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Cell Injury Flashcards

1
Q

What are cell adaptations

A

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.

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2
Q

List out possible stimuli and cellular adaptations

A

• 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

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3
Q

When does cell injury occur

A

occurs at the limit of adaptation

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4
Q

What does a cell’s ability to adapt depend on

A

the nature of the stress (duration and aetiology) as well as the nature of the cell/tissue (brain/colon cells in hypoxia)

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5
Q

What are the possible outcomes of cellular injury

A

Adaptation
Intracellular accumulation
Reversible cell injury
Irreversible cell injury

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6
Q

What causes intracellular accumulation

A

The after effects of reversible injury may persist in some cells

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7
Q

What causes reversible injury

A

Mild to moderate stressors within a cell’s tolerance limit

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8
Q

What causes irreversible injury

A

Persistent and severe stressors

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9
Q

What is hypertrophy

A

Increased cell size increased organ size

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10
Q

Example of physiologic hypertrophy

A

Uterine growth during pregnancy. Hormone induced

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11
Q

Example of pathologic hypertrophy

A

Cardiac hypertrophy caused by HTN.

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12
Q

What is the mechanism of hypertrophy

A

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.

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13
Q

What is hyperplasia

A

Increase in cell numbers in response to stimuli.

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14
Q

What is the mechanism of hyperplasia

A

Proliferation of mature cells +/- new cells from tissue stem cells e.g. regenerative liver growth

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15
Q

Examples of physiological hyperplasia

A

• Increase functional capacity e.g. breast in pregnancy
• Compensatory increase e.g. liver regeneration after hepatectomy, bone marrow after blood loss.

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16
Q

Examples of pathologic hyperplasia

A

•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

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17
Q

What is atrophy

A

Decrease in cell size and number resulting in reduction in size of the organ or tissue.

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18
Q

What’s the mechanism of atrophy

A

• Decreased protein synthesis - reduced metabolic activity
• Increased protein degradation - ubiquitin/proteasome pathway.

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19
Q

How can you help an attophying tissue

A

The goal is to reduce the metabolic needs of the cell enough to ensure its survival

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20
Q

Example of physiologic atrophy

A

● Seen during normal development e.g. atrophy of thyroglossal duct during fetal development

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21
Q

Examples of pathological atrophy

A

• Disuse atrophy
• Denervation atrophy
• Diminished blood supply
• Inadequate nutrition
• Loss of endocrine stimulation
• Pressure effect

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22
Q

What is metaplasia

A

Replacement of one differentiated cell type by another cell type able to survive in the adverse environment

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23
Q

Examples of metaplasia

A

• 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

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24
Q

Mechanisms of metaplasia

A

• Results from reprogramming of stem cells or undifferentiated mesenchymal cells present in connective tissue
• The environmental stimulants program these cells towards a differentiation pathway

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25
Q

Effect of metaplasia

A

Fertile ground for development of malignancy.
E.g. is Barrett’s oesophagus leading to squamous cell carcinoma

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26
Q

What are the types of cell injury

A

 Reversible and irreversible

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27
Q

What are the two features Of reversible cell injury

A

•Reduced oxidative phosphorylation (reducedATP generation)
•Changes in ion concentration lead to water influx and cell swelling

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28
Q

Example of irreversible sell injury

A

heart muscle With increased hemodynamic load hypertrophy results (reversible). Persistently increased load leads to point of no return (cell death).

29
Q

What are the Causes of cell injury

A
  1. 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
  2. Physical agents e.g. mechanical trauma, extreme heat/cold etc
  3. Chemical agents/drugs: Acid, insecticides, narcotics
  4. Infectious agents: Bacteria, viruses, fungi
  5. Immunologic agents : Hypersensitivity, anaphylaxis, autoimmune dxs
  6. Genetic derangements :
    • Chromosomal abnormalities e.g. Down’s syndrome
    • Susceptibility to injurious agents
    • Deficiency of functional proteins (e.g. inborn errors of metabolism)
  7. Nutritional imbalances : e.g. Protein-Energy malnutrition (Kwashiokor/Marasmus), Cholesterol (Atherosclerosis) yh
30
Q

What are the pathogenesis of cell injury

A
  1. 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)
  2. General underlying mechanism:
    a. Mitochondrial damage ATP depletion
    b. Cell membrane damage
    c. Protein synthesis and packaging machinery
    d. DNA damage
  3. Biochemical and molecular effects lead to ultrastructural changes which eventually manifest as light microscopic and gross tissue changes
  4. Eventually tissue function may be impaired and this may result in disease conditions
31
Q

What kind of cell can withstand hypoxia

A

Skeletal muscle than cardiac muscles

32
Q

Mechanism for atp depletion

A

• Most commonly results from ischaemia/hypoxia, mitochondrial damage or toxins
• The cell may resort to anaerobic glycolysis

