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Flashcards in Cell injury Deck (27):
1

Describe the process of adaptation in response to cellular stress

Adaptations are reversible functional and structural responses to more severe physiologic stresses or pathologic stimuli to new, altered steady state. This allows the cell to survive and continue to function. 

The adaptive responses include:

  • increase in the size of cells (hypertrophy) and functional activity, an increase in their number (hyperplasia)
    [Increased demand or stimulation]
  • decrease in the size and metabolic activity of cells (atrophy)
    [Decreased nutrients or stimulation

     
  • change in the phenotype of cells (metaplasia).
    [Chronic irritation]

When the stress is eliminated the cell  recover to its original state. If stress is extensive cell injury and death may result

2

Describe 3 cellular resonses to altered stimuli

Altered biological stimuli or non-lethal injuries cause cell adaptations: 

Hyperplasia or hypertrophy - due to increased demand or stimulation (e.g. by growth factors or hormones)

Atrophy - due to decreased nutrients or stimulation

Metaplasia - change due to chronic physical or chemical irritation

 

3

What affects the outcomes following cell injury?

Acute transient injury is reversible. Produces rapid changes in the cell which may be lethal if not quickly reversed.

Progressive or severe injury is irreversible. Results in cell death by necrosis or apoptosis

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4

Define Necrosis

Death of groups of contiguous cells in tissue or an organ caused by lethal injury

 Necrosis is always pathologic. Occurs in acute cell injury that causes damage to the plasma membrane (e.g.ischemia, toxins, infections, trauma). 

Results in enzymatic digestion of the cell. Intracellular contents leak out of the cell and may produce an inflammatory response. 

5

What are the three patterns of tissue necrosis?

Coagulative

Liquefactive

Caseous

 

Also: 

Fat necrosis

Gangrene

Infarct

6

Describe coagulative necrosis

Basic shape and architecture of the tissue is preserved

Affected tissue maintains solid consistency.

In most cases the necrotic cells are ultimately removed by phagocytosis.

The dead cells may be replaced by regeneration from neighboring cells, or by scar (fibrosis).


Most common manifestation of ischaemic necrosis in tissues.Localised area of coagulative necrosis is called an infarct.

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7

Describe liquefactive necrosis

Complete dissolution of necrotic tissue into a liquid visous mass

Massive infiltration by neutrophils which release reactive oxygen species and proteases to digest infected/dead cells, causing abscess formation 

Most commonly due to focal bacterial or fungal infection. Liquefaction is also characteristic of ischaemic necrosis in the brain.

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8

Describe gangrene

Gangrene is not a separate type of necrosis. Used to describe necrosis that is advanced and visible grossly. 

If there is mostly coagulation necrosis, (i.e. blackening, desiccating limb which dried up before the bacteria could overgrow), we call it dry gangrene.

If there's mostly liquefactive necrosis (i.e. foul-smelling, oozing foot infected with several different kinds of bacteria), or if it's in a wet body cavity, we call it wet gangrene.

9

Describe caseous necrosis

Accumulation of amorphous (no structure) debris within an area of necrosis. Tissue architecture is abolished and viable cells are no longer recognizable.


Characteristically associated with the granulomatous inflammation (what appearance in the area of necrosis with an inflammatory border). Characteristic of TB and sarcoidosis. Also seen in some fungal infections.

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10

Describe fat necrosis

Not a specific pattern of necrosis. Refers to focal areas of fat destruction. 

Results from the action of lipases released into adipose tissue e.g. pancreatitis, trauma.

Free fatty acids accumulate and precipitate as calcium soaps (saponification). These precipitates are grossly visible as pale yellow/white nodules


Microscopically, the digested fat loses its cellular outlines. There is often local inflammation

 

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11

Name 7 common causes of cell injury

Hypoxia/ Ischemia

Toxins

Heat

Cold

Trauma

Radiation

Micro-organisms

Immune mechanisms

12

Desccribe 7 common causes of cell injury

 Hypoxia: reduces aeorbic respiration. Can be due to reduction of blood flow or interrption of blood supply (ischemia), low O2 supply to the tissues (e.g. high altitude, anaemia) or following severe blood loss

Physical: direct physical effects by exposure of tissue to extreme heat or cold, mechanical trauma, radiation or electric shock. This injury is often irreversible, resulting in a coagulative necrosis. Radiation causes DNA damage

Chemical: can interfere with electrolye balance. Poisons interfere with cell metabolism and prevent ATP synthesis. Arsenic/cyanide - GI symptoms, mercury - erratic behaviour. Pharmaceuticals have toxic effects on cells, some act directly and some are indirect.

Infections: pathogens cause cell injury through a variety of mechanisms e.g. the release of toxins, intracellular replication

Immune system: alter gene expression and cellular metabolism in order to combat infection, however some inflammatory mediators can produce stress on the cells that produce them. Complement forms MAC which can cause direct attack on the body's own cells. Tc cells and NK cells have cytotoxic effects.Immune reactions against self antigens cause autoimmune diseases

*

Diet: insufficiencies in the diet can lead to injury at a cellular level due to disruption of metabolic pathways e.g. vitamins. Nutritional excess can also cause cell injury (e.g. cholesterol and athersclerosis)

 

13

Describe the morphological changes that occur in necrosis and apoptosis

Necrosis: 
Enlarged cell size
Plasma membrane disrputed
Fragmented nucleus
Cytoplasmic proteins denatured (amorphous debris)
Enzymatic digestion = cytoplasm 'moth-eaten' appearance
Damaged cell membrane = intracytoplasmic myelin figures
Calcification of dead cells
Inflammation

Apoptosis:
Cell shrinkage
Chromatic condensation and fragmentation
Plasma membrane remains intact
Formation of cytoplasmic blebs and apoptotic bodies
Phagocytosis of apoptotic bodies by macrophages.

