Module 27: Cell Injury and Death Flashcards
Define the characteristic terms of disease.
Aetiology: cause of disease
Pathogenesis: mechanism causing disease
Pathology: molecular or morphological changes to cells/tissues
Clinical Manifestations: signs/symptoms
Complications: secondary, systemic, or remote consequences of disease
Prognosis: anticipated course of the disease
Epidemiology: incidence, prevalence, and distribution
Describe hypoxia (a type of cell injury).
Hypoxia:
- oxygen deficiency
- interferes with aerobic oxidative respiration
- arise from
- pneumonia
- blood loss anaemia
- CO poisoning
- Ischemia: loss of blood tissue supply
Differ between pathological and physiological adaption.
- Physiological adaptation: cellular response to normal stimulation
- Pathological adaptation: cellular response to stimulation secondary to underlying disease/ to avoid injury
Mention the types of adaptation in response to injury.
- Hypertrophy: increase in both cell size and organ size
- Hyperplasia: increase in both cell number and organ size
- Atrophy: decrease in cell size/number and organ size
- Metaplasia: change in cell type
Reversible if stimulus removed
Describe hypertrophy mechanism. Provide an example.
Occurs due to increases workload (physiological and pathological). No new cells are created only larger cells (increases amounts of structural protein and organelles). Occurs in non-dividing cells (myocytes, skeletal muscle).
Hypertension ➔ increased workload ➔ enlarged heart ➔ improved performance ➔ degeneration
Describe the mechanism of hyperplasia. Give examples.
Leads to an increase in the number of cells in an organ or tissue (not size). Occurs only in cell populations capable of dividing. Caused by growth factor-driven proliferation of the mature cell.
Physiological: Hormonal (puberty), Compensatory (liver resection), Increased demand (Low atmospheric O2 leads to increased erythrocytes)
Pathological: Hormonal (endometriosis), Viral infection (skin warts), Chronic stress (callous)
Describe the mechanism of atrophy. Give examples.
Leads to a reduced size of an organ resulting from a decrease in cell size and number due to decreased amount of structural proteins and organelles due to decreased protein synthesis and increased protein degradation.
Physiological atrophy is common during normal development (embryonic structures, uterus following pregnancy). Pathologic atrophy depends on the underlying cause.
Describe the mechanism of metaplasia.
It refers to the replacement of one differentiated cell type with another. Cells sensitive to stress replaced by a cell type better able to withstand stress (involving stem-cell reprogramming).
Eg. Cigarette smoking (ciliated columnar -> stratified squamous)
Define adaptation, reversible injury, and irreversible injury.
Adaptation: A response to stress or increased demand that maintains the steady state of the cell without compromising cellular function.
Reversible/ sublethal injury: stage at which deranged function and morphology of the injured cells can return to normal if the damaging stimulus is removed
Irreversible injury: A response to stress/ stimuli that compromises cellular function to the point that it cannot recover (leads to necrosis or apoptosis)
Draw a diagram describing cell responses due to stress or injury-inducing stimulus.
Describe the concept of sequential development of changes seen in cell injury.
Cells may be non-functional but viable (as long as it is still in the reversible cell injury stage). Cells then may undergo biochemical changes and become non-viable (irreversible). The sequential development of these changes means this state may not be clear until macroscopic morphological changes are apparent.
Describe the usage of haemotoxylin and eosin stain.
- Most popular staining method used in histology (the study of the microscopic structure of tissues).
- H&E contains the two dyes haematoxylin and eosin.
-
Haematoxylin can be considered as a basic dye
- It is used to stain acidic (or basophilic) structures a purplish blue.
- Stains nucleic acids (DNA in nucleus, RNA in ribosomes and RER)
-
Eosin is an acidic dye
- It stains basic (or acidophilic) structures red or pink (also sometimes termed ‘eosinophilic’)
- Stains most proteins
Mention the morphological features of reversible injury.
Macroscopic changes:
- Cellular swelling: associated with increases permeability of plasma membrane
- Fatty change: appearange of lipid vacuoles in cytoplasm
Ultrastructural:
- plasma membrane blebbing
- ER (detachment of ribosomes) and mitochondrial swellin
- Nuclear alterations (clumping of chromatin)
- “myelin figures” - collection of damaged phospholipids
Explain when an irreversible injury occurs.
It occurs when:
- inability to restore mitochondrial function
- membranes lose their structural integrity such as plasma and intracellular membranes
- loss of DNA and chromatin structural integrity
Summarize mechanisms of cell injury.
Explain how the reduction of ATP leads to cell injury.
- Reduced activity of ATP-dependent Na+ pumps -> influx of sodium and efflux of potassium -> isoosmotic gain of water -> cell swelling and dilation of the ER.
- Reduced activity of ATP-dependent Ca2+ pumps -> influx of calcium -> apoptosis, membrane damage, nuclear damage
- Increase in anaerobic glycolysis -> lactic acid accumulation -> decreased intracellular pH -> decreased activity of many cellular enzymes & chromatin clumping
- Detachment of ribosome -> protein misfolding -> apoptosis
Explain how damage to mitochondria leads to cell injury.
Mitochondria are sensitive to many types of injurious stimuli, including hypoxia, chemical toxins, and radiation. Mitochondrial changes occur in necrosis and apoptosis.
