Cell Injury Flashcards
What are cell adaptations
adaptations are reversible functional and structural responses to changes in the environment
Adaptations are reversible changes in size, number, phenotype, metabolic activity or function of a cell in response to its environment.
List out possible stimuli and cellular adaptations
• Increased demand–Hyperplasia/Hypertrophy
• Decreased nutrients–• Atrophy
• Chronic irritation–• Metaplasia
• Metabolic alteration–Intracellular accumulation
• Cumulative sublethal injury–Cellular aging
• Injurious stimuli–Cell injury (transient:reversible, progressive:irreversible/cell death
When does cell injury occur
occurs at the limit of adaptation
What does a cell’s ability to adapt depend on
the nature of the stress (duration and aetiology) as well as the nature of the cell/tissue (brain/colon cells in hypoxia)
What are the possible outcomes of cellular injury
Adaptation
Intracellular accumulation
Reversible cell injury
Irreversible cell injury
What causes intracellular accumulation
The after effects of reversible injury may persist in some cells
What causes reversible injury
Mild to moderate stressors within a cell’s tolerance limit
What causes irreversible injury
Persistent and severe stressors
What is hypertrophy
Increased cell size increased organ size
Example of physiologic hypertrophy
Uterine growth during pregnancy. Hormone induced
Example of pathologic hypertrophy
Cardiac hypertrophy caused by HTN.
What is the 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.
What is hyperplasia
Increase in cell numbers in response to stimuli.
What is the mechanism of hyperplasia
Proliferation of mature cells +/- new cells from tissue stem cells e.g. regenerative liver growth
Examples of physiological hyperplasia
• Increase functional capacity e.g. breast in pregnancy
• Compensatory increase e.g. liver regeneration after hepatectomy, bone marrow after blood loss.
Examples 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 carcinom
What is atrophy
Decrease in cell size and number resulting in reduction in size of the organ or tissue.
What’s the mechanism of atrophy
• Decreased protein synthesis - reduced metabolic activity
• Increased protein degradation - ubiquitin/proteasome pathway.
How can you help an attophying tissue
The goal is to reduce the metabolic needs of the cell enough to ensure its survival
Example of physiologic atrophy
● Seen during normal development e.g. atrophy of thyroglossal duct during fetal development
Examples of pathological atrophy
• Disuse atrophy
• Denervation atrophy
• Diminished blood supply
• Inadequate nutrition
• Loss of endocrine stimulation
• Pressure effect
What is metaplasia
Replacement of one differentiated cell type by another cell type able to survive in the adverse environment
Examples of metaplasia
• Squamous metaplasia (from columnar)
-Ciliated columnar (smokers)
-Secretory columnar (gallstone)
•Columnar metaplasia (from squamous)
-Barrett’s oesophagus
• Connective tissue metaplasia
-Myositis ossificans
•Columnar metaplasia (from a different columnar)
-H.pylori
•Squamous metaplasia (from transitional)
-Schistosomiasis of bladder
Mechanisms of metaplasia
• Results from reprogramming of stem cells or undifferentiated mesenchymal cells present in connective tissue
• The environmental stimulants program these cells towards a differentiation pathway
Effect of metaplasia
Fertile ground for development of malignancy.
E.g. is Barrett’s oesophagus leading to squamous cell carcinoma
What are the types of cell injury
 Reversible and irreversible
What are the two features Of reversible cell injury
•Reduced oxidative phosphorylation (reducedATP generation)
•Changes in ion concentration lead to water influx and cell swelling
Example of irreversible sell injury
heart muscle With increased hemodynamic load hypertrophy results (reversible). Persistently increased load leads to point of no return (cell death).
