Cellular Injury Flashcards
How do physicochemical agents cause cell destruction (2)
- Gross membrane disruption
2. Functional impairment
How does trauma and thermal injury caused by physicochemical agents cause cell destruction
- Denaturing proteins
2. Local vascular thrombosis -> Ischaemia or infarction
define thrombosis
Local clotting of blood in part of the circulatory system
How does freezing caused by physicochemical agents cause cell death
- Membranes are perforated by ice crystals
What are missile injuries
Combines effects of trauma and heat - energy is dissipated into tissues around the track
What are blast injuries
Result of SHEARING forces - where structures of differing density and mobility are moved with respect to one another
Give an example of blast injuries
Traumatic amputation
What wave causes thermal injury
Microwaves
What is the effect of low-energy laser light on cells
Produces tissue heating with coagulation
What is the effect of high-energy laser light on cells
Breaks intramolecular bonds by a photochemical reaction and vaporises tissue
Why do caustic agents cause rapid local cell death
Due to their EXTREME alkalinity and acidity
How do biological agents cause cell damage
By toxins and metabolic products that are secreted by bacteria
How do toxins cause cell death
- Affects membrane integrity or metabolism
What symptom is usually seen with toxin cell deaths
Acute Inflammation
How does acute inflammation induced by toxins affect neighbouring cells
Harms them
What are organisms secreting toxins called
Pyogenic
How do bacterial endotoxins function
- Induces apoptosis
Two factors that affect damage inflicted on tissues when toxins are involved
- Affect of toxins/ intracellular agents
2. Impact of host immune response to toxin
What effect on the metabolic pathway can cause cell injury
Blockage of the pathway
How does blockage of the metabolic pathway effect cellular respiration
Lack of Oxygen = Cell Death go many cells
How does cyanide effect the metabolic pathway
Cyanide ions bind to cytochrome oxidase and interrupt oxygen utilisation
How does blockage of metabolic pathway impact glucose levels
Deprives glucose levels which some cells are heavily dependant on
What cell depends on glucose the most
Cerebral neurones
How does a blockage in the metabolic pathway effect protein synthesis
Protein synthesis can be blocked at the translational level and there is a CONSTANT requirement to replenish enzymes and structural proteins
Name two antibiotics that would block the metabolic pathway for protein synthesis
Tetracycline
Streptomycin
How would growth factor or hormonal influence cause cell damage
A loss of them
How does a loss of growth factor or hormonal influence cause cell death
No intracellular cascade pathway -> cell undergoes apoptosis
Organs receiving hormones as messengers will shrink
How does ischaemia cause cell damage
Inadequate oxygen delivery
Mitochondrial production of ATP stops
Anaerobic Glycolysis = Acidosis due to lactate
Acidosis -> calcium influx
How does repercussion injury cause cell death
- After Ischaemia, blood supply may be restored
2. Large supply of O2 causes burst of mitochondrial activity and excessive release of free radicals of O2
How can free radicals be generated
- Deposition of energy
2. Oxidation-reduction reactions
How do free radicals cause cell damage
Damage to poly-unsaturated fatty acids or cell DNA
Why are poly-unsaturated fatty acids important
Important part of cell membrane
Why are poly-unsaturated fatty acids important
Important part of cell membrane
What happens to cells irreversibly damaged by free radicals
Deleted by apoptosis
Describe the four stages of clinicopathological events involving free radicals that lead up to cell death
- Toxicity of some poison
- Oxygen toxicity
- Tissue damage in inflammation
- Intracellular killing
What is the most important method by which cell death occurs
Failure of membrane integrity
What five ways can cause failure of membrane integrity
- Complement-mediated cytolysis
- Perforin-mediated cytolysis
- Specific blockage of ion channels
- Failure of membrane ion pumps
- Free radical attack
Define cytolysis
Disruption of cells
Define complement-mediated cytolysis
End products of complement cascade have cytolytic activity
What is perforin
Mediator of lymphocyte cytotoxicity
Define perforin-mediated cytolysis
Damage to cell membrane of target cells such as those infected by viruses
Why does specific blockage of ion channels cause lack of membrane integrity
Because they are needed for homeostasis
How does membrane pump failure effect membrane integrity
Interferes with mitochondrial oxidative phosphorylation or consuming ATP in chemical agent metabolism
Causes cell swelling
What is cell swelling due to pump failure called
Oncosis or hydronic change
What is cell swelling due to pump failure called
Oncosis or hydronic change
How do free radical attacks effect membrane integrity (2)
- Reactive oxygen species or phospholipase react with phospholipids causes lysosome permeability and release of its contents can cause further cell damage.
