Cell injury and death (IAS38, 40) Flashcards
Know that the effects of cell injury causes pathogenesis from homeostasis > adaptation > reversible cell injury > cell death
The effects are:
1) at molecular/biochemical level then
2) at structural changes then
3) histochemical/ultrastructural changes occur mins to hrs after injury
4) changes observable by light microscope days later
Also know that: Principal biochemical mechanisms and sites of damage in cell injury:
Intracellular aerobic respiration, enzymatic & structural proteins, cell/nuclear membrane, genetic apparatus
Question:
Rank: CNS neurons, fibroblasts/epidermis/skeletal muscle, myocardium, hepatocytes, renal epithelium in how susceptible they are to damage by ischemia
Most susceptible: CNS neurons (3-5 mins)
Intermediate: myocardium, hepatocytes, renal epithelium (0.5-2 hours)
Lowest: Fibroblasts, epidermis, skeletal muscles: many hours
List major causes of cell injury
1) Hypoxia - low oxygen supply
commonly caused by ischemia (inadequate and lowered blood supply) but also from lowered O2 carrying capacity of blood and poisoning of intracellular oxidative enzyme
2) Physical agents eg trauma/atmospheric pressure/ electricity/temperature/radiation
3) Chemical agents eg drugs/poisons/alcohol
4) biological agents eg bacti/fungus/virus/parasite
5) immunological reactions (hypersensitivity states/autoimmunity)
6) other factors - eg nutrition/genetics
List 4 reversible cell injuries
1 form of sublethal cell injury
And the 2 forms of cell death
Fatty change
Intracellular edema
Hyaline degeneration
Intracellular accumulation
sublethal nuclear damage
Cell death:
apoptosis, necrosis
Intracellular edema cause and morphology?
Morphology: cells become swollen with water and Na+ with or without vacuoles
Cause: Derangement of cell membrane, excessive influx of isotonic fluids
Fatty change cause and morphology? Where can this occur?
Fats abnormally accumulate in non-adipocytes - morphology: fat vacuoles present in cells, nucleus may be displaced
Causes: Chemicals and toxins (esp ALCOHOL - alcoholic liver disease), hypoxia, starvation/wasting diseases, metabolic disorders eg diabetes mellitus
Occurs in: liver, heart muscle, renal tubule
Hyaline degeneration morphology and examples
Glassy pink alterations (intra and extracellular)
Examples: Alcoholic liver disease, viral inclusion, arteriolosclerosis
Intracellular accumulation of what pigments or possible?
lipofuscin (aging pigment)
haemosiderin
Lysosomal storage disease
Some consequences of sublethal nuclear damage?
Sublethal nuclear damage method of action?
somatic cell neoplasia, heritable germ cell diseases
Causes altered gene transcription but no morphological changes
Apoptosis and necrosis - how many cells die?
Apoptosis: programmed cell death of individual cells
Necrosis: entire sheets of cells die
Know that for apoptosis:
1) tissue structure is preserved
2) no acute inflammation
Question: causes of apoptosis?
Pathological: UV/ionizing radiation, cytotoxic T cells, cell-mediated immunity, drugs, tumor cell death
Physiological: programmed cell destruction in embryonic development and normal cell turnover in adults
Process of apoptosis? (this is just the basic concept - for the in depth details of death receptor and mitochondrial pathways check kihiro’s notes)
Process:
Triggered by the mitochondrial (intrinsic) or death receptor (extrinsic) pathway
DNA fragmentation,
chromatin and cytoplasm condensation,
formation of apoptotic bodies,
and being phagocytosed by adjacent cells
Necrosis: Any tissue damage? Any inflammation?
The 2 forms of cell death in necrosis?
Can necrosis be caused physiologically?
Changes in nucleus for necrotic cells?
Tissue structure is disrupted, acute inflammation present, sometimes scarring present
autolysis and heterolysis -
autolysis: Structural disintegration due to digestion by lysosomal hydrolases
heterolysis: Digestion by immigrant leukocytes upon release of cytokines
NECROSIS IS ALWAYS PATHOLOGICAL
pyknosis (nuclear shrinkage), karyorrhexis (nuclear fragmentation), karyolysis (nuclear dissolution)
Morphological types of necrosis?
Caseous necrosis
Coagulative necrosis
Liquefaction necrosis
Fat necrosis
Fibrinoid necrosis
Caseous necrosis: most common locations and cause
morphology?
solid organs, commonly caused by infarctions
Tombstone appearance - acidophilic, opaque cells
Tissue architecture and outline preserved but loss of nucleus
Polymorphonuclear cells infiltrate to handle the infarcted area - blue rim in histological slides under H&E staining
Liquefaction necrosis: causes?
Morphology?
Infarction, most commonly brain ischemia
tissue structure lost because of hydrolytic enzymes
cystic spaces left, cell debris cleared
Caseous necrosis: causes and morphology?
Causes: mycobacterial infections eg TB
morphology: cream cheese appearance
Cell outline disappears, tissue changes into amorphous mass surrounded by granulomatous inflammation, with macrophage accumulation
fat necrosis origins, causes and pathogenesis?
