infection (to eliminate pathogen)
  2. Tissue necrosis (to clear necrotic debris)
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18
Q

5 mediators of acute inflammation (overview)

A
  1. Toll-like receptors
  2. Arachidonic Acid metabolites
  3. Mast Cells
  4. Complement
  5. Hageman Factor (Factor XII)
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19
Q

Toll-like receptors (TLR)

A

Present on macrophages and dendritic cells (innate)

CD14 (co-receptor for TLR-4) on macrophages recognizes lipopolysaccharide (PAMP) on outter membrane Gram - bacteria

-Results in upregulation of NFKB

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20
Q

Arachadoinic Acid pathway overview

A

AA is released from the phospholipid cell membane by phospholipase A2 amd then acted upon by cyclooxygenase or 5-lipoxygenase

cyclooxygenase –> prostaglandins (mediate vasodilation, increased vascular permability) PGE2 mediate pain and fever

5-lipoxygenase –> leukotriene (mediate vasoconstriction, bronchospasm, increased vascular permeability via pericytes)

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21
Q

Mast Cells activated by 3 things

A
  1. Tissue trauma
  2. Complement C3a and C5a
  3. Cross-linking of cell-surface IgE by antigen
    - release pre-formed histamine granules, which mediate vasodilation of arterioles and increase vascular permeability
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22
Q

Complement System 3 pathways of activation

A

System of hepatically synthesized plasma proteins that play a role in innate immunity and inflammation. Membrane attack complex (MAC) defends against gram-negative bacteria.

1. Classical: C1 binds IgG and IgM (GM makes classic cars)

2. Alternative: microbial products directly activate

3. Mannose-binding lectin (MBL): MBL binds mannose on miccroorganisms

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23
Q

Complement pathway (general overview)

A

All pathways result in production of C3 convertase, which in turn produces C5 convertase.

C5b complexes with C6-C9 to form the MAC

C3b—opsonization.

C3a, C4a, C5a—anaphylaxis.

C5a—neutrophil chemotaxis.

24
Q

Hageman factor (Factor XII)

A

Inactive pro-inflammatory protein produced in liver

Activated in response to exposure to subendothelial or tissue collagen

Activates clotting cascade when exposed to subendothlial collagen

25
Q

Cardinal Signals of Inflammation (5)

A
  1. Rubor (redness): due to vasodilation. Mediated by histamine, bradykinin and prostaglandins
  2. Calor (warmth): due to vasodilation. Mediated by histamine, bradykinin and prostaglandins
  3. Tumor (swelling): due to leakage of fluid from postcapillary venules. Mediated histamine/tissue damage
  4. Dolor (pain): sensitize nerve endings. Mediated bradykinin, PGE2
  5. (Fever): macrophages release IL-1 and TNF –> increase cyclooxygenase activity in hypothalamus
26
Q

Leukocyte Extravasation steps (first 5)

A
  1. Margination: vasodilation, cells move to periphery
  2. Rolling: selectin “speed bumps” P-selectin from Weibel-Palade bodies mediated by histamine. E-selectin by TNF and IL-1. Bind Sialyl Lewis X on leukocytes
  3. Adhesion via CAM on endothelium and integrin on leukocyte (via C5a and LTB4). Results firm adhesion
  4. Transmigration and Chemotaxis: neutrophil attracted by Il-8, C5a, LTB4 and bacterial products
  5. Phagocytosis: enhanced by opsonins (IgG and C3b)
27
Q

Leukocyte Adhesion Deficiency

A

Defect in LFA-1 integrin (CD18) protein on phagocytes; impaired migration and chemotaxis; autosomal recessive.

  • delayed separation of umbilical cord (> 30 days)
  • absent pus formation, impaired wound healing
28
Q

Chédiak-Higashi syndrome

A

Defect in lysosomal traficking regulator gene (LYST).

CheCK that LYST

Microtubule dysfunction in phagosome-lysosome fusion; autosomal recessive.

