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
Ischaemic hypoxia injury
Decreased generation of cellular ATP.
• Failure of Na pump, influx of H20
• Ca influx/release, enzyme activation
• Reduced protein synthesis
• Reduced cell glycogen
• Destruction of cytoskeleton, membrane blebs
- CNS neurons, myocardial and kidney cells are solely dependent on aerobic respiration and are rapidly susceptible to damage.
- Due to low oxygen supply and subsequent anaerobic respiration, there is increased lactic acid accumulation in the cell (lactic acidosis) which leads to a fall in intracellular pH and clumping of nuclear chromatin
- Reduced ATP generation also affects the integrity of the plasma membrane. There is reduced synthesis of phospholipids which are useful for membrane repair, impaired function of NA-K ATPase pump (hydropic swelling) and impaired Ca pump resulting in excess Ca influx
Ischaemic-hypoxic injury cont.
Irreversible injury is associated with:
• Severe mitochondrial swelling
• Extensively damaged plasma membranes
• Lysosomal swelling/damage
Clinical significance
• Hypothermic therapy
• Mechanism: Reduction of temperature leads to reduction in cellular
metabolic demands, production of free radicals and host immune
response.
• Current meta-analyses: Not useful, infact may cause more mortality.
Ischaemia-Reperfusion injury
• Occurs as a result of restoration of blood flow to ischaemic tissue.
• It may result in additional death of reversibly damaged cells.
• Commonly seen in tissue damage ff M.I. & cerebral infarction
• Mechanisms:
• Oxidative stress: Increased ROS generation
• Intracellular Ca overload
• Increased inflammation
• Activation of complement system by binding Ab e.g. IgM.
Pathogenesis of chemical injury
Chemicals induce injury by:
• Direct cytotoxicity
• Conversion of chemicals to reactive metabolites
Direct cytotoxicity:
• Mostly affects cells which are directly involved in the metabolism of such chemicals E.g. HgCl, Cyanide, Chemotherapy drugs
• HgCl poisoning: Hg binds -SH grp of cell membrane proteins, increased membrane permeability. Mostly affects cells of the GIT, Kidney
• Cyanide: Targets mitochondrial cytochrome oxidade, reduction in ATP generation
Conversion to reactive metabolites: • The chemical agent is metabolized to yield the toxin which interacts with the target cells. Usually by cytochrome P450 in sER of liver. • Mechanism: Formation of free radicals • E.g. is Carbon tetrachloride (CCl4), Acetaminophen.
Morphologic features of reversible injury
Microscopic
• Cellular swelling secondary to failure of energy dependent ion pumps responsible for maintaining homeostasis
• Fatty change. Seen in hepatocytes and myocardial cells ff hypoxic/toxic injury
Ultrastructural
• Plasma membrane alterations e.g. blebbing. Blunting, loss of microvilli
• Mitochondrial changes e.g. amorphous densities
• ER dilation
• Nuclear alterations
Irreversible injury
• The point of transition from reversible to irreversible injury is not clear cut. However, with persistence of the stressor, the cell reaches a point of no return where it can no longer repair the damage done.
Pathogenesis of irreversible injury
- Membrane damage >Ca ion influx > excess accumulates in mitochondria disabling its function
- Ca ion influx >phospholipase activation >degrade membrane phospholipids >destroy cell membrane
- Intracellular proteases are also activated> destruction of cytoskeletal proteins
- Activated endonucleases damage the DNA in the nucleus. This may occur in 3 forms: Pyknosis, karryohexis, karyolysis
- Lysosomal membranes are compromised> leakage of their content >hydrolytic enzymes (e.g. hydrolase, DNAase etc) digest cellular
components
Clinical significance of irreversible injury
Enzymes released from the cell can be detected by laboratory assays. Examples include:
• Cardiac troponins, CK-MB (myocardial infarction)
• Amylase, Lipase (Acute pancreatitis)
• Aspartate/Alanine aminotransferase (hepatocyte damage)
Histology of reversible injury
• Two major changes:
• Cellular swelling : results from failure of pumps in the plasma membrane leading to ion and fluid imbalance. Usually the first manifestation of cell injury
• Fatty change : seen most especially in cells dependent on lipid metabolism e.g. hepatocytes, myocardial cells. Vacuoles are seen within the cytoplasm
• Others include increased eosinophilia (hyaline change)