- Failure of oxidative phosphorylation -> depletion of ATP -> necrosis
- Abnormal oxidative phosphorylation -> formation of ROS -> damage to DNA and protein
- Damage to mitochondria is often with increased permeability of membrane -> release of apoptotic proteins
Explain how the influx of calcium leads to cell injury.
Influx of intracellular calcium leads to:
- Activation of various cellular enzymes, such as:
- Phospholipases and proteases -> membrane damage
- Endonucleases -> nuclear damage
- ATPase
- Increased mitochondrial permeability -> release of apoptotic proteins and activation of caspases
Explain how the accumulation of radical oxidative species (ROS) leads to cell injury.
- Lipid peroxidation of membraners -> membrane damage
- Triggering misfolding of proteins -> ER stress -> apoptosis
- DNA damage -> apoptosis
Explain how membrane damage can lead to cell injury.
- Mitochndrial membrane damage -> reduction in ATP -> mutiple cell abnormalities -> necrosis
- Plasma membrane damage
- Lysosomal membranes -> leakage of enzymes -? enzymatic digestion of cell -> necrosis
Define necrosis.
Necrosis refers to cell death that happens without the participation of the cell. It is always associated with a pathological process (disease)
Mention the morphological features of necrosis.
-
Cytoplasmic changes:
- Increased eosinophilic staining-denatured protein and loss of RNA
- Vacuolation-digested cytoplasmic organelles
- Swelling of ER and mitochondria
- Myelin figures - whorls of phospholipid from damaged membranes
- Nuclear change: due to the breakdown of DNA and chromatin: Karyolysis, Pyknosis, Karyorrhexis
- Discontinuous plasma and organelle membranes
Differ between coagulative and liquefactive necrosis.
Coagulative necrosis:
- arises due to denaturation of proteins leading to dead cells (but tissue architecture preserved).
- firm texture
- characteristic of infarcts (necrosis due to ischemia) in all solid organs except brain
Liquefactive necrosis:
- arises due to enzymatic digestion of all macromolecules, leading to loss of tissue structure.
- baterial or fungal infections stimulate rapid accumulation of inflammatory cells
Mention the types of necrosis.
- Coagulative Necrosis
- Liquefactive Necrosis
- Caseous Necrosis: digestion and denaturation. fragmented lysed cells with amorphous granular appearance (associated with infection of M. tuberculosis)
- Fat necrosis: focal areas of fat destruction, liquefy membranes of fat cells leads to fat saponification (reacts with calcium)
- Fibrinoid Necrosis: occurs in blood vessels, associated with leakage of fibrin and inflammatory cells
- Gangrenous Necrosis: coagulative necrosis that occurs in a lower limb which has lost its blood supply; maybe liquefactive necrosis if accompanied by bacterial infection (wet gangrene)
Define apoptosis
Apoptosis is a pathway of cell death in which cells activate enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins .
It is triggered by loss of survival signals, DNA damage, and accumulation of misfolded proteins (ER stress)
Mention the morphological features of apoptosis.
- Intensely eosinophillic cytoplasm (H&E stain)
- Nuclear chromatin condensation and fragmentation (Karryorhexis)
- Cells shrink -> Formation of apoptotic bodies (nuclei and cytoplasm)
- Quickly phagocytosed
- No inflammatory response
Mention the methods of physiological induction of apoptosis.
- During embryogenesis
- Involution of endometrium
- Cell loss in a proliferating cell population
- Elimination of cells that have reached their used by date
Mention the methods of pathological induction of apoptosis.
- DNA damage
- Accumulation of misfolded protein
- Cell injury in infection
- Pathologic atrophy
Describe the mechanism of the intrinsic (mitochondrial) apoptotic pathway
It is initiated either by growth factor withdrawal, DNA damage, or accumulation of protein misfolding (ER stress).
Sensors sense these injuries and interfere with the balance between pro-apoptotic and anti-apoptotic members of the Bcl-2 family, with the latter winning out and activating caspase activation and apoptotic death.
Describe the mechanism of the extrinsic apoptosis pathway.
- CD8+ T lymphocyte-recognition of infected cells (receptor-ligand interaction) initiate caspases activation and apoptotic pathway
- Note: It also eliminates autoreactive lymphocyte
Describe the resulting outcome of apoptosis after activation (intrinsic or extrinsic)
Apoptotic Cell Death -> due to the activation of enzymes (caspases) - degrades nuclear and cytoplasmic proteins, forming apoptotic bodies.
Clearance of apoptotic bodies -> Phosphatidylserine ‘flips’ to the outer layer of the plasma membrane and dying cells secrete soluble factors which act as recruiters for phagocytosis without inducing an inflammatory response.
Summary of necrosis and apoptosis.
Describe how hypoxia causes cell injury
How do one detect the difference between a MI and angina due to hypoxia of the heart?
By measuring the serum levels (cardiac specific enzymes leaked), such as creatine kinase and troponin. If these are present, MI (irreversible injury, membrane integrity lost) most likely occur. Otherwise, angina is the most probable diagnosis.
Mention the types of cell injury.
- Toxins
- Infectious agents
- Immune response
- Aging
- Physical Agents
- Genetic Defects
- Hypoxia and Ischemia
- Nutritional Imbalance
