Necrosis, Apoptosis, Topics A1-A5 Flashcards
A/1 Causes, morphology, and mechanisms of cell necrosis
What is the Definition of necrosis
List the Causes of necrosis (9)
Necrosis: dead or dying cells inside of a living host, undergoing cell death due to severe cellular damage. Involves mitochondrial damage, membrane disruption and lysosomal leakage into the cell, and cytoplasm leakage into surroundings. Causes inflammation and is always pathologic.
1) Ischemia - no blood supply, no oxygen, no nutrients or energy sources, and no clearance of metabolic wastes. pH drop, CO2 accumulation. Can occur suddenly.
2) Hypoxia - lack of oxygen due to impaired gas exchange in the lung (pneumonia, pnemothorax, ARDS) or impaired oxygen carrying of the blood (hemeglobin deficit, CO poisoning, or anemia). Hypoxia usually occurs more gradually and is dispersed throughout the whole blood so it does not usually cause local necrosis.
3) Toxins or Chemicals - many different kinds and different mechanisms, may disrupt membranes, inhibit ion pumps and disrupt osmotic balance, inhibit RNA transcription, may be highly reactive such as ROS and non-specifically damage many proteins, DNA, and membranes, lipid peroxidation.
4) Infectious agents - viruses, bacteria, fungi
5) Genetic defects- lysosomal storage diseases, DNA repair or chaperone protein defects, accumulation of DNA injuries or misfolded proteins.
6) Nutritional deficits or over-excess - vitamin deficiency, ROS accumulation, Folate defeiciency and megaloblastic anemia. Lipid excess may cause adipocytes to burst.
7) Physical damage - Trauma, burns or freezing, radiation
8) Immune related damage - Autoimmune reactions, antibody accumulation, immune complex deposition, granzymes, ROS, MAC, lysosomal enzymes, bystander effect toxicity, direct Tc and NK mediated damage.
9) Aging - telomere shortening and eventual cell cycle arrest. accumulation of cellular DNA defects causing many problems.
A/1. Causes, morphology and mechanisms of cell necrosis.
Describe the cellular morphology of necrosis (6 major changes occur)
What is the main cause of the cellular morphology changes?
The cellular changes are primary due to the enzymatic digestion of cellular components.
Either by Autolysis (from cells own enzymes)
or Heterolysis (another cells enzymes, either an immune cell or an infectious cell ex. hemolysis enzymes from bacteria)
1) Eosinophilia - from the coagulation of proteins that have denatured and aggregated, most proteins are eosinophilic.
2) Glassy appearance - Glycogen depletion and loss of granules making them look clearer and more glossy.
3) Vacuolated Cytoplasm - from organelles being digested
4) Myelin figure formation - intracellular aggregations of cell membrane in lamellaed clumps, seen by electron microscopy
5) Membrane fragmentation
6) Nuclear changes: pyknosis: DNA condensation and staining darker, more basophilic, or karyorhexis; the pyknotic nuclei then fragments, and finally karylysis, in which the nucleus fades and dissapears from DNAse digestion.
A/1. Causes, morphology and mechanisms of cell necrosis.
Describe the different types of Tissue Necrosis
1) Coagulative necrosis: Cell outlines preserved, coagulation of proteins causes acidophilic granular appearance of cell bodies.
2) Liquefactive necrosis: Enzymatic digestion liquifies the tissue, cell membranes dissapear, inflammatory cells accumulate, and pus is formed.
3) Gangrenous necrosis: Due to loss of blood flow, happens in extremities and moves inward.
- Gangrena Sicca, coagulative gangrene, dry: dry blackened tissue
- Gangrena Humida, liquifactive gangrene, wet: bacterial infected, wet, pus filled tissue.
4) Caseous necrosis: Occurs in tuberculosis, has both coagulative and liquifactive regions. Granuloma formation around a central liquified region.
5) Fat necrosis: Liquifactive with calcification of fat tissue. Seen in pancreatitis. Visible as a chalky white calcified areas.
6) Fibrinoid necrosis: Damaged/Leaky Endothelial lining of vessels causes protein leakage and precipitation out into the basal lamina. Immune complexes, and f__ibrin form eosinophilic deposits. Is ONLY seen by histology, and not grossly visible.
