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Flashcards in Pathology - Inflammation Deck (27):
1

Apoptosis

  • Definition
  • Characterized by...
  • DNA laddering

  • Definition
    • Programmed cell death
    • ATP required.
    • Intrinsic or extrinsic pathway
      • Both pathways -->Ž activation of cytosolic caspases that mediate cellular breakdown.
    • No significant inflammation (unlike necrosis).
  • Characterized by...
    • Deeply eosinophilic cytoplasm, cell shrinkage, nuclear shrinkage (pyknosis) and basophilia, membrane blebbing, nuclear fragmentation (karyorrhexis), and formation of apoptotic bodies, which are then phagocytosed.
  • DNA laddering
    • A sensitive indicator of apoptosis
    • During karyorrhexis, endonucleases cleave at internucleosomal regions, yielding 180-bp fragments.
    • Radiation therapy causes apoptosis of tumors and surrounding tissue via free radical formation and dsDNA breakage.
    • Rapidly dividing cells (e.g., skin, GI mucosa) are very susceptible to radiation therapy-induced apoptosis.

2

Intrinsic pathway

  • Involved in...
  • Mechanisms

  • Involved in tissue remodeling in embryogenesis.
    • Occurs when a regulating factor is withdrawn from a proliferating cell population (e.g., decreased IL-2 after a completed immunological reaction -->Ž apoptosis of proliferating effector cells).
    • Also occurs after exposure to injurious stimuli (e.g., radiation, toxins, hypoxia).
  • Mechanisms
    • Changes in proportions of anti- and proapoptotic factors lead to increased mitochondrial permeability and cytochrome c release.
      • BAX and BAK are pro-apoptotic proteins
      • Bcl-2 is anti-apoptotic.
    • Bcl-2 prevents cytochrome c release by binding to and inhibiting Apaf-1.
      • Apaf-1 normally induces the activation of caspases.
      • If Bcl-2 is overexpressed (e.g., follicular lymphoma), then Apaf-1 is overly inhibited, leading to decreased caspase activation and tumorigenesis.

3

Extrinsic pathway

  • 2 pathways
  • Mechanisms

  • 2 pathways:
    • Ligand receptor interactions (FasL binding to Fas [CD95])
    • Immune cell (cytotoxic T-cell release of perforin and granzyme B)
  • Mechanisms
    • Fas-FasL interaction is necessary in thymic medullary negative selection.
      • Mutations in Fas increase numbers of circulating self-reacting lymphocytes due to failure of clonal deletion.
    • After Fas crosslinks with FasL, multiple Fas molecules coalesce, forming a binding site for a death domain–containing adapter protein, FADD.
      • FADD binds inactive caspases, activating them.
    • Defective Fas-FasL interaction is the basis for autoimmune disorders.

4

Necrosis

  • Definition
  • Coagulative
  • Liquefactive
  • Caseous
  • Fatty
  • Fibrinoid
  • Gangrenous

  • Definition
    • Enzymatic degradation and protein denaturation of a cell resulting from exogenous injury.
    • Intracellular components leak
    • Inflammatory process (unlike apoptosis).
  • Coagulative
    • Occurs in tissues supplied by end-arteries (heart, liver, kidney)
    • Increased cytoplasmic binding of acidophilic dye.
    • Proteins denature first, followed by enzymatic degradation.
  • Liquefactive
    • Occurs in CNS due to high fat content.
      • Brain, bacterial abscess
    • In contrast to coagulative necrosis, enzymatic degradation due to the release of lysosomal enzymes occurs first.
  • Caseous
    • TB, systemic fungi, Nocardia.
  • Fatty
    • Enzymatic (pancreatitis [saponification]) and nonenzymatic (e.g., breast trauma)
    • Calcium deposits appear dark blue on staining.
  • Fibrinoid
    • Vasculitides (e.g., Henoch-Schönlein purpura, Churg-Strauss syndrome), malignant hypertension
    • Amorphous and pink on H&E.
  • Gangrenous
    • Dry (ischemic coagulative) and wet (infection)
    • Common in limbs and GI tract.