1) Enzymatic in origin, eg acute pancreatitis (necrosis of pancreatic cells)
Causes: bile stones, ALCOHOL
Enzymes released from the pancreatic cells would digest their neighbours. Pancreatic lipase hydrolyses TAG into glycerol and fatty acids, which complex with Ca2+ to form soap (deposited as chalky white patches)
2) traumatic in origin, eg in breast
Lipids released from fat cells provoke a chronic inflammatory and giant cell reaction.
A hard indurated mass is formed; patients may perceive it to be cancer
Fibrinoid necrosis: Morphology and examples
Tissue death is accompanied by fibrin deposits
Examples:
Rheumatoid nodules, Arthus reaction, arteriolar lesions of malignant HTN
Effects of necrosis?
1) loss of function
2) Release of cell contents
3) Acute inflammation
4) Acute inflammation
5) Effects of repair (scar formation) and regeneration
6) Dystrophic calcification
7) Infection
Autophagy mechanism?
Functions of autophagy and consequences of dysregulation?
The cell components undergo lysosomal digestion; this is enhanced by nutrient deprivation.
Cellular organelles are sequestered into cytoplasmic autophagic vacuoles (autophagosomes), which fuse with lysosomes and digest the enclosed materials.
It plays a role in host defence against certain microbes.
It may be used as a renewable source of nutrients under stress.
Dysregulation occurs in diseases such as cancers, neurodegenerative disorders and inflammatory bowel disease.
General tissue response to cell injury? In chronological order
1) acute inflammation
2) demolition of necrotic tissues and debris
3) Healing (stimulus removal, restoration of function)
4) resolution
What does healing include
Repair and regeneration
repair: replacing lost tissue by granulation tissue (ingrowth of vascular tissue from surrounding connective tissue), granulation tissue matures to form scar (fibrous) tissue
regeneration: lost tissue replaced by similar type, driven by growth factors
Granulation tissue components?
1)Fibroblasts,
2) myofibroblasts (to draw wound edges together and produce connective tissue stroma),
3) thin-walled capillaries,
4) inflammatory cells (macrophages)
What do growth factors include
Vascular endothelial growth factors (VEGFs)
Fibroblast growth factors (FGFs) → collagen
Transforming growth factor-β (TGF-β) → connective tissue proteins
Mitogenesis: e.g. EGF
3 types of cells based on their regenerative properties:
1) labile cells
2) stable cells
3) permanent cells
Question: describe their properties and give examples
1) Labile cells: constantly proliferating and lost, constant regeneration (as part of normal cell turnover - replaced by maturation of tissues and proliferation of cells)
Cells lining the surface epithelium, red blood cell lineage cells
2) Stable cells: usually quiescent (in G0 of cell cycle), minimal proliferation, can reenter cell cycle in response to injury
eg Solid organs (liver, kidney, pancreas), smooth muscle cells
3) permanent cells: CANNOT PROLIFERATE EVEN WHEN THERE IS LOSS (terminally proliferated)
eg most neurons, cardiac muscle cells
Process of wound healing?
Mechanism:
1) Migration & regeneration of parenchymal cells
2) Migration & proliferation of connective tissue cells (repair); cell-cell and cell-matrix interaction causes cells to stop proliferating after defect healed
3) Synthesis of ECM proteins by fibroblasts (upon recruitment by macrophages): e.g. proteoglycans / type III collagen
o Remodelling of connective tissues & parenchyma
o Collagenization & acquisition of wound strength
¨ Type III collagen is eventually replaced by type I collagen to form a permanent scar.
¨ MMPs digest the ECM, and it is inhibited by TIMPs
Process of healing for skin/epithelial ulceration?
1) stop bleeding (hemostasis)
2) form scab, acute inflammation
3) regenerate epithelial covering + granulation tissue formation
4) collagen deposition, resorption of capillaries
5) scar formed
Compare healing by primary (abbreviated as 1 here) and secondary intention (abbreviated as 2) (in terms of wound type, tissue loss, amount of inflammatory and necrotic materials to remove, amount of granulation tissue, wound contraction, size of scar, healing speed, liability to infection)
Describe reasoning for incision during birth
Wound type:
1: clean incision
2: open wound
Tissue loss:
1: less
2: more
Amount of materials to remove:
1: less
2: more
Amount of granulation tissue:
1: less
2: more
Wound contraction:
1: No
2: yes
Scar size:
1: smaller
2: larger
healing speed:
1: faster
2: slower
Infection liability:
1: less liable
2: more liable
Reason for incision during birth:
gives a clean incision in vagina for fetus passage instead of irregularly shaped tear/wound
so doc can suture the wound for easier healing (primary intention) with less granulation tissue/scarring
Bone fracture healing process?
1) Haematoma formation and inflammation
2) demolition of necrotic tissue by phagocytosis
3) Granulation tissue formed
4) Callus formation
- Osteoblasts are formed to deposit new bones.