A/1. Causes, morphology and mechanisms of cell necrosis.
Describe the molecular mechanism of necrosis
1) Mitochondrial damage or prolonged hypoxia
- glycogen used up by anaerobic metabolism
- glycogen depletion, lactate acumulation
- pH decrease
- formation of mitochondrial permeability transition pore
- Cyt-c leakage –> apoptosis pathway activation
- ROS leakage
2) ATP depletion
3) Membrane pumps fail.
- H2O influx
- ion dysregulation
- cell swelling
4) Ca++ increases, causing the point of no return. Caused by pump failure and leakage from the ER and mitochondria.
5) Ca++ activated proteolytic enzymes, and also facilitates mitochondrial transition pore formation, so if they weren’t damaged yet they will be once Ca++ elevates.
- ATPases
- Phospholipases
- Proteases
- Endonucleases
- All activated by Ca++
6) Membrane breakdown,
- ROS and lipid peroxidation
- ATP depletion and no more phospholipid synthesis
- Phospholipases and proteases activated by Ca++
7) DNA and protein widspread damage
* From DNAses, proteases, and non-specific ROS damage.
What are the major reactive oxogen species and free radicals?
Superoxide Anion: O2<strong>-</strong> Made by incomplete oxidation of O2 in the mitochondria.
H2O2: Made by from two superoxide anions by Superoxide Dismutase or by Peroxisomal enzymes. peroxisome is a major site of very long chain fatty acid breakdown
Hyroxyl Radical: _._OH Made by radiation or from H2O2 reacting with water
Peroxynitrite: ONOO: made by phagocytes and cytotoxic cells, and also within mitochondria when NO reacts with Superoxide anions.
Iron and Copper can catalyze ROS forming reactions, and so transferrin and ferritin are antioxidants.
A/2. The causes and mechanisms of apoptosis. Apoptosis in pathologic conditions.
List the causes of apoptosis
Physiologic situations
- Development, fingers example
- Death of hormone dependent tissues on hormone or trophic factor removal -menstruation, breast tissue reduction after breastfeeding
- Death of proliferative cells, on a mucous membrane or of the epidermis
- Inflammatory cells at the end of their lifespan
- Elimination of lymphocytes during negative/positive selection in the marrow and thymus
- Cell death induced by cytotoxic T-cells, FasL expressed on T-cells, type 1 TNF receptor on target cells. Other cytokine pathways that may induce apoptosis, other TNF-receptors
Pathologic situations
- DNA damage, radiation, chemotherapy, hypoxia and ROS
- Accumulation of misfolded proteins
- Infection induced apoptosis, often by viruses, or by the immune system response to the infection.
- Obstruction of an organ duct causing apoptosis of the organ parenchyma
- Cell atrophy due to shortage of nutrients
A/2. The causes and mechanisms of apoptosis. Apoptosis in pathologic conditions.
Describe the appearance of apoptotic cells
Cell shrinks
The nucleus condenses and fragments (Pyknosis and Karyorrhexis)
The membrane remains in-tact
The cell fragments in a controlled manner, forming apoptotic bodies,
Which are phagocytosed by local tissue macrophages
There is no adjacent inflammatory response.
eosinophilic cytoplasm
A/2. The causes and mechanisms of apoptosis. Apoptosis in pathologic conditions.
1) Mechanism of apoptosis:
2) What are the main anti-apoptotic Bcl-2 proteins?
1) Intrinsic, mitochondrial pathway:
Cell injury -> Bcl-2 sensor proteins activate Bcl-2 effectors, Bax and Bak
Bax and Bak dimerize and form pores in the mitochondrial membrane.
Cytochrome c leaks to the cytosol and initiates apoptosome formation and activates Caspase-9, inducing the apoptosis cascade. and activation of the executioner caspases 3, 6, 7
Other mitochondrial proteins also leak out and inhibit anti-apoptotic signaling pathways.
2) Extrinsic Pathway, Death Receptor Pathway
- Cell expresses a Death Receptor such as Fas, usually a member of the TNF receptor family.
- Fas Ligand expressed by cytotoxic T cells activates the receptor, causing Trimerization of the FasR
- Aggregation of the receptor Death Domains allows FADD adaptor protein to bind (Fas-associated Death Domain protein).