5

Cell injury

  • Reversible with O2
  • Irreversible

  • Reversible with O2
    • ATP depletion
    • Cellular/mitochondrial swelling (decreased ATPŽ --> decreased activity of Na+/K+ pumps)
    • Nuclear chromatin clumping
    • Decreased glycogen
    • Fatty change
    • Ribosomal/polysomal detachment (decreased protein synthesis)
    • Membrane blebbing
  • Irreversible
    • Nuclear pyknosis, karyorrhexis, karyolysis
    • Plasma membrane damage (degradation of membrane phospholipid)
    • Lysosomal rupture
    • Mitochondrial permeability/vacuolization
      • Phospholipid-containing amorphous densities within mitochondria (swelling alone is reversible)

6

Ischemia:
Areas susceptible to hypoxia/ischemia and infarction

  • Brain
  • Heart
  • Kidney
  • Liver
  • Colon

  • Brain
    • ACA/MCA/PCA boundary areas
    • Watershed areas (border zones) receive dual blood supply from most distal branches of 2 arteries, which protects these areas from single-vessel focal blockage.
      • However, these areas are susceptible to ischemia from systemic hypoperfusion.
    • Hypoxic ischemic encephalopathy (HIE) affects pyramidal cells of hippocampus and Purkinje cells of cerebellum.
  • Heart
    • Subendocardium (LV)
  • Kidney
    • Straight segment of proximal tubule (medulla)
    • Thick ascending limb (medulla)
  • Liver
    • Area around central vein (zone III)
  • Colon
    • Splenic flexure, rectum
    • Watershed areas (border zones) receive dual blood supply from most distal branches of 2 arteries, which protects these areas from single-vessel focal blockage.
      • However, these areas are susceptible to ischemia from systemic hypoperfusion.

7

Infarcts

  • Reperfusion injury
  • Red infarcts
  • Pale infarcts

  • Reperfusion injury
    • Due to damage by free radicals.
  • Red infarcts
    • Red (hemorrhagic) infarcts (left in [A]) occur in loose tissues with multiple blood supplies, such as liver, lungs, and intestine.
    • Red = reperfusion.
  • Pale infarcts
    • Pale infarcts (right in [A]) occur in solid tissues with a single blood supply, such as heart, kidney, and spleen.

8

Shock

  • First sign of shock
  • Shock in the setting of DIC 2° to trauma
  • For each
    • Output failure (high/low)
    • PCWP (increased/decreased)
    • Vasodilation/vasoconstriction
    • Correctability
  • Distributive shock
  • Hypovolemic/cardiogenic

  • First sign of shock
    • Tachycardia.
  • Shock in the setting of DIC 2° to trauma
    • Likely due to sepsis.
  • Distributive shock (includes septic, neurogenic, and anaphylactic shock)
    • High-output failure (decreased TPR, increased CO, increased venous return)
    • Decreased PCWP
    • Vasodilation (warm, dry skin)
    • Failure to increase blood pressure with IV fluids
  • Hypovolemic/cardiogenic shock
    • Low-output failure (increased TPR, decreased CO, decreased venous return)
    • PCWP
      • Increased in cardiogenic
      • Decreased in hypovolemic
    • Vasoconstriction (cold, clammy patient)
    • Blood pressure restored with IV fluids

9

Atrophy

  • Definition
  • Causes include:

  • Definition
    • Reduction in the size and/or number of cells.
  • Causes include:
    • Decreased endogenous hormones (e.g., post-menopausal ovaries)
    • Increased exogenous hormones (e.g., factitious thyrotoxicosis, steroid use)
    • Decreased innervation (e.g., motor neuron damage)
    • Decreased blood flow/nutrients
    • Decreased metabolic demand (e.g., prolonged hospitalization, paralysis)
    • Increased pressure (e.g., nephrolithiasis)
    • ƒƒOcclusion of secretory ducts (e.g., cystic fibrosis)

10

Inflammation

  • Characterized by...
  • Vascular component
  • Cellular component
    • Definition
    • Acute
    • Chronic

