Patho - PPT2 (slides 1-42) and PPT3 (slides 1-7)
Metaplasia and its mechanism
Definition: metaplasia is when one normal cell type is substituted for another type due to stressors.
Common example discussed: columnar ciliated epithelium being replaced by squamous epithelial cells in response to a chronic irritant.
Mechanism emphasized:
A stressor (e.g., smoking) causes chronic irritation and inflammation.
Stem cells in the tissue get reprogrammed, leading to a change in cell lineage (metaplasia).
Key takeaway: metaplasia arises from stress-induced stem cell reprogramming, not from a single isolated event.
Glutathione as an endogenous antioxidant
Glutathione (GSH) is your endogenous antioxidant found throughout the body.
Function: protects cells from free radicals by donating electrons and becoming oxidized.
Reduced form: (the active form).
Oxidized form: (glutathione disulfide).
Recycling/reduction process: enzymes convert back to , restoring antioxidant capacity.
Important nuance: the reduced form is the active antioxidant, and the cycle restores from .
Clinical note mentioned: the body produces a limited amount of glutathione; deficiency in recycling can sensitize cells to oxidative damage (e.g., G6PD deficiency discussed later).
Specific reaction example (glutathione recycling):
Mention of G6PD deficiency (in spring module): patients with this deficiency have impaired ability to recycle glutathione and may have increased vulnerability to oxidative damage.
Causes of cellular injury
Physical (mechanical) injury: crushing, tearing, cutting; disruption of cellular membrane.
Thermal injury: burns, freezing; temperature extremes denature proteins.
Analogy: denaturation of proteins when cooking an egg; similar processes in cells under heat or cold stress.
Toxic exposures: chemicals causing cellular damage, including DNA damage and pH-induced protein denaturation.
Pathogens: bacteria, viruses, fungi can injure cells.
Nutritional imbalances: both excess and deficiency can injure tissues (no such thing as a truly “too good” thing in excess).
Examples discussed:
Water intoxication: rapid excessive water intake can be fatal.
Vitamin C excess: anecdote of GI bleeding from megadoses of vitamin C (acidic irritation of GI lining).
Iron deficiency anemia as a deficiency example.
Radiation: DNA damage (strand breaks, kinks) and potential neoplasia.
Summary: injuries can arise from multiple pathways; the same tissue can be damaged by different insults.
Consequences of cellular injury
Biochemical changes: cells may attempt to reestablish homeostasis; some changes are difficult to detect visually.
Morphological changes (visible under microscope) usually occur with more severe injury:
Cellular swelling (hydropic changes) due to ion channel disruption, leading to increased Na^+ influx and water entry.
Fatty changes (lipid accumulation) in tissues like the liver when stressed; fatty liver disease.
Liver-specific example:
Fatty liver (steatosis) with triglyceride accumulation; concern increases with ongoing stress.
Progression from steatosis to cirrhosis (scar tissue replaces dead hepatocytes) is not always reversible; cirrhosis is generally irreversible.
Liver regeneration capacity: the liver is highly regenerative; a liver lobe transplant can regenerate to restore function, but cirrhosis limits this.
Fibrosis: scar tissue formation that holds tissue together but does not restore function (stopgap rather than functional replacement).
Relevance to other tissues: heart and brain have limited regenerative capacity; damage here leads to lasting functional deficits.
Cell death: apoptosis vs necrosis
Apoptosis (programmed cell death):
Clean, organized, energy-dependent process that eliminates single cells with minimal disruption to neighboring cells.
No inflammation typically associated with apoptotic death.
Mechanistic hallmarks: activation of caspases; DNA fragmentation; cell shrinkage; formation of apoptotic bodies; phosphatidylserine exposure on the outer membrane as an "eat me" signal for phagocytes.
Necrosis:
Unregulated, messy cell death often due to severe injury or toxin exposure.
Leads to leakage of cell contents, inflammation, and potential damage to surrounding tissue.
Necrosis tends to cause more necrosis if not contained, creating a spreading inflammatory environment.
Visual differences and consequences:
Necrosis: swelling, rupture, release of lysosomal enzymes, inflammation.
Apoptosis: cell fragments into apoptotic bodies; contained and cleared with minimal inflammation.