- Membrane proteins can be altered by cross-linking induced by free radicals
What sub-population of cells are most susceptible to DNA damage
Those that are constantly dividing
How can we tell if cell populations have DNA damage
Using a growth or metabolic stimulus
What is a neoplastic transformation
none-lethe DNA passed onto daughter cells causing abnormal growth characteristics
What can neoplastic transformations result in
Tumours
How is mitosis effected in cells that have severely damaged nuclei and what factors can cause this damage
It is blocked
Strand breaks
Base alterations
Cross-linking
How is DNA strand breakage usually caused
Radiation
How is the process of repair different if one strand was damaged compared to two strands damaged + why
- Single-damaged can be repaired (template present)
2. Double-damage cannot as multiple breaks can cause incorrect rejoining (template not present)
How does DNA strand cross-linking occur
When reactive oxygen species cause linkages between complementary strands + they can’t separate - this blocks replication
What are the two main sublethal cellular alteration types
- Hydropic change
2. Fatty Change
What is hydropic change
Results from disturbances of metabolism such as hypoxia or chemical poisoning
What is fatty change
Vacuolation of cells due to accumulation of lipid droplets as a result of disturbance to ribosomal function + uncoupling of lipid from protein metabolism
Can fatty change be reversed
Yes - moderate
No - Severe
What is autophagy
Cellular response to stress
1. Cell components are isolated into intracellular vacuoles and processed through to lysosomes
How can autophagy result in cell death
If stimulus is severe or metabolic pathway is switched to apoptosis
In what two ways does cell death happen
Apoptosis
Necrosis
What follows cell necrosis
Inflammation and repair
How is necrosis characterised
Bioenergetic failure
Loss of plasma membrane integrity
Why is an influx of calcium ions dangerous when ion channels are blocked
Because calcium uptake exceeds storage in mitochondria and disrupts inner membrane -> stopping production of ATP -> Contents leak into cytosol
How does DNA damage result in NAD and thus ATP depletion
- Initiates repair sequences
- Activates PARP enzyme
- Causes necrosis in cells proliferating due to lack of NAD and ATP (going into repair sequence instead)
How does falling ATP levels effect calcium ion uptake
Increases calcium conc. in cell cytosol
Activates calcium-dependant proteases
Decreased inner mitochondrial membrane permeability
Necrosis
How does free radical damage to the ER effect calcium stores and what is the effect of this on the cell
Causes leakage into cytosol
Apoptosis (not necrosis)
How does free radical damage to lysosomal membranes cause necrosis
Release of cathepsin (protease) which damages membrane
How does tumour necrosis factor cause cell death
Binding to receptor -> excessive mitochondrial reactive oxygen species
Pathways that result in necrosis have one separate process that takes place, what is this?
Inflammation caused by immunostimulation
Repair process
Name the 6 types of necrosis
Coagulative Colliquative Gaseous Gangrene Fibrinoid Fat Necrosis
What is the most common type of necrosis
Coagulative
Describe the process of coagulative necrosis
- Proteins coagulate to keep cell shape in tact.