Recurrent pyogenic infections by staphylococci and streptococci, partial albinism, peripheral neuropath

see pancytopenia

29
Q
A
30
Q

Leukocyte extravasation (step 6-7)

A
  1. Destruction of phagocytosed material: O2 dependent is most effective mechanism
  2. Generation of HOCl (bleech) via oxidative burst in phagolysosomes
31
Q

Chronic Granulomatous Disease

A
  • Deficiency in NADPH oxidase (X-linked most common, can be AR)
  • Leads to recurrent infection and granuloma formation with catalase-positive organisms

Need PLACESS: Nocardia (think fast gun), Pseudomonas, Listeria, Aspergillus, Candida, E. coli, S. aureus, Serratia.

Nitroblue tetrazolium dye reduction test is ⊝. (turns blue of NADPH oxidase can convert O2 –> O2-

32
Q

Myeloperoxidase Deficiency (MPO)

A
  • results in defective conversion of H2O2 –> HOCl (bleech)
  • Usually asymptomatic, can have increased risk for Candida infections
  • Nitroblue Tetrazolium test is normal (+, blue) because respiratory burst is intact (upstream)
33
Q

Macrophages in acute inflammation (and next possible 4 steps)

A
  • Predominate after neutrophils and peak 2-3 days
  • Derived from monocytes in blood

Manage next steps

  1. Resolution and healing via antiinflammatory cytokines: IL-10 and TBF-B (TGF-β and IL-10 both attenuate the immune response.)
  2. Continued acute inflammation via secretion IL-8 to recruit more neutrophils (Clean up on aisle 8.” Neutrophils are recruited by IL-8 to clear infections)
  3. Abscess formation: inflam surrounded by fibrosis
  4. Chronic inflammation via CD4+ T cells
34
Q

T cells express what for antigen surveilence

A

TCR complex and CD3

-overall, T-cells express, CD3, TCR, CD28 (binds B7 on APC)

35
Q

CD4 and CD8 with MHC classes

A

CD4+ recognize antigens presented on MHC Class II

CD8+ recognize antigens presented on MHC Class I

Remember:

4x2=8

8x1=8

BOTH need to equal 8

36
Q

Activation of CD4 helper T cells via 2 things and then what does the activated CD4 helpter T cell do

A
  1. Extracellular antigen is phagocytosed, processed and expressed via MHC CLass II (expressed on APC)
  2. B7 on APC binds CD28 on CD4 T cells proving 2nd activation signal (need antigen/MHC complex + additional 2nd signal)
    - Activated CD4 helper T cell secrete cytokines that “help” Th1 and Th2
37
Q

Th1 and Th2 helper T cells (via CD4+ activation)

A

Th1: generate IL-2, secrete INF-y (activates macrophages, promotes B-cell class switching from IgM –> IgG)

Th2: secrete IL-4 (facilitate B-cell switching IgG –> IgE), and IL-5 (eosinophil chemotaxis and activation, and class switching to IgA) and IL-10, IL-13

38
Q

CD8 T cell activation and action

A

Intracellular antigen is processed and presented on MHC Class I (expressed by all nucleated cells and platelets)

-IL-2 from Th1 provides 2nd activation signal

Killing occurs via secretion of perforin and granzyme which activate capsases and cause apoptosis. Also expres FasL which binds Fas to activate apoptosis (2 of the ways apoptosis occurs, the third is via BCL2 and cytochrome C)

39
Q

Immature B cell and activation

A

-produced in bone marrow, express IgM and IgD

Activation occurs via:

  1. Antigen binds surface IgM or IgD, mature to plasma cell
  2. B cell antigen presentation to CD4+ helper T cell via MHC Class II. CD40 receptor provides 2nd activation signal.
  3. Helper T cell secrete IL-4 and IL-5 that mediates isotype switching –> IgE, IgA, IgG
40
Q

what is characteristic feature of a granuloma

A

Granuloma: nodular collections of epithelioid macrophages and giant cells. Outcomes include scarring and amyloidosis.