Signals and triggers: increased intracellular calcium can trigger apoptosis; multiple signals can converge on caspases.
Apoptosis: pathways and features
Two main pathways:
Extrinsic pathway (external signals): death receptors on the cell surface bind ligands (death ligands) leading to caspase activation.
Intrinsic pathway (internal signals): cellular stress (DNA damage, ROS, hypoxia) triggers mitochondrial cytochrome c release and caspase activation; p53 tumor suppressor plays a key role when DNA damage is detected.
Extrinsic pathway details:
Death receptors include various ligands such as inflammatory mediators; binding activates a cascade of caspases (caspases 9, 3, 6, 7, etc.; order not required to memorize).
Activation leads to mitochondrial cytochrome c release and downstream effector caspases.
Intrinsic pathway details:
Triggered by ROS, DNA damage, hypoxia, low ATP, etc.
Mitochondria release cytochrome c, activating caspases.
p53 responds to DNA mutations by halting cell division and promoting repair; if irreparable, it promotes apoptosis via mitochondrial pathway.
Common apoptotic features:
ATP-dependent process; organized dismantling of cellular components.
Phosphatidylserine flips from inner to outer leaflet of the plasma membrane, marking the cell for phagocytosis.
Relevance to disease and therapy:
Apoptosis acts to prevent cancer by eliminating damaged cells.
Cancer cells often evade apoptosis, contributing to unchecked growth.
Brief on practical visualization:
Apoptosis shows membrane changes and apoptotic bodies without inflammation; necrosis shows leakage and inflammation.
Necrosis: types and clinical implications
Liquefactive necrosis: enzymatic digestion leading to liquefied tissue; commonly seen in brain infarcts or abscesses due to active lysosomal enzymes.
Coagulative necrosis: protein denaturation forms a gel-like mass; typically seen in hypoxic injury in solid organs (e.g., heart); tissue architecture is preserved for a time.
Fat necrosis: adipocytes die and fat tissue decomposes; can appear as soapy appearance; clinically observed with certain fat-late injuries or drug effects (e.g., warfarin-associated necrosis).
Caseous necrosis: cheese-like appearance; characteristic of pulmonary tuberculosis.
Infarction: tissue death due to ischemia; heart muscle infarction due to atherosclerotic blockage; scar tissue forms and regeneration is limited.
Gangrene: widespread necrosis with tissue decay; three types:
Dry gangrene: dry, with definite line of demarcation; typically not infection-associated.
Wet gangrene: tissue appears wet and has poor demarcation; often accompanied by infection and foul odor; high risk of sepsis.
Gas gangrene: infection with anaerobic bacteria (e.g., Clostridium perfringens) producing gas; rapidly progressive and life-threatening; often requires amputation and aggressive antibiotics.
Management of necrosis:
Debridement (removal of necrotic tissue) and possible amputation depending on extent.
Antibiotics (usually IV for severe infection) and monitoring for sepsis.
In some cases, maggot therapy uses medical-grade larvae to selectively consume necrotic tissue while sparing healthy tissue.
Sequelae of necrosis:
Local loss of function depending on affected tissue.
Infection spread and sepsis risk.
Release of intracellular enzymes (e.g., CK, LDH) into the bloodstream indicating cell death.
Potential systemic consequences including somatic death in extreme cases.
Containment strategy by the body:
Wall off necrotic tissue with fibrous connective tissue and calcification to limit spread (tuberculosis example with calcifications).
Pathologic calcification and stones
Dystrophic calcification: calcification in necrotic tissue with normal serum calcium levels; body walls off damaged tissue.
Metastatic calcification: calcification in otherwise healthy tissue due to hypercalcemia (e.g., parathyroid hormone excess) irrespective of local tissue necrosis.
Calculi (stones):
Gallstones: can form in the gallbladder; bile acids may compose stones; rapid weight loss or familial predisposition increases risk; stones may block bile ducts.
Kidney stones: typically calcium oxalate; stones can deposit in nephrons and cause severe pain; block filtrate flow.
Aging theories and somatic death
Theories of aging (overview):
Programmed/teleomere theory: telomere shortening limits cell division.
Lipofuscin accumulation: aging pigment accumulating in cells disrupts function.
Accumulated damage theory: lifelong exposure to free radicals causes cumulative cellular damage.
