Cell Injury Flashcards
The hall mark of reversible cellular injury is
Cellular swelling
The hallmark of irreversible cell injury is
Membrane damage
How does cellular swelling come about
Reduction in ATP reduction is activity of calcium and Na K pump and Na isn’t going out therefore water will come in therefore cellular swelling
Homesostasis
• Homeostasis is the ability to maintain internal stability in a cell in response to the environmental changes. For example, the shivering response of the body in response to cold is aimed at generating heat.
• In the cell, adaptations are reversible functional and structural responses to changes in the environment.
• Adaptations create an altered steady state which allows the cell to continue to function
• However, adaptation has its limits…
What are the cellular adaptations to these
• Increased demand
• Decreased nutrients
• Chronic irritation
• Metabolic alteration
• Cumulative sublethal injury
• Injurious stimuli
• Hyperplasia/Hypertrophy
• Atrophy
• Metaplasia
• Intracellular accumulation
• Cellular aging
• Cell injury (transient:reversible, progressive:irreversible/cell death)
What is cell injury
• Cell injury occurs at the limit of adaptation.
• Most cells are built to adapt to stressors but different
cells have different tolerance limits
• A cell’s ability to adapt depends on ____& _____
the nature of the stress (duration and aetiology)
the nature of the cell/tissue (brain/colon cells in hypoxia)
Outcomes of cellular injury
• Adaptation: The cell may adopt changes for the duration of the stress which can be expressed morphologically and then revert back to normal immediately the stress is removed.
• Intracellular accumulations: The after effects of reversible injury may persist in some cells
• Reversible injury: Mild to moderate stressors within a cell’s tolerance limit
• Irreversible injury: Persistent and severe stressors
Adaptations are reversible changes
in size, number, phenotype, metabolic activity or function of a cell in response to its environment.
Hypertrophy
Increased cell size increased organ size
• Synthesis of additional structural components.
• Physiologic: Uterine growth during pregnancy. Hormone induced
• Pathologic: Cardiac hypertrophy caused by HTN.
Mechanism of Hypertrophy
• Mechanical sensors, growth factors & vasoactive agents work together to activate signal transduction pathways e.g. PI3K & G-protein coupled receptors.
• The signal pathways then activate transcription factors which enhance synthesis of muscle proteins.
Hyperplasia
• Increase in cell numbers in response to stimuli.
• Seen in cells which have the ability to divide. May also undergo hypertrophy.
• Mechanism: Proliferation of mature cells +/- new cells from tissue stem cells e.g. regenerative liver growth
Examples of physiologic hyperplasia
• Increase functional capacity e.g. breast in pregnancy
• Compensatory increase e.g. liver regeneration after hepatectomy, bone marrow after blood loss.
Eg of pathologic hyperplasia
• Hormonal action: Endometrial hyperplasia ff increase in estrogen, Prostatic hyperplasia.
• Viral infection: Wart from papillomaviruses
• Hyperplasia is a fertile soil for cancerous proliferation e.g. endometrial carcinoma.
What is atrophy & its mechanism
Goal of atrophy
• Decrease in cell size and number resulting in reduction in size of the organ or tissue.
Mechanism:
• Decreased protein synthesis - reduced metabolic activity
• Increased protein degradation - ubiquitin/proteasome pathway.
The goal is to reduce the metabolic needs of the cell enough to ensure its survival
Atrophy
Physiologic and pathologic atp
● Seen during normal development e.g. atrophy of thyroglossal duct during fetal development.
Pathologic
• Disuse atrophy
• Denervation atrophy
• Diminished blood supply
• Inadequate nutrition
• Loss of endocrine stimulation • Pressure effect
Types of cell injury and explain
Reversible : offending stimulus is removed
Reduced oxidative phosphorylation (reducedATP generation)
Changes in ion concentration lead to water influx and cell swelling
Irreversible : point of no return.