  • Characterized by...
    • Rubor (redness), dolor (pain), calor (heat), tumor (swelling), and functio laesa (loss of function).
  • Vascular component 
    • Increased vascular permeability, vasodilation, endothelial injury.
  • Cellular component
    • Definition
      • Neutrophils extravasate from circulation to injured tissue to participate in inflammation through phagocytosis, degranulation, and inflammatory mediator release.
    • Acute
      • Neutrophil, eosinophil, and antibody mediated.
      • Acute inflammation is rapid onset (seconds to minutes), lasts minutes to days.
      • Outcomes include complete resolution, abscess formation, and progression to chronic inflammation.
    • Chronic
      • Mononuclear cell and fibroblast mediated
      • Characterized by persistent destruction and repair.
      • Associated with blood vessel proliferation, fibrosis.
      • Granuloma: nodular collections of epithelioid macrophages and giant cells.
      • Outcomes include scarring and amyloidosis.

11

Chromatolysis

  • Definition
  • Characterized by:

  • Definition
    • Process involving the cell body following axonal injury.
    • Changes reflect increased protein synthesis in effort to repair the damaged axon.
  • Characterized by:
    • Round cellular swelling [A]
    • ƒƒDisplacement of the nucleus to the periphery
    • ƒƒDispersion of Nissl substance throughout cytoplasm

12

Dystrophic calcification

  • Calcium deposition in tissues 2° to necrosis.
  • Tends to be localized (e.g., on heart valves).
  • Seen in TB (lungs and pericardium), liquefactive necrosis of chronic abscesses, fat necrosis, infarcts, thrombi, schistosomiasis, Mönckeberg arteriolosclerosis, congenital CMV + toxoplasmosis, psammoma bodies.
  • Is not directly associated with hypercalcemia
  • Patients are usually normocalcemic.

13

Metastatic calcification

  • Widespread (i.e., diffuse, metastatic) deposition of calcium in normal tissue.
  • 2° to hypercalcemia (e.g., 1° hyperparathyroidism, sarcoidosis, hypervitaminosis D) or high calcium-phosphate product (e.g., chronic renal failure + 2° hyperparathyroidism, long-term dialysis, calciphylaxis, warfarin).
  • Calcium deposits predominantly in interstitial tissues of kidney, lungs, and gastric mucosa (these tissues lose acid quickly; increased pH favors deposition).
  • Patients are usually not normocalcemic.

14

Leukocyte extravasation

  • Extravasation predominantly occurs...
  • 4 steps

  • Extravasation predominantly occurs at postcapillary venules.
  • Leukocytes exit from blood vessels at sites of tissue injury and inflammation in 4 steps:
    • Margination and rolling
    • Tight-binding
    • Diapedesis
    • Migration

15

Leukocyte extravasation

  • For each:
    • Vasculature / stroma --> leukocyte
  • Margination and rolling
  • Tight-binding
  • Diapedesis
  • Migration

  • Margination and rolling
    • E-selectin --> Sialyl-LewisX
    • P-selectin --> Sialyl-LewisX
    • GlyCAM-1, CD34 --> L-selectin
  • Tight-binding
    • ICAM-1 (CD54) --> CD11/18 integrins (LFA-1, Mac-1)
    • VCAM-1 (CD106) --> VLA-4 integrin
  • Diapedesis—leukocyte travels between endothelial cells and exits blood vessel
    • PECAM-1 (CD31) --> PECAM-1 (CD31)
  • Migration—leukocyte travels through interstitium to site of injury or infection guided by chemotactic signals
    • Chemotactic products released in response to bacteria: C5a, IL- 8, LTB4, kallikrein, platelet-activating factor --> Various leukocytes

16

Free radical injury

  • Free radicals
  • Injury initiated via...
  • Pathologies include:

  • Free radicals 
    • Damage cells via membrane lipid peroxidation, protein modification, and DNA breakage.
    • Can be eliminated by enzymes (e.g., catalase, superoxide dismutase, glutathione peroxidase), spontaneous decay, antioxidants (e.g., vitamins A, C, E).
  • Injury initiated via...
    • Radiation exposure (e.g., cancer therapy), metabolism of drugs (phase I), redox reactions, nitric oxide, transition metals, leukocyte oxidative burst.
  • Pathologies include:
    • Retinopathy of prematurity
    • Bronchopulmonary dysplasia
    • Carbon tetrachloride, leading to liver necrosis (fatty change)
    • Acetaminophen overdose (fulminant hepatitis, renal papillary necrosis)
    • Iron overload (hemochromatosis)
    • Reperfusion injury (e.g., superoxide), especially after thrombolytic therapy

17

Inhalation injury

  • Most common pulmonary complication after exposure to fire.
  • Inhalation of products of combustion (e.g., carbon particles, toxic fumes) Ž--> chemical tracheobronchitis, edema, and pneumonia.

18

Scar formation

  • Tensile strength
  • Hypertrophic vs. Keloid scars
    • Collagen synthesis
    • Collagen arrangement
    • Extent
    • Recurrence

  • Tensile strength
    • 70–80% of tensile strength returns at 3 months following wound
    • Little additional tensile strength will be regained.
  • Hypertrophic [A] vs. Keloid scars [B]
    • Collagen synthesis
      • H: Increased
      • K: Really increased
    • Collagen arrangement
      • H: Parallel
      • K: Disorganized
    • Extent
      • H: Confined to borders of original wound
      • K: Extend beyond borders of original wound
    • Recurrence
      • H: Infrequently recur following resection
      • K: Frequently recur following resection

19

Roles of wound healing tissue mediators

  • PDGF
  • FGF
  • EGF
  • TGF-beta
  • Metalloproteinases

  • PDGF
    • Secreted by activated platelets and macrophages
    • Induces vascular remodeling and smooth muscle cell migration
    • Stimulates fibroblast growth for collagen synthesis
  • FGF
    • Stimulates all aspects of angiogenesis
  • EGF
    • Stimulates cell growth via tyrosine kinases (e.g., EGFR, as expressed by ERBB2)
  • TGF-beta
    • Angiogenesis, fibrosis, cell cycle arrest
  • Metalloproteinases
    • Tissue remodeling

20

Phases of wound healing

  • For each
    • Timing
    • Mediators
    • Characteristics
  • Inflammatory
  • Proliferative
  • Remodeling

  • Inflammatory
    • Timing: immediate
    • Mediators: Platelets, neutrophils, macrophages
    • Characteristics: Clot formation, increased vessel permeability and neutrophil migration into tissue; macrophages clear debris 2 days later
  • Proliferative
    • Timing: 2–3 days after wound
    • Mediators: Fibroblasts, myofibroblasts, endothelial cells, keratinocytes, macrophages
    • Characteristics: Deposition of granulation tissue and collagen, angiogenesis, epithelial cell proliferation, dissolution of clot, and wound contraction (mediated by myofibroblasts)
  • Remodeling
    • Timing: 1 week after wound
    • Mediators: Fibroblasts
    • Characteristics: Type III collagen replaced by type I collagen, increased tensile strength of tissue

21

Granulomatous diseases

  • Diseases
  • Mechanisms / characteristics

  • Diseases
    • Bartonella henselae (cat scratch disease)
    • Berylliosis
    • Churg-Strauss syndrome
    • Crohn disease
    • Francisella tularensis
    • Fungal infections (e.g., histoplasmosis, blastomycosis)
    • Granulomatosis with polyangiitis (Wegener)
    • Listeria monocytogenes (granulomatosis infantiseptica)
    • M. leprae (leprosy; Hansen disease)
    • M. tuberculosis
    • Treponema pallidum (tertiary syphilis)
    • Sarcoidosis [A]
    • Schistosomiasis
  • Mechanisms / characteristics
    • Th1 cells secrete γ-interferon, activating macrophages.
    • TNF-α from macrophages induce and maintain granuloma formation. 
    • Anti-TNF drugs can, as a side effect, cause sequestering granulomas to breakdown, leading to disseminated disease.
    • Always test for latent TB before starting anti-TNF therapy.