Cross-linking theory: glycation cross-links proteins, impairing function.
Neuroendocrine theory: hormonal changes with age contribute to aging.
Likely a combination of multiple factors, including genetics and lifestyle.
Somatic death:
Brain electrical activity ceases; brain death defined by flat EEG.
Not all cells die at once; some persist longer which allows for organ transplantation windows.
Postmortem changes:
Rigor mortis: muscles stiffen due to ATP depletion, preventing detachment of myosin from actin.
Temperature decrease toward ambient temperature.
Blood pooling and eventual autolysis and putrefaction.
Neoplasia and cancer biology
Neoplasia concept: abnormal, uncontrolled cell proliferation forming a tumor.
Variability in mitosis by cell type:
Some cells divide rapidly (e.g., hair, mucosal epithelial cells, bone marrow).
Some cells do not divide (e.g., neurons, cardiac muscle); regeneration capacity varies (neural/neurogenesis in limited brain regions).
Cancer therapy relevance:
Chemotherapy targets rapidly dividing cells (reason for side effects like alopecia, mucositis, bone marrow suppression).
Cell turnover balance:
In normal tissue, cell production roughly equals cell loss to maintain homeostasis.
Gene regulation of cell division:
Proto-oncogenes: normal genes that promote cell division; mutation converts them to oncogenes, driving excessive division.
Oncogenes: mutated, constitutively active drivers of proliferation.
Growth factor signaling: growth factors bind receptors (often tyrosine kinase receptors) to stimulate division via intracellular cascades.
EGFR (HER1): a common receptor amplified in cancer, increasing sensitivity to growth signals; some receptors become constitutively active, driving growth without ligand.
Autocrine signaling in cancer: tumor cells may secrete growth factors that stimulate their own receptors, promoting self-sustained division.
Tumor suppressor genes (e.g., p53): act as brakes on cell cycle; mutations disable braking, allowing unchecked division.
Contact inhibition: normal cells stop dividing when touching neighbors; cancer cells often lose this signal and continue to proliferate.
Multi-hit model of cancer:
Cancer typically requires multiple mutations in several division-control genes; no single mutation is sufficient for full malignant transformation.
Practical implications and visuals:
A quick explanatory video described the interplay between proto-oncogenes and tumor suppressor genes in regulating division; cancer arises when signals to divide dominate over inhibitory controls.
The lecture emphasizes that cancer development is gradual, often spanning years with cumulative genetic changes.
Practical clinical connections and takeaways
Smoking and metaplasia: smoking induces metaplastic changes via chronic irritation and inflammation.
Alcohol and fatty liver: sustained stress can lead to fatty degeneration and progression to cirrhosis; cirrhosis is irreversible.
Ischemia and infarction: lack of blood flow causes tissue death; heart tissue does not regenerate well, leading to scar formation and functional loss.
Chemo side effects:
Alopecia (hair loss) due to rapid turnover of hair follicle cells.
Mucositis due to rapidly dividing mucosal cells.
Bone marrow suppression leading to infection risk due to reduced white blood cell production.
TB and calcification: caseous necrosis is typical in pulmonary TB and can lead to calcified granulomas in the lung.
Debridement and infection control: removal of necrotic tissue reduces spread and supports healing; maggot therapy is an uncommon but approved method for selective debridement.
Quick recap: key terms to remember
Metaplasia: replacement of one adult cell type by another.
Glutathione redox cycle: active antioxidant system with GSH and GSSG, recycling via specific enzymes.
Apoptosis vs necrosis: programmed, orderly cell death vs uncontrolled, inflammatory cell death.
Extrinsic vs intrinsic apoptosis pathways: external death receptors vs internal mitochondrial signals.
Types of necrosis: liquefactive, coagulative, fat, caseous; infarction and gangrene variants (dry, wet, gas).
Calcification types: dystrophic, metastatic; calculi (kidney/gallstones).
Aging theories: telomere shortening, lipofuscin, cross-linking, oxidative damage, neuroendocrine changes.
Neoplasia and cancer biology: proto-oncogenes vs oncogenes, tumor suppressor genes (p53), growth factor signaling (EGFR), autocrine loops, and multi-hit carcinogenesis.
Clinical implications of rapidly dividing tissues in cancer therapy and the rationale for side effects.