What are the 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) yh
What are the 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 - 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
What kind of cell can withstand hypoxia
Skeletal muscle than cardiac muscles
Mechanism for atp depletion
• Most commonly results from ischaemia/hypoxia, mitochondrial damage or toxins
• The cell may resort to anaerobic glycolysis
What are the consequences of atp depletion
• 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 protein
What’s the mechanism for mitochondrial damage
• Damaged by increased cytosolic Ca, ROS, hypoxia • Toxins
• Genetic mutations
Consequences of mitochondrial damage
•Formation of MPTP, failure of oxidative phosphorylation, ATP depletion
• Increased ROS formation • Leakage of cytochromec &
caspases, stimulation of apoptosis
Mechanism of Ca influx
• 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
What are the consequences of Ca influx
• MPTP, failure of ATP generation
• Activate phospholipases
(membrane damage), protease (cytoskeletal damage), endonuclease (fragment DNA, chromatin), ATPases (ATP depletion)
What are the enzymes that Ca influx activate
Phospholipase (membrane damage)
Protease (cytoskeleton damage)
ATPase ( ATP depletion)
Endonuclease (Fragment DNA,chromatin)
What enzymes do influx of Ca activate
What enzymes do Ca influx activate
Phospholipase ( membrane damage)
Protease (cytoskeleton damage)
ATPase (ATP depletion)
Endonuclease (DNA fragment, chromatin)
What’s the mechanism of ROS
• 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
What are the consequences of ROS
• Lipid peroxidation, membrane damage
• Oxidative modification of proteins, damaged enzymes
• Single & double strand DNA breaks.
What’s the mechanism for defect in membrane permeability
• ROS
• Decreased phospholipid
synthesis (from ATP depletion)
• Increased phospholipid
breakdown (from
phospholipases)
• Cytoskeletal damage by
protease
Consequences of damage membrane permeability
• Mitochondrial membrane: reduced ATP generation
• Plasma membrane: Cell
content leakage
• Lysosomal membrane:
Enzymatic digestion of the cell
What does ischemic hypoxic injury cause
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
What is irreversible cell injury associated with
• Severe mitochondrial swelling
• Extensively damaged plasma membranes
• Lysosomal swelling/damage
Ch
What are the major things caused by ischemic hypoxic cel injury
- 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 (which leads to activation of Phospholipase which destroys the membrane phospholipids)
What’s the clinical significance of ischemic hypoxic cel injury (how to treat it)
• 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.
What is 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
Where is ischemia reperfusion injury commonly seen
tissue damage ff M.I. & cerebral infarction
What’s the mechanism of ischemia reperfusion injury
• Oxidative stress: Increased ROS generation
• Intracellular Ca overload
• Increased inflammation
• Activation of complement system by binding Ab e.g. IgM.
How do chemicals induce injury
• Direct cytotoxicity
• Conversion of chemicals to reactive metabolites
Which cells are affected in direct cytotoxicity cell injury
Mostly affects cells which are directly involved in the metabolism of such chemicals
Examples of toxic chemicals that cause direct cytotoxic injury to cells
HgCl, Cyanide, Chemotherapy drugs
What happens in Hg poisoning
Hg binds -SH grp of cell membrane proteins, increased membrane permeability
What cells are mostly affected in Hg poisoning
cells of the GIT, Kidney
How does cyanide poisoning occur
Targets mitochondrial cytochrome oxidase, reduction in ATP generation
How does chemical injury by conversion of chemicals to reactive metabolites occur
The chemical agent is metabolized to yield the toxin which interacts with the target cells.
Usually by cytochrome P450 in sER of liver.
What’s the mechanism for chemical injury by conversion of chemicals to reactive metabolites
Formation of free radicals
Example of chemicals that cause chemical injury by conversion of chemicals to reactive metabolites
Carbon tetrachloride (CCl4), Acetaminophen.
What are microscopic features of reversible cell injury
• 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
Examples of ultra structural features seen in reversible cell injury
• Plasma membrane alterations e.g. blebbing. Blunting, loss of microvilli
• Mitochondrial changes e.g. amorphous densities
• ER dilation ( reduced protein synthesis)
•Myelin figures
• Nuclear alterations (chromatin clumping)
What is irreversible cell 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.
What happens in irreversible cell injury
Cell membrane damage – Ca influx – activation of enzymes (Phospholipase, protease, Endonuclease)
Lysosomal membrane damage – leakage of their content hydrolytic enzymes (e.g. hydrolase, DNAase etc) digest cellular
components
How does Endonuclease damage the DNA in the nucleus
occurs in 3 forms:
Pyknosis (nuclear shrinkage)
karryohexis (nuclear fragmentation)
karyolysis (nuclear dissolution)
Enzymes released from the cell can be detected by laboratory assays. Give examples
• Cardiac troponins, CK-MB (myocardial infarction)
• Amylase, Lipase (Acute pancreatitis)
• Aspartate/Alanine aminotransferase (hepatocyte damage)
What is seen in the histology of a reversible cell injury
•Cellular swelling - Usually the first manifestation of cell injury
•Fatty changes - 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)
