CELLULAR RESPONSES TO STRESS AND TOXIC INSULTS: ADAPTATION, INJURY, AND DEATH Flashcards
Four aspects of Pathology
- Etiology (causation – genetic or acquired, or both)
- Pathogenesis (mechanisms of development – often, we know only a part of the story)
- Molecular and morphologic alterations
- Clinical manifestations (end result of genetic, biochemical, and structural changes in cells and tissues are functional abnormalities which lead to clinical manifestations)
List and explain the adaptive responses to physiologic stimuli and injurious stimuli (hypertrophy, hyperplasia, atrophy, and metaplasia)
HYPERTROPHY - Increase in cell size –>increased production of cellular proteins.
HYPERPLASIA - increase in cell #; ); new cells may arise from mature cells or tissue stem cells.
ATROPHY - Decrease in cell size AND #, –> reduced size of a tissue or organ. Due to decreased protein synthesis and increased protein degradation
METAPLASIA - Reprogramming of stem cells present in normal tissue or reprogramming of undifferentiated mesenchymal cells; change in cell differentiation type. If persistent, can lead to cancer. E.g.columnar to squamous in esophagus.
Describe the two pathways of cell death
Apoptosis -
Necrosis - Inflammatory
Describe the gross patterns and microscopic findings of tissue necrosis (coagulative, liquefactive, gangrenous, caseous, fat, and fibrinoid necrosis).
- Due to denaturation of intracellular proteins and enzymatic digestion of lethally injured cells
- Necrotic cells are unable to maintain membrane integrity and their cell contents can leak out
- Increased cytoplasmic eosinophilia in tissue stains
- Myelin figures (dead cell replaced by mass of damaged cell membranes)
- Nuclear changes: karyolysis (nucleus fades away), pyknosis (shrunken nucleus, can also be seen in apoptosis), karyorrhexis (pyknotic nucleus undergoes fragmentation)
List the causes and describe the mechanisms of cell injury.
OXYGEN DEPRIVATION: Hypoxia from 1) reduced blood flow (ischemia), 2) inadequate oxygenation of blood, 3) decreased oxygen-carrying capacity of blood (anemia, carbon monoxide poisoning, severe blood loss).
PHYSICAL AGENTS: Trauma, temp, sudden, pressure, radiation, electric shock.
Can be CHEMICAL, INFECTIOUS, IMMUNILOGIC
GENETIC or NUTRITIONAL
**Mild forms may be reversible/transient; Continuing damage –> irreversible injury –> cell death via necrosis or apoptosis
Depletion of ATP (ischemia decreased O2/nutrients)
**Examples -Mitochondrial damage, Ca++ Influx –> loss of calcium homeostasis, ROS accumulation, Defects in membrane permeability, Damage to DNA and proteins
Define apoptosis, and describe the typical microscopic findings. Which enzyme pathway is typically activated in apoptosis?
Apoptosis is programmed cell death. Both intracellular and extracellular paths exist.
*Cells appear as a round or oval mass of eosinophilic cytoplasm with fragments of condensed/fragmented nuclear chromatin
*Cells appear shrunken
*Generally membranes stay in tact, but cell blebs –> fragmentation.
*Facilitates easier phagocytosis.
Apoptosis can be physiologic or pathologic (Infection –> DNA damage/misfolded proteins)
*Mitochondrial pathway w/ Bax/Cytochrome C –> caspases
*Death receptor (extracellular) - Fas receptor/ligand –> initiator caspases
*Often, apoptosis & necrosis appear together
Define autophagy.
Cell death process in which the cell “eats” itself. Stress –> formation of an autophagic vacuole, which then acquires lysosomes to form an autophagolysosome, and the cellular components are digested by lysosomal enzymes. This process may play a role in degenerative diseases of the nervous system and muscle.
Describe the four mechanisms of intracellular accumulations, and list some examples discussed in class.
ABNORMAL METABOLISM - normal to fatty live
PROTEIN TRANSPORT MISFOLDING - protein accumulation
MISSING ENZYME - lysosomal storage disease –> accumulation of ENDOGENOUS materials, e.g.
–Lipofuscin (brown lipid), results from free radical injury and lipid peroxidation of subcellular membranes - seen in liver and heart as part of aging process, malnutrition, cancer cachexia Melanin (skin).
–Hemosiderin granules/aggregates of ferritin, a protein iron complex. The common bruise is an example of localized hemosiderosis. Systemic hemosiderosis can occur in disorders resulting in systemic overload of iron.
INGESTION of INDIGESTIBLE MATERIALS - accumulation of exogenous materials., e.g.
–tatoo
Describe the two types of pathologic calcification.
DYSTROPHIC CALCIFICATIONS (normal serum calcium level): Basically, dead tissue attracts Ca++
–Occurs in areas of necrosis by deposition of crystalline calcium phosphate; can get heterotopic bone formation
–Often seen in association with atherosclerosis, damaged heart valves, fat necrosis, tuberculosis
METASTATIC CALCIFICATION: disregulation –> Ca++ in normal tissues
–Due to hypercalcemia SECONDARY to disordered calcium metabolism (elevated serum calcium)
–Calcium phosphate is deposited in normal tissues (lung, kidney (nephrocalcinosis), gastric mucosa, systemic arteries, pulmonary veins); can get heterotopic bone formation
In your own words, describe cellular aging.
Telomere shortening + exogenous insults + DNA repair inability –> A progressive decline in cellular function/viability. Accumulated “minor” damage from metabolic and exogenous influences take their toll.
Using examples discussed in class, explain the rationale for measuring biomarkers of cellular necrosis.
Cellular constituents escape into the extracellular space, and then into the blood where they can be measured. Tissue specificity increases level of helpfulness in determining pathology. E.g.
AST (aspartate aminotransferase):
-Present in the liver as well as heart, skeletal muscle, brain, and kidneys. NOT specific for liver.
ALT (alanine aminotransferase): **more specific of liver injury
Alkaline phosphatase (ALP): Consists of various isoenzymes found in bone, liver, placenta, intestine, and leukocytes. **Usually indicates BONE or LIVER disease.
Troponin I - BY ITSELF, elevation of cardiac troponin I typically reflects damage to cardiac muscle. Don’t even need to look at CK-MB or mygolobin.
Coagulative necrosis
Architecture of dead tissue is preserved (infarct)
Liquefactive necrosis
Digestion of the dead tissue–> liquid viscous mass; typically seen in focal bacterial or occasionally fungal infections, the microbes stimulate the accumulation of neutrophils which liberate tissue destroying enzymes–> creamy necrotic material filled with neutrophils (pus) – like from a zit
Gangenous necrosis
Clinical term, not specific pattern, usually applied to necrosis of a limb undergoing coagulative ischemic necrosis
Caseous necrosis
Cheese-like necrosis associated with necrotizing granulomas, seen with tuberculosis and fungal infections