- The provisional callus bridges the gap (first osteoid tissue, then
woven bone). - There is remodelling by resorption of healthy bones.
- As the callus forms and mineralizes to form a firm union, there is
both osteoblastic and osteoclastic activity; remodelling proceeds. - The trabeculae of the newly woven bone is rimmed by osteoblasts
which produced it.
5) Lamellar bone formation to increase bone strength
6) remodelling and then final reconstruction
Damage in cardiopulmonary system - 3 types, myocardial infarction, bronchopneumonia and inhalation of toxic fumes
Describe the pathogenesis of each form and what happens in subsequent healing
Bronchopneumonia: damage mainly in pneumocytes lining alveoli due to infection BUT alveolar wall connective tissue is minimally damaged - minimal granulation/scar tissue
so pneumocytes (they are labile cells and constantly regenerate) can regenerate to restore normal lung
Inhalation of toxic fumes: damage to BOTH pneumocytes and alveolar wall connective tissue - so alveolar wall has to undergo repairs and causes scarring (interstitial fibrosis)
Myocardial infarction (heart attack): Cardiac muscles die - they cannot regenerate anymore as they are permanent cells, replaced by granulation tissue that later forms scar tissue
Damage to liver and kidneys: know the levels of damage
If hepatocytes/renal tubular cells die - CAN regenerate as they are stable cells
BUT if connective tissue stroma is broken what happens?
Formation of granulation tissues - SCARRING (eg liver cirrhosis)
Regeneration capacity of muscles, cartilage and tendons?
Cartilage: very poor regeneration capacity
tendons: good regeneration capacity but very slow
Muscles:
cardiac cannot regenerate
skeletal muscles can regenerate by satellite cells
smooth muscles have highest regeneration abilities
Damage to neurons: how does recovery occur
And pathogenesis of stroke?
Mature neurons are permanent cells, cannot regenerate (for CNS basically no chance of regeneration but possible for CNS)
1) wallerian degeneration at distal side of axon
2) If site of damage is not too close to cell body (soma) regeneration possible
3) Schwann cells proliferate and axons sprout (for 20mm/week)
4) apposition of nerve ends (reattachment) BUT if apposition is POOR can lead to traumatic neuroma (VERY PAINFUL) and severe muscle atrophy
Neuronal connection can only be re-established by re-growth and re-organisation of cell processes of surviving neurons
Stroke: Nerve cells in area of infarction destroyed, inflammation of surrounding brain, swelling and congestion occurs
inflammation subsides and affected area becomes smaller, so some function regained BUT NO REGENERATION where neurons are destroyed
Know some factors affecting wound healing:
Local factors: e.g. type of wound, apposition of wound margins, blood supply, infection (delays healing), presence of foreign bodies (induce chronic inflammation), irradiation (prolong inflammatory response)
General factors (adverse effect): e.g. nutrition (protein / vitamin C deficiency), steroid administration (causes scar weakness),
systemic diseases (diabetes mellitus, renal failure, cancer cachexia)
General factors (enhancing effect): Exposure to UV light
Name 3 possible complications of wound healing (more listed in the answer)
Infection
Wound dehiscence - breakdown of unhealthy sutured wound ends
Keloid formation - excessive scar tissue formation (with genetic predisposition)
Painful scars: caused by nerve damage, formation of traumatic neuromas by bundles of nerve endings (poor apposition of nerve endings)
Weak scars: caused by excessive motion/tension on wound
Pigmentation: Delayed healing / excessive bleeding → deposition of haemosiderin
Cicatrisation: Narrowing of lumen due to scarring
Abdominal surgery and weak scars:
Know that patients become reluctant to cough to avoid aggravating the wound - more susceptible to chest infections, and should avoid lifting heavy objects
hernias: may cause bowel loop to protrude through abdominal wall and get strangled when abdominal muscles contract - may cause infarction and even death
Stem cell key properties for wound healing?
asymmetric division, self renewal
Stem cell sources?
In adults: bone marrow, blood, fat, muscle, skin, conjunctiva
Embryos: inner cell mass of blastocyst
Or by genetic engineering: program adult cells to assume stem cell-like state (induced pluripotent)
How to extract embryonic stem cells
From inner cell mass of blastocyst at day 4 after fertilization from IVF embryos and then frozen
Pros, cons and risks of embryonic stem cells?
Pros: versatile, can be cultured rapidly
Cons: BUT difficult to induce them into the desired tissues
Risks: immune rejection, tumor formation, infection transmission (they can grow on rat fibroblasts)
BUT HAVE NOT BEEN SUCCESSFULLY USED FOR TREATMENT
Some advantages of adult stem cells?
Easier to coax them into the desired tissues (even though their lifespan is still finite)
Less risk of tumor growth and immune rejection
Versatility (less than embryonic but still there) -
eg bone marrow stem cells can develop into epithelial cells of: liver, lungs, GI tract, skin
human fat cells from liposuction can develop into fat cells/bone cells/cartilage cells/muscle cells
