Inflammation Flashcards
Apoptosis
Programmed cell death
ATP required
Intrinsic and extrinsic pathways: activation of cytosolic caspases that mediate cellular breakdown
No significant inflammation (unlike necrosis)
Characterized by sequentially eosinophilic cytoplasm, cell shrinkage, nuclear shrinkage (pyknosis), membrane blabbing, nuclear fragmentation (karyorrhexis), and formation of apoptotic bodies, which are then phagocytosed
DNA laddering is a sensitive indicator of apoptosis with endonucleases cleavage yielding 180 bp fragments
Radiation therapy causes apoptosis of tumors and surrounding tissue via free radical formation and dsDNA breakage
Intrinsic pathway
Involved in tissue remodeling in embroygenesis
Occurs when a regulating factor is withdrawn from a proliferating cell population (IL2 and leukocytes) or after exposure to injurious stimuli (radiation, hypoxia)
Changes in proportions of anti- and pro-apoptotic factors lead to increased mitochondrial permeability and cytochrome release.
BAX and BAK are pro apoptotic proteins while Bcl-2 is anti-apoptotic
Bcl-2 prevents cytochrome c release by binding to inhibiting Apaf1, which normally induces the activation of caspases. Thus Bcl-2 over expression leads to decreased caspase activation and tumor genesis
Extrinsic pathway
2 pathways:
- Ligand receptor interactions (Fas ligand binding to Fas)
After Fas cross links w/ FasL, multiple Fas molecules coalesce, forming a binding site for Fas associated protein with death domain (FADD), which intern binds inactive caspases and activate them
Necessary in thymic medullary negative selection. Mutations in Fas increase the numbers of circulating self-reacting lymphocytes due to failure of negative selection
- Immune cell (Tc release of perforin and granzyme B)
Necrosis
Enzymatic degradation and protein denaturation of a cell resulting from exogenous injury
Characterized by intracellular component leak and inflammation
Coagulative necrosis
Occurs in tissues supplied by end arteries (liver, kidney)
Proteins denature first followed by enzymatic degradation
Liquefactive necrosis
Occurs in CNS due to high fat content (brain, brain bacterial abscess)
Enzymatic degradation occurs first due to release of lysosomal enzymes
Caseous necrosis
Occurs in TB and systemic fungi infections
Fatty necrosis
Occurs either enzymatic (pancreatitis) or nonenzymatic (breast trauma), results in calcium deposits that appear dark blue on staining
Fibrinoid necrosis
Occurs in vasculides (HSP, Churg-Strauss), stains amorphous and pink on H&E stain
Gangrenous
Dry (ischemic coagulative) and wet (infection), common in limbs and GI tract
Reversible cell injury
Reverse w/ O2
Causes:
ATP depletion
Cellular/mitochondrial swelling due to decreased activity of Na/K pump w ATP depletion
Ribosomal detachment due to decreased protein synthesis
Nuclear chromatin clumping
Irreversible cell injury
Causes:
Nuclear pyknosis, karyorrhexis, karyolysis
Plasma membrane damage
Lysosomal rupture
Mitochondrial permeability
Susceptible ares of ischemia
Brain: ACA/MCA/PCA boundary areas (watershed)
Heart: subendocardium
Kidney: straight segment of proximal tubule
Liver: area around central vein
Colon: splenic flexure, rectum (watershed)
Watershed areas
Regions that receive dual blood supply from most distal branches of 2 large arteries, which protect these areas from single-vessel focal blockage but make them vulnerable to ischemia during systemic hypoprofusion
Red infarct
Occur in tissues w/ multiple blood supplies such as liver, lungs, and intestine
Often 2ndary to repression injury, which is due to damage by free radicals
Pale infarct
Occur in solid tissue with a single blood supple, such as heart, kidney, and spleen
Atrophy
Reduction in size and/or number of cells
Causes:
Decreased endogenous hormones (post menopausal ovaries)
Increased exogenous hormones (steroids)
Decreased innervation (motor neuron damage)
Decreased blood flow/nutrients
Decreased metabolic demand (prolonged hospitalization)
Occlusion of secretory ducts (CF)
Inflammation
Characterized by redness, pain, heat, swelling, and loss of function
Vascular component: increased vascular permeability, vasodilation, endothelial injury
Cellular component: neutrophils extravasate from circulation to injured tissue to participate in inflammation through phagocytosis, degranulation, and inflammatory mediator release
Acute inflammation
Mediated by neutrophil, eosinophil, and antibody
Rapid onset, lasting minutes to days
Outcomes include complete resolution, abscess formation, or progression to chronic inflammation
Chronic inflammation
Mediated by mononuclear cell and fibroblasts
Persistant destruction and repair
Associated w/ blood vessel proliferation and fibrosis
Outcomes include scarring and amyloidosis
Chromatolysis
Following axonal injury in neurons
Round cellular swelling
Displacement of nucleus to the periphery
Dispersion of Nissl bodies (RER) throughout cytoplasm
Changes reflect increase protein synthesis in effort to repair the damaged axon
Dystrophic calcification
Calcium deposition in tissues 2ndary to necrosis
Tends to be localized
Seen in TB (lungs and pericardium), liquefactive necrosis of chronic abscesses, fat necrosis, infarcts, thrombi