22

Exudate vs. transudate

  • Thickness
  • Cellularity
  • Protein composition
  • Specific gravity
  • Due to:

  • Thickness
    • Exudate: Thick
    • Transudate: thin
  • Cellularity
    • Exudate: Cellular
    • TransudateT: Hypocellular
  • Protein composition
    • Exudate: Protein-rich
    • Transudate: Protein-poor
  • Specific gravity
    • Exudate: Specific gravity > 1.020
    • Transudate: Specific gravity < 1.012
  • Due to:
    • Exudate
      • Lymphatic obstruction
      • Inflammation/infection
      • Malignancy
    • Transudate:
      • Increased hydrostatic pressure (e.g., CHF)
      • Decreased oncotic pressure (e.g., cirrhosis)
      • Na+ retention

23

Erythrocyte sedimentation rate

  • Definition
  • Increased ESR
  • Decreased ESR

  • Definition
    • Products of inflammation (e.g., fibrinogen) coat RBCs and cause aggregation.
    • When aggregated, RBCs fall at a faster rate within the test tube.
  • Increased ESR
    • Most anemias
    • Infections
    • Inflammation (e.g., temporal arteritis)
    • Cancer (e.g., multiple myeloma)
    • Pregnancy
    • Autoimmune disorders (e.g., SLE)
  • Decreased ESR
    • Sickle cell (altered shape)
    • Polycythemia (increased RBCs “dilute” aggregation factors)
    • CHF (unknown)

24

Iron poisoning

  • Epidemiology
  • Mechanism
  • Symptoms
  • Treatment

  • Epidemiology
    • One of the leading causes of fatality from toxicologic agents in children.
  • Mechanism
    • Cell death due to peroxidation of membrane lipids.
  • Symptoms
    • Acute—nausea, vomiting, gastric bleeding, lethargy.
    • Chronic—metabolic acidosis, scarring leading to GI obstruction.
  • Treatment
    • Chelation (e.g., IV deferoxamine, oral deferasirox) and dialysis.

25

Amyloidosis

  • Definition
  • AL (primary)
  • AA (secondary)

  • Definition
    • Abnormal aggregation of proteins (or their fragments) into β-pleated sheet structures [A] [B] -->Ž damage and apoptosis.
  • AL (primary)
    • Due to deposition of proteins from Ig Light chains.
    • Can occur as a plasma cell disorder or associated with multiple myeloma.
    • Often affects multiple organ systems, including renal (nephrotic syndrome), cardiac (restrictive cardiomyopathy, arrhythmia), hematologic (easy bruising), GI (hepatomegaly), and neurologic (neuropathy).
  • AA (secondary)
    • Seen with chronic conditions, such as rheumatoid arthritis, IBD, spondyloarthropathy, protracted infection.
    • Fibrils composed of serum Amyloid A.
    • Often multisystem like AL amyloidosis.

26

Amyloidosis

  • Dialysis-related
  • Heritable
  • Age-related (senile) systemic
  • Organ-specific

  • Dialysis-related
    • Fibrils composed of β2-microglobulin in patients with ESRD and/or on long-term dialysis.
    • May present as carpal tunnel syndrome.
  • Heritable
    • Heterogeneous group of disorders.
    • Example is ATTR neurologic/cardiac amyloidosis due to transthyretin (TTR or prealbumin) gene mutation.
  • Age-related (senile) systemic
    • Due to deposition of normal (wild-type) TTR in myocardium and other sites.
    • Slower progression of cardiac dysfunction relative to AL amyloidosis.
  • Organ-specific
    • Amyloid deposition localized to a single organ.
    • Most important form is amyloidosis in Alzheimer disease due to deposition of amyloid-β protein cleaved from amyloid precursor protein (APP). 
    • Islet amyloid polypeptide (IAPP) is commonly seen in diabetes mellitus type 2 and is caused by deposition of amylin in pancreatic islets.

27

Lipofuscin

  • A yellow-brown “wear and tear” pigment associated with normal aging.
  • Formed by oxidation and polymerization of autophagocytosed organellar membranes.
  • Autopsy of elderly person will reveal deposits in heart, liver, kidney, eye, and other organs.

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