2. Tissue texture goes from firm to soft due to digestion by macrophages
Where in and why is coagulative necrosis dangerous in the heart
Myocardium following infarction can increase risk of ventricular rupture
How can I tell if a cell is undergoing coagulative necrosis
Nuclei and cellular detail will be lost but you can still see a faint outline of the cell itself
What effect follows coagulative necrosis
Inflammation
Where does colliquative necrosis take place and why
Brain
Has a lack of support for the storm
What happens during colliquative necrosis
- Necrotic neural tissue will totally liquidify
- Glial reaction around periphery
- Site of necrosis is marked by a cyst
What happens during caseous necrosis
Dead tissue is structureless
What disease can caseous necrosis be seen in
TB
What happens during Gangrene
Necrosis with putrefaction of tissues
Why do tissue effected by gangrene appear black
Due to deposition of iron sulphide from degraded haemoglobin
What bacteria typically causes gangrene
Clostridia
Where are clostridia typically found
Bowel
What type of necrosis can lead to gangrene necrosis
Ischaemic
Intestinal
Where is ‘wet’ gangrene found
Bowel (intestinal necrosis -> gangrene)
Where is ‘dry’ gangrene found
In the toes due to ischaemic necrosis
Name two types of gangrene that can be caused directly by bacteria
Gas Gangrene
Synergistic gangrene
When does fibrinoid necrosis take place
- During malignant hypertension when high tension in arterioles causes necrosis of smooth muscle wall
- Allows seeping of plasma into media + deposition of fibrin
How can I tell if fibrinoid necrosis has taken place on a slide
Vessel wall is bright red
Two ways fat necrosis is caused
- Direct trauma to adipose tissue and extracellular liberation of fat
- Enzymatic lysis of fat due to release of lipases
Describe the process of fat necrosis
- Trauma to adipose tissue causes release of intracellular fat
- Release -> inflammation
- Macrophages phagocytose fat
- Fibrosis
Example of disease where fat necrosis takes place
Acute pancreatitis
What are labile cells
Cells with a good capacity to regenerate
Example of labile cells
Epithelium
What are stable cell population cells
Divide at a slow rate and have capacity to replicate if necessary
What are permanent cells
Cells with no regeneration abilities
Examples of permanent cells
Nerve and striated muscle cells
Where can stem cells be found
Basal layer of epidermis
Sebaceous glands
Bottom of crypts
Bone Marrow
What can damage stem cell populations
Radiation
What is complete restitution
Where labile cell population is completely restored
Where can complete restitution take place
Epidermis
Describe complete restitution in skin
- Epidermis lost over small area during abrasion
- Cells at margin of lesions and at sweat glands transected by braised site proliferate
- Spread until covered -> form confluent layer
- After layer is formed, stimulus is switched off (contact inhibition)
^ Scab - Epidermis rebuilds from base upwards in process called healing
What happens in neoplasia
Contact inhibition and process of healing is disrupted -> proliferation of cells into tumour
When does granulation tissue develop
When specialised or complex tissue is destroyed
Describe the process of granulation tissue development
- Repair takes place
- Capillary endothelium proliferate and grow into area to be repaired (start as buds -> channels)
- Channels loop around damaged area
- Fibroblasts stimulated to secrete collagen and divide
- Fibroblasts acquire muscle filaments and attach to adjacent cells (called myofibroblasts)
- Cause wound contraction and secrete collagen
What does granulation tissue consist of
Loops of capillaries and myofibroblasts
What is excessive granulation called
Proud flesh
Why is wound contraction important
Reduce volume of tissue for repair by 80%
What structure does collagen secreted by myofibroblasts produce
Scar
What problems can wound contraction lead to
Stenosis (narrowing of blood vessels) and obstruction due to a stricture
How does skin healed during an incised wound
- Little damage to tissues on either side of cut are brought close together
- Blood vessels cut are occluded by thrombosis
- Fibrin deposits and binds two sides.
- Coagulated blood on surfaces forms scab to keep wound clean.