33
Q

What are the consequences of atp depletion

A

• 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

34
Q

What’s the mechanism for mitochondrial damage

A

• Damaged by increased cytosolic Ca, ROS, hypoxia • Toxins
• Genetic mutations

35
Q

Consequences of mitochondrial damage

A

•Formation of MPTP, failure of oxidative phosphorylation, ATP depletion
• Increased ROS formation • Leakage of cytochromec &
caspases, stimulation of apoptosis

36
Q

Mechanism of Ca influx

A

• 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

37
Q

What are the consequences of Ca influx

A

• MPTP, failure of ATP generation
• Activate phospholipases
(membrane damage), protease (cytoskeletal damage), endonuclease (fragment DNA, chromatin), ATPases (ATP depletion)

38
Q

What are the enzymes that Ca influx activate

A

Phospholipase (membrane damage)
Protease (cytoskeleton damage)
ATPase ( ATP depletion)
Endonuclease (Fragment DNA,chromatin)

39
Q

What enzymes do influx of Ca activate

A
40
Q

What enzymes do Ca influx activate

A

Phospholipase ( membrane damage)
Protease (cytoskeleton damage)
ATPase (ATP depletion)
Endonuclease (DNA fragment, chromatin)

41
Q

What’s the mechanism of ROS

A

• 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

42
Q

What are the consequences of ROS

A

• Lipid peroxidation, membrane damage
• Oxidative modification of proteins, damaged enzymes
• Single & double strand DNA breaks.

43
Q

What’s the mechanism for defect in membrane permeability

A

• ROS
• Decreased phospholipid
synthesis (from ATP depletion)
• Increased phospholipid
breakdown (from
phospholipases)
• Cytoskeletal damage by
protease

44
Q

Consequences of damage membrane permeability

A

• Mitochondrial membrane: reduced ATP generation
• Plasma membrane: Cell
content leakage
• Lysosomal membrane:
Enzymatic digestion of the cell

45
Q

What does ischemic hypoxic injury cause

A

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

46
Q

What is irreversible cell injury associated with

A

• Severe mitochondrial swelling
• Extensively damaged plasma membranes
• Lysosomal swelling/damage

47
Q

Ch

A
48
Q

What are the major things caused by ischemic hypoxic cel injury

A
  1. CNS neurons, myocardial and kidney cells are solely dependent on aerobic respiration and are rapidly susceptible to damage.
  2. 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
  3. 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)
49
Q

What’s the clinical significance of ischemic hypoxic cel injury (how to treat it)

A

• 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.

50
Q

What is Ischaemia-Reperfusion injury

A

Occurs as a result of restoration of blood flow to ischaemic tissue.

It may result in additional death of reversibly damaged cells

51
Q

Where is ischemia reperfusion injury commonly seen

A

tissue damage ff M.I. & cerebral infarction

52
Q

What’s the mechanism of ischemia reperfusion injury

A

• Oxidative stress: Increased ROS generation
• Intracellular Ca overload
• Increased inflammation
• Activation of complement system by binding Ab e.g. IgM.

53
Q

How do chemicals induce injury

A

• Direct cytotoxicity
• Conversion of chemicals to reactive metabolites

54
Q

Which cells are affected in direct cytotoxicity cell injury

A

Mostly affects cells which are directly involved in the metabolism of such chemicals

55
Q

Examples of toxic chemicals that cause direct cytotoxic injury to cells

A

HgCl, Cyanide, Chemotherapy drugs

56
Q

What happens in Hg poisoning

A

Hg binds -SH grp of cell membrane proteins, increased membrane permeability

57
Q

What cells are mostly affected in Hg poisoning

A

cells of the GIT, Kidney

58
Q

How does cyanide poisoning occur

A

Targets mitochondrial cytochrome oxidase, reduction in ATP generation

59
Q

How does chemical injury by conversion of chemicals to reactive metabolites occur

A

The chemical agent is metabolized to yield the toxin which interacts with the target cells.

Usually by cytochrome P450 in sER of liver.

60
Q

What’s the mechanism for chemical injury by conversion of chemicals to reactive metabolites

A

Formation of free radicals

61
Q

Example of chemicals that cause chemical injury by conversion of chemicals to reactive metabolites

A

Carbon tetrachloride (CCl4), Acetaminophen.

62
Q

What are microscopic features of reversible cell injury

A

• 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

63
Q

Examples of ultra structural features seen in reversible cell injury

A

• 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)

64
Q

What is irreversible cell injury

A

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.

65
Q

What happens in irreversible cell injury

A

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

66
Q

How does Endonuclease damage the DNA in the nucleus

A

occurs in 3 forms:
Pyknosis (nuclear shrinkage)
karryohexis (nuclear fragmentation)
karyolysis (nuclear dissolution)

67
Q

Enzymes released from the cell can be detected by laboratory assays. Give examples

A

• Cardiac troponins, CK-MB (myocardial infarction)
• Amylase, Lipase (Acute pancreatitis)
• Aspartate/Alanine aminotransferase (hepatocyte damage)

68
Q

What is seen in the histology of a reversible cell injury

A

•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)

amp fpp (6 decks)

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