Is not directly associated w/ hypercalcemia
Metastatic calcification
Widespread deposition of calcium in normal tissue 2ndary to hypercalcemia (primary hyperparathyroidism) or high calcium-phosphate product (chronic renal failure)
Calcium deposits predominantly in interstitial tissue of kidney, lungs, and gastric mucosa (these tissue lose acid quickly and high pH favors calcium deposition)
Leukocyte extravasation
Primary occurs at post capillary venues
- Margination and rolling: mediated by selectin and Sialyl-Lewis (carbohydrate involved in cell-cell recognition)
- Tight binding: mediated by ICAM-1 and LEA-1 (integrin)
- Diapedesis: leukocyte travels between endothelial cells and exits blood vessel, mediated by PECAM-1
- Migration: leukocyte travels through interstitial to site of injury or infection guided by chemotactic agents such as IL8 and LTB4o
Free radical injury
Free radicals damage cells via membrane lipid per oxidation, protein modification, and DNA breakage
Initiated via radiation exposure, metabolism of drugs (phase I), redox reaction, leukocyte oxidative burst
Free radicals can be removed by enzymes (catalase, glutathione peroxidase), spontaneous decay, or antioxidants (vitamin A, C, E)
Pathologies of free radical injury: Retinopathy of prematurity Bronchopulmonary dysplasia Acetaminophen overdose Iron overload Reperfusion injury
Inhalation injury
Most common pulmonary complications after exposure to fire
Inhalation of products of combustion leads to chemical tracheobronchitis, edema, and pneumonia
Hypertrophic scars
Increased collagen synthesis
Parallel collagen alignment
Scarring confined to borders of original wound
Infrequently recur following resection
Keloid scars
Highly elevated collagen synthesis
Disorganized collagen alignment
Scarring extends beyond borders of original wound
Frequently recur following resection
More common in AA
PDGF (platelet derived)
Secreted by activated platelets and macrophages
Induces vascular remodeling and smooth muscle cell migration
Stimulates fibroblast growth for collagen synthesis
FGF (fibroblast)
Stimulates all aspects angiogenesis
EGF (epidermal)
Stimulates cell growth via tyrosine kinases
TGFbeta
Angiogenesis, fibrosis, cell cycle arrest
Metalloproteinases
Tissue remodeling
Inflammatory phase of wound healing
Immediate
Mediated by platelets, neutrophils, and macrophages
Clot formation, increased vessel permeability and neutrophil migration into tissue
Macrophages clear debris 2 days later
Proliferative phase of wound healing
2-3 days after wound
Mediated by fibroblasts, myofibroblasts, endothelial cells, macrophages
Deposition of granulation tissue and collage, angiogenesis, epithelial cell proliferation, dissolution of clot, and wound contraction
Remodeling phase of wound healing
1 week after wound
Mediated by fibroblasts
Type III collagen replaced by type 1 collagen
Increases tensile strength of tissue (70-80% tensile strength returns at 3 months, little after)
Granulomatous diseases
Th1 cells secrete IFNgamma, activating macrophages
TNFalpha 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
Examples: Churg-Strauss, TB, sarcoidosis, Wegner, fungal infections
Exudate
Thick, cellular, protein rich, specific gravity > 1.020
2ndary to lymphatic obstruction, inflammation/infection, malignancy
Transudate
Thin, hypocellular, protein poor, specific gravity < 1.020
2ndary to increased hydrostatic pressure (CHF), decreased oncotic pressure (cirrhosis), or sodium retention
Erythrocyte sedimentation rate
Products of inflammation coat RBC and cause aggregation, causing RBCs to fall at faster rate
Increased ESR: anemias, infection, inflammation, cancer, autoimmune disorders
Decreased ESR: sickle cell (altered shape), polycythemia (RBCS “dilute” aggregation), CHF
Iron poisoning
Leading cause of fatality from toxicologic agents in children
Causes cell death 2ndary to per oxidation of membrane lipids
Acute: nausea, vomiting, gastric bleeding, lethargy
Chronic: metabolic acidosis, scarring leading to GI obstruction
Treatment: chelation (deferasirox) and dialysis
Amyloidosis
Abnormal aggregation of proteins into beta-pleated sheet structures leading to cellular damage and apoptosis
Stain w/ congo-red to show deposits
AL (primary): due to deposition of light chains, associated with plasma cell disorders, affecting multiple organs (nephrotic syndrome, restrictive cardiomyopathy, arrhythmia, neuropathy)
AA (secondary): due to fibrils composed of serum Amyloid A, seen w/ chronic conditions (RA, IBD, protracted infection)
Dialysis related: due to fibrils composed of beta2-microglobulin in patients w/ ESRD, present w/ carpal tunnel syndrome
Heritable: neurologic/cardiac amyloidosis due to transthyretin gene mutation
Age-related: deposition of transthyretin in myocardium and other sites
Organ specific: Amyloid deposition localized to one organ, ie Alzheimer disease due to amyloid-beta protein cleaved from amyloid precursor protein
Lipofuscin
Yellow-brown “wear and tear” pigments shown w/ H&E stain associated w/ normal aging
Formed by oxidation and polymerization of autophagocytosed organellar membranes
Deposits in elderly heart, liver, kidney, eye