- Capillaries proliferate to bridge gap
- Fibroblasts secrete collagen as they migrate into fibrin network
- Basal epidermal cells proliferate and spread over gap
- Wound is healed
How does the size of the wound effect migration of fibroblasts
Migration would be less
What happens to the excess of basal epidermal cells after the skin has healed
Resorbed
How is healing different when tissues is lost or the sides of a wound are not close enough together
- Phagocytosis removes debris
- Granulation tissue to fill in defects and repairs specialised tissues
- Epithelial regeneration to cover the surface
What factor effects the time-scale of healing by second intention
The amount of granulation tissue needed to cover the wound
How are keloid nodules formed
Excessive fibroblast proliferation and collagen production after dermal injury
What growth factor is produced by keratinocytes and macrophages
VEGF (vascular endothelial growth factor) - new blood vessels
Role of PDGF (platelet - derived growth factor)
Facilitates local accumulation of macrophages, proliferation of fibroblasts and matrix production
What growth factor controls myofibroblasts and collagen formation
TGF-beta
Describe healing of mucosal erosions in the GI tract
- Epithelial cells adjacent to the defect proliferate to regenerate mucosa
How long does it take for mucosal erosions to be fixed
Hours
What is dangerous about mucosal erosions
Patients can lose a lot of blood before they heal
Describe the process of healing during mucosal ulcerations
- Destroyed muscle can’t be regenerated
- Mucosa replaced from margins and spreads across base of ulcer
- Damaged blood vessels will have bled and surface is covered by fibrin
- Macrophages remove dead tissue
- Granulation tissue produced at ulcer base
- Capillaries and myofibroblasts proliferate
What is the long-term consequence if the cause of an ulcer persists
- Ulcer becomes chronic and gastric wall can be destroyed
- Fibrous scar tissue replaces muscle and this will contract distorting stomach
Larger arteries in path of ulcer are at risk of rupture
What is an endarteritis
Zone of inflammation around chronic ulcerations can obliterate the lumen
What follows immediately from a bone fracture
Haemorrhage within the bone
Where does haemorrhage in the bone come from
Ruptured blood vessels in the marrow cavity
What is the benefit of a haematoma in bone fracture healing
It facilitates repair by providing a foundation for cell growth
What are the stages of repair in fracture healing of bone
- Removal of necrosis tissue
- Organisation of haematoma
- Deposit bone as woven - forms a callus
- Woven bone replaced by lamellar bone
What is a callus
Mass of bone with islands of cartilage
What are the two layers of a callus (woven) bone
- Inner callus (medullary cavity)
2. Outer Callus (periosteum)
What are five problems that can interfere with fracture healing
- Movement
- Interposed soft tissue
- Infection
- Misalignment
- Pre-existing bone disease
How does movement delay bone fracture healing
Movement between two ends of bone causes excessive callus production - slows tissue union
Prevents bone formation
Collagen is laid down to give fibrous union
False Joint
How does interposed soft tissue interfere with bone fracture healing
Found between broken ends and deals healing
How does misalignment effect bone fracture healing
Prevent good functional result - leads to degenerative disease in joint
In what type of fracture is infection most likely to have a negative impact on the healing process
Compound fractures
Why is the liver able to heal effectively
High regenerative capacity of hepatocytes
Other than hepatocytes, how can the liver regenerate (2)
From liver progenitor cells or bone marrow stem cells
When can the liver not be healed
When hepatocytes AND hepatic architecture are severely destroyed
What condition can failure to reconstruct hepatic architecture but regeneration of hepatocytes result in
Cirrhosis
What other organ can be regenerated if the epithelium is destroyed but not when architecture is
Kidney
What is the consequence of loss of tubular epithelium in the kidneys
Renal failure (this is the only exception where regeneration can’t happen) or damage to the glomerulus
What is the issue with smooth muscle and cardiac muscle fibre damage during healing
They tend to be replaced by fibrous tissue
In what condition can muscles be completely restored
If only the contractile proteins are lost
What cell do voluntary muscle cells regenerate from
Satellite cells
Define gliosis
Glial cells proliferate in response to injury to the CNS
Can neurones regenerate in the CNS
No
What two structures does peripheral nerve damage affect
- Axons
2. Schwann cells Oligodendrocyte
When does wallerian degeneration take place
if there is a transection of the nerve
What follows wallerian degeneration
Proliferation of Schwann cells
Why do Schwann cells proliferate
For axonal regrowth
Is full recovery of the CNS usual
No
What can occur if the ends of the axons proliferate but the cut is uneven
Amputation neuroma
What is the consequence of cell injury early in life
Prevention of normal growth and development of an organ.
What can cause cell injury to a child
Infection
Mechanical Stress
Why does ability to repair damaged tissues decrease as we get older
- Connective tissue becomes less elastic
- Renal function diminishes
- Bones weaken
- Cerebral neurones lost
What immune response do nerves have a role in mediating
Inflammation
if denervated, inflammation may not work properly
How are x-rays ionising
- High energy waves crash into atom causing it to become unstable and emit a photon.
What particles cause ionisation
Alpha, beta and gamma particles
how does UV light cause tumours
Damages DNA by inducing pyrimidine and strand linkages and is immunosuppressive
What cells are found in skin tumours
Basal and squamous cell carcinomas
What areas of the body are most sensitive to radiation
Gonads
Breast and bone marrow (half as sensitive)
Thyroid and bone
