Pathology - Inflammation Flashcards
1
Q
Apoptosis
- Definition
- Characterized by…
- DNA laddering
A
- Definition
- Programmed cell death
- ATP required.
- Intrinsic or extrinsic pathway
- Both pathways –> 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
Q
Intrinsic pathway
- Involved in…
- Mechanisms
A
- 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- Occurs when a regulating factor is withdrawn from a proliferating cell population (e.g., decreased IL-2 after a completed immunological reaction –> 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.
- Changes in proportions of anti- and proapoptotic factors lead to increased mitochondrial permeability and cytochrome c release.
3
Q
Extrinsic pathway
- 2 pathways
- Mechanisms
A
- 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.
- Fas-FasL interaction is necessary in thymic medullary negative selection.
4
Q
Necrosis
- Definition
- Coagulative
- Liquefactive
- Caseous
- Fatty
- Fibrinoid
- Gangrenous
A
- 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.
- Occurs in CNS due to high fat content.
- 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
Q
Cell injury
- Reversible with O2
- Irreversible
A
- Reversible with O2
- ATP depletion
- Cellular/mitochondrial swelling (decreased ATP –> 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
Q
Ischemia:
Areas susceptible to hypoxia/ischemia and infarction
- Brain
- Heart
- Kidney
- Liver
- Colon
A
- 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
Q
Infarcts
- Reperfusion injury
- Red infarcts
- Pale infarcts
A
- 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
Q
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
A
- 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
Q
Atrophy
- Definition
- Causes include:
A
- 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)
- Occlusion of secretory ducts (e.g., cystic fibrosis)
10
Q
Inflammation
- Characterized by…
- Vascular component
- Cellular component
- Definition
- Acute
- Chronic
A
- 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.
- Definition
11
Q
Chromatolysis
- Definition
- Characterized by:
A
- 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]
- Displacement of the nucleus to the periphery
- Dispersion of Nissl substance throughout cytoplasm
12
Q
Dystrophic calcification
A
- 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
Q
Metastatic calcification
A
- 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
Q
Leukocyte extravasation
- Extravasation predominantly occurs…
- 4 steps
A
- 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
Q
Leukocyte extravasation
- For each:
- Vasculature / stroma –> leukocyte
- Margination and rolling
- Tight-binding
- Diapedesis
- Migration
A
- 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
18
Q
Scar formation
- Tensile strength
- Hypertrophic vs. Keloid scars
- Collagen synthesis
- Collagen arrangement
- Extent
- Recurrence
A
- 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
- Collagen synthesis
21
Q
Granulomatous diseases
- Diseases
- Mechanisms / characteristics
A
- 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.
25
Q
Amyloidosis
- Definition
- AL (primary)
- AA (secondary)
A
- Definition
- Abnormal aggregation of proteins (or their fragments) into β-pleated sheet structures [A] [B] –> 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.
27
Q
Lipofuscin
A
- 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.