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14

What are the principle structural tagets for cell damage?

Cell membane 

DNA

Structural proteins

Enzymes

Mitochondria

15

What 4 events are involved in the pathogenesis of cell injury

Reduced ATP synthesis (mitochondrial damage)

Loss of calcium homeostasis

Disrupted membrane permeability

Free radicals

16

Describe the consequences of decreased intracellular ATP during cell injury

The major causes of ATP depletion are reduced supply of oxygen and nutrients, mitochondrial damage, and the actions of some toxins (e.g., cyanide). Depletion of ATP has widespread effects on many critical cellular systems:


• Failure of the Na/K+ pump causes increase in intracellular [solute] results in osmosis, causing cell swelling, and dilation of the ER.

• In ischemia, oxidative phosphorylation leading to  anaerobic glycolysis.  Accumulation of lactic acid and inorganic phosphates reduces the intracellular pH, resulting in decreased activity of many cellular enzymes.

• Failure of the Ca2+ pump leads to influx of Ca2+, with damaging effects on numerous cellular components.

• reduction in protein synthesis.

• In cells deprived of oxygen or glucose, proteins may become misfolded, these trigger a cellular reaction that may culminate in cell injury and even death.


If there is irreversible damage to mitochondrial and lysosomal membranes, and the cell undergoes necrosis.

 

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17

How does a loss of calcium homeostasis cause cell injury?

Intracellular calcium is normally maintaned at low concentrations. 

The accumulation of Ca2+ in mitochondria results in damage to the mitochondrial membrane and failure of ATP generation.

Increased cytosolic Ca2+ activates a number of enzymes, with potentially deleterious cellular effects. These enzymes include phospholipases (which cause membrane damage), proteases (which break down both membrane and cytoskeletal proteins), endonucleases (which are responsible for DNA and chromatin fragmentation), and ATPases (thereby hastening ATP depletion).

Increased intracellular Ca2+ levels also result in the induction of apoptosis, by direct activation of caspases and by increasing mitochondrial permeability

18

How does the production of free radicals cause cell injury?

ROS have a role in cellular defense mechanisms. Normally tightly regulated. Increased production or defective scavenging systems cause an excess of free radicals leading to oxidative stress. 

Injure cells by…..

Membrane lipid peroxidation
Loss of enzyme function
Abnormal protein folding
DNA damage (mutations)
Single strand breaks (genomic and mitochondrial)

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19

Describe the two types of infarction

White:
Arterial occlusion in most solid tissues

Red/haemorrhagic: 
Venous occlusion
Loose tissues
Organs with dual blood supply
 

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20

Describe the process of apoptosis

Intrinsic pathway: 
Anti-apoptotic proteins such as Bcl-2 induced by survival signals maintain the integrity of mitochondrial membranes and prevent leakage of mitochondrial proteins. Loss of survival signals, DNA damage, and other insults activate sensors that antagonize the anti-apoptotic proteins and activate the pro-apoptotic proteins Bax and Bak, which form channels in the mitochondrial membrane. The subsequent leakage of cytochrome c and other proteins leads to caspase activation and apoptosis.

 

Extrinsic pathway:
Activated by death receptors on the surface of cells. These activate the cleavage of procaspses to caspases and intiate apoptosis

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21

What are the effects of mitochondrial damage on a cell?

Mitochondrial damage can be due to increased [Ca]. oxygen deprivation, ROS or toxins. 

Mitochondrial damage often results in the formation of a channel in the mitochondrial membrane. This results in failure of oxidative phosphorylation and progressive depletion of ATP, culminating in necrosis of the cell.

The mitochondria also sequester several proteins that are capable of activating apoptotic pathways; these include cytochrome c and proteins that indirectly activate caspases. Increased permeability of the outer mitochondrial membrane may result in leakage of these proteins into the cytosol, and death by apoptosis

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22

Name 3 ways free radicals are produced

Absorption of radiation

Endogenous normal metabolic reactions

Transition metals

Nitric oxide

Toxins

23

How are free radicals removed from the body?

Spontaneous decay

Antioxidants: vitamin A, C, E, glutathione

Storage proteins: ferritin, transferrin

Enzymes: catalase, glutathione peroxidase, SOD

24

What are the histological features of acute pancreatitis

Liquefactive necrosis, haemorrhage

 

Acute pancreatitis is reversible injury to the pancraetic parenchyma associated with inflammation. 

Necrosis of fat by lipolytic enxymes
Acute inflammation
Proteiolytic destruction of the parenchyma
Destruction of the blood vessels and microvasculature - oedema and haemorrhage. 

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25

What are the histological features of alcoholic hepatitis

Hepatocyte swelling and necrosis 

Inflammatory infiltrate: Mostly neutrophils accumulate around degenerating hepatocytes, macrophages and lymphocytes also present. 

Fibrosis

Mallory bodies: inclusions found in the cytoplasm of hepatocytes

26

What are the histological features seen in the liver of a patient following paracetamol overdose?

Coagulative necrosis of the hepatocytes

Acinar zones closer to the portal vein are more damaged because they are further from the oxygen supply. 

27

What are the histological features seen in the liver of a patient following paracetamol overdose?

Coagulative necrosis of the hepatocytes

Acinar zones closer to the portal vein are more damaged because they are further from the oxygen supply. 

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