E.g. is heart muscle. With increased hemodynamic load hypertrophy results (reversible). Persistently increased load leads to point of no return (cell death).
• •
6 causes of cell injury
- Hypoxia (reduced O2 supply) / Ischaemia (reduced blood flow) - most common
• Cardiorespiratory failure
• Reduced blood flow (arterial/venous obstruction)
• Reduced O2 carrying capacity of blood (e.g. carbon monoxide, sickle cells) • Blood loss - Physical agents e.g. mechanical trauma, extreme heat/cold etc
- Chemical agents/drugs: Acid, insecticides, narcotics
- Infectious agents: Bacteria, viruses, fungi
- Immunologic agents : Hypersensitivity, anaphylaxis, autoimmune dxs
- Genetic derangements :
• Chromosomal abnormalities e.g. Down’s syndrome
• Susceptibility to injurious agents
• Deficiency of functional proteins (e.g. inborn errors of metabolism) - Nutritional imbalances : e.g. Protein-Energy malnutrition (Kwashiokor/Marasmus), Cholesterol (Atherosclerosis)
4 pathogenesis of cell injury
- Type of aetiologic agent and host cell.
a. The type, duration, severity of injurious agent. E.g. a low dose chemical vs.
same chemical at toxic doses (one time or accumulated)
b. Type, status and adaptability of target cell. E.g skeletal muscle can withstand
hypoxia for longer periods cf. heart muscle. Genetic polymorphisms (CCl4) - General underlying mechanism:
a. Mitochondrial damage ATP depletion
b. Cell membrane damage
c. Protein synthesis and packaging machinery
d. DNA damage
Pathogenesis of cell injury - Biochemical and molecular effects lead to ultrastructural changes which eventually manifest as light microscopic and gross tissue changes
- Eventually tissue function may be impaired and this may result in disease conditions
Mechanism and consequences of ATP depletion
Mechanisms
• Most commonly results from ischaemia/hypoxia, mitochondrial damage or toxins
• The cell may resort to anaerobic glycolysis
Consequences
• Defective NA/K ATP-dependent pump; H20 gain, swelling
• Anaerobic glycolysis, reduction in glycogen stores, lactic acidosis, reduced IC enzyme activity
• Failure of Ca pump, Ca influx, enzyme stimulation
• Protein synthesis disruption
• Misfolded proteins
Mechanism and consequences of mitochondrial damage
Mechanism
• Damaged by increased cytosolic Ca, ROS, hypoxia
Also,
• Toxins
• Genetic mutations
Consequences
• Formation of MPTP, failure of oxidative phosphorylation, ATP depletion
• Increased ROS formation • Leakage of cytochromec &
caspases, stimulation of apoptosis
Mechanism and consequence of calcium influx
Mechanism
• Ca is maintained at low levels within the cell. Most sequestered in mitochondria & ER
• In injury, cytoplasmic conc are increased because of release from stores & influx
Consequence
• MPTP, failure of ATP generation
• Activate phospholipases
(membrane damage), protease (cytoskeletal damage), endonuclease (fragment DNA, chromatin), ATPases (ATP depletion)
Mechanism and consequences of Reactive oxygen species
Mechanism
• Generation: Oxidation/reduction during normal metabolic process, absorption of radiant energy, leukocytes, breakdown of drugs eg CCl4
• Removal: spontaneous decay, antioxidants (Vit E,A), enzymes eg catalase, SOD etc,
• Increased generation or reduced removal
Consequences
• Lipid peroxidation, membrane damage
• Oxidative modification of proteins, damaged enzymes
• Single & double strand DNA breaks.
Defect in membrane permeability
Mechanism
• ROS
• Decreased phospholipid
synthesis (from ATP depletion)
• Increased phospholipid
breakdown (from
phospholipases)
• Cytoskeletal damage by
proteases
Consequences
• Mitochondrial membrane: reduced ATP generation • Plasma membrane: Cell
content leakage
• Lysosomal membrane:
Enzymatic digestion of the cell