41
Q

2 types of granulomatous infections and examples of each

A
  1. noncaseating granulomas: lack central nectrosi. ex: reaction to foreign material, sarcoidosis, beryllium exposure, Crohn disease, cat scratch
  2. Caseating granulomatous: central necrosis. ex: TB and fungal infections
42
Q

DiGeorge syndrome

A

22q11 deletion; failure
to develop 3rd and 4th pharyngeal pouches absent thymus and parathyroids.

-Tetany (hypocalcemia), recurrent viral/fungal infections (T-cell deficiency), conotruncal abnormalities (e.g., tetralogy of Fallot, truncus arteriosus)

43
Q
A
44
Q

Systemic Lupus Erythematosus

A

type 3 hypersensitivity reaction due to poorly cleared apoptotic debris (often from UV damage to DNA)

  • *RASH OR PAIN:**
  • *R**ash (malar or discoid)
  • *A**rthritis
  • *S**oft tissues/serositis
  • *H**ematologic disorders (e.g., cytopenias) Oral/nasopharyngeal ulcers
  • *R**enal disease, Raynaud phenomenon Photosensitivity, Positive VDRL/RPR Antinuclear antibodies
  • *I**mmunosuppressants
  • *N**eurologic disorders (e.g. seizures, psychosis)
45
Q

Antibodies found and tested for in SLE

A

Antinuclear antibody (sensitive but not specific)

Anti-dsDNA or Anti-Smith AB (highly specific, poor prognosis, kidney involvement)

Antiphospholipid antibody (1/3 of pts) can be own disorder**

_____________________________________

Antihistone antibody (drug induced lupus)

46
Q

Drug induced Lupus

A
  • Procainamide
  • Hydralazine
  • Isoniazid

Antihistone antibody is characteristic

ANA is positive by definition

Remove drug and sx resolve

47
Q

Treatment of Lupus

A

Avoid sunlight (first line)

NSAIDs

steroids (for flares)

immunosuppressants (for refractory)

hydroxychloroquine.

48
Q

two types of Scleroderma and definining characteristics

A
  1. Limited type: CREST, anticentromere antibodies
  2. Diffuse Type: more severe, antibodies to topoisomerase I (anti-SCL-70). Widespread systemic infection
49
Q

Mixed connective tissue disease

(think mixed rocky mountain national park)

A

Anti-U1 RNP (ribonucleoprotein)

Autoimmune mediated tissue damage with mixed features of SLE, sclerosis, polymyositis

50
Q

three types of tissue based on regenerative capacity

A
  1. Labile tissue (stem cells are continuously regenerating: GI, SKin, bone marrow)
  2. Stable tissue (usually in G0 phase but can reenter cell cycle: liver)
  3. Permanent (lacks regenerative potential: Neurons, Myocardium, Skeletal muscle)
51
Q

Initial phase of wound repair

A

Granulation tissue formation

consists of:

  1. fibroblasts (deposit type III collagen)
  2. capillaries (provide nutrients)
  3. myelofibroblasts (contract wound)
52
Q

Scar formation and collagen transformation

A

Type III collagen –> Type 1 collagen via collagenase and requires zinc as a cofactor

53
Q

hypertrophic vs keloid scar

A
54
Q

Mediators of tissue regeneration and repair (5)

A
  1. TGF-alpha
  2. TGF-beta: secreted by macrophages when inflam complete
  3. Patelet-derived growth factor: endothelium, smooth muscle, fibroblasts
  4. Fibroblast growth factor: angiogenesis, skeletal development
  5. Vascular endothelial growth factor (VEGF): angiogenesis
55
Q

delayed wound healing occurs in

A
  1. Vitamin C deficiency (hydroxylation of proline and lysine)
  2. Zinc deficiency (cofactor for collagenase)
  3. Copper (cofactor for lysyl oxidase)
    - also foreign body, infection ischemia, diabetes, malnutrition
56
Q

Hyper IgE syndrome (Job syndrome)

A

Deficiency of Th17 cells due to STAT3 mutation impaired recruitment of neutrophils to sites of infection.

FATED: coarse Facies, cold (nonin amed) staphylococcal Abscesses, retained primary Teeth, IgE, Dermatologic problems (eczema).