- DISC complex (death induced signaling complex) forms and activates Caspase-8.
- Caspase-8 activates pro-apoptotic Bid protein, and Caspase-8 and Bid induce apoptosis.
Bcl-2 and Bcl-XL are the main anti-apoptotic Bcl-2 proteins.
A/3. Coagulative necrosis, organ manifestations
What does the tissue look like in coagulative necrosis?
What organs exhibit this, and after what kind of lesions?
In coagulative necrosis, the cells die, the nuclei disspear but the cell outlines are preserved and the tissue remains firm. The injury causes protein denaturation and the intracellular proteins become coagulated.
Eventually, inflammatory cells migrate in and digest the necrotic tissue,
It is replaced by fibrotic tissue scar, that then retracts.
It occurs after both Anemic (white) or Hemorrhagic (red) Infarcts in different organs.
Anemic infarcts with coagulative necrosis:
- Kidney infarct
- Spleen infarct
- Gangrena sica
- some rare cases of AMI, AMI before reperfusion
Hemorrhagic infarcts with coagulative necrosis
- AMI after reperfusion
- Pulmonary infarct
- Intestinal infarct
What is the difference between a hemorrhage and an anemic infarct?
Where do they occur and what causes them?
Hemorrhagic or Red Infarcts:
- From Veinous occlusions
- In loose tissues where blood can easily accumulate, like the lung
- In tissue with dual circulation, like the lung and intestines.
- After reperfusion
- Lung, Intestines, Heart after AMI-reperfusion
Anemic or White Infarcts
- From arterial occlusions in solid organs with terminal arteries
- coronaries, spleen, kidney,
- During Gangrena sicca.
- AMI with no reperfusion.
A/3. Coagulative necrosis, organ manifestations
desccribe pulmonary infarcts
Caused thromboembolisms originating from:
- DVT of the leg or femoral vein, due to prolonged inactivity, bedrest, fractures.
- Periprostatic veins in men with prostatic hyperplasia
- Parametric veins in pregnant women.
Large emboli, block a main artery and will cause acute hypoxia or acute right heart failure, causing death before necrosis can occur.
If bronchial circulation is good (young people), then small emboli may not cause any necrosis.
But, a small emboli in the context of weak circulation (old patients, CHD, HF) causes hemorrhagic coagulative necrosis.
Wedge shaped with the base near the border of the lung and the apex pointing towards the hilus.
First 48 hours, it is blue-red.
Then becomes red-brown as macrophages clear the RBCs and form hemosiderin
last, fibrotic white scar tissue forms.
A/3. Coagulative necrosis, organ manifestations
Describe Kidney and Spleen infarcts
- a thromboemboli obstructs an end artery, causing anemic coagulative necrosis.
- Wedge shaped, with occlusion at the apex then extending outward.
- In a few hours, the infarct borders become defined by a hyperemic rim due to inflammation.
- 1-2 days later the infarct is pale/whitish with sharply defined borders which is later replaced by a fibrotic scar.
A/3. Coagulative necrosis, organ manifestations
Describe gangrena sicca
Reduced blood flow usually due to angiopathies and/or atherosclerosis.
Chronic hypoxia and ischemia causes the anemic coagulative necrosis.
One warning sign for gangrena sicca is Claudication Intermittens, when a patient performs an action like walking, it evokes muscle pain due to the increased muscle energy demand and the inability to increase supply.
A/3. Coagulative necrosis, organ manifestations
Describe Intestinal Infarct
Because the intestine has two circulations, occlusion of the inferior mesenteric doesn’t cause infarcts, since the SMA is strong enough to compensate via its anastomoses.
SMA thromboembolism - hemorrhagic necrosis of the duodenum and jejunum.
Portal vein occlusion - hemorrhagic necrosis of the entire intestinal tract.
Causes a transmural infarction of the intestine. (all layers)
Within 24 hours, bacterial proliferation causes septic/wet gangrene and intestinal perforations, sepsis and septic shock.
A/3. Coagulative necrosis, organ manifestations
Describe AMI
Separate cards for this, but with relation to this topic:
Non-reperfused AMI causes Anemic Coagulative Necrosis.
Reperfusion after AMI causes Hemorrhagic Coagulative Necrosis.
