3- Mechanisms of Disease II: Cell Damage and cell death Flashcards
What are the 6 causes of cell damage?
→ Physical → Genetic → Inflammation → Infection → Traumatic damage → chemical
What are the functions of necrosis?
Removes damaged cells from an organism
Failure to do so may lead to chronic inflammation
Necrosis causes acute inflammation to clear cell debris via phagocytosis
What are the causes of necrosis?
Usually lack of blood supply, e.g. injury, infection, cancer, infarction, inflammation
When does necrosis occur?
→ occurs after stresses such as ischemia, trauma and chemical injury
What is the most common cause of cell death?
→ Necrosis
What is apoptosis?
→ Programmed cell death
What are the three basic mechanisms of cell death?
→ Necrosis
→ Apoptosis
→ Autophagic cell death
What is the relationship between pH + oxygen levels and distance from the vessel?
→ the further away from the blood vessel the O2 and pH drop
What are 2 characteristics of necrosis?
→ Result of an injurious agent or event. Whole groups of cells are affected
→ reversible events proceed irreversibly
What occurs as a result of O2 deprivation in cells?
→ unable to produce ATP due to O2 deprivation
→ cells swell due to influx of water (ATP needed for ion pumps)
What causes destruction of organelles?
→ Ruptured lysosomes
What does cellular debris released from necrosis cause?
→ Inflammatory cell response
Describe necrosis step-by-step.
- Result of an injurious agent or event. (Whole groups of cells are affected.)
- Initial events are reversible, later ones are not.
- Lack of oxygen prevents ATP production.
- Cells swell due to influx of water (ATP is required for ion pumps to work).
- Lysosomes rupture; enzymes degrade other organelles and nuclear material hapzardly
- Cellular debris released, triggering inflammation
What are the 3 types of changes in a necrotic cell?
→ Nuclear
→ Cytoplasmic
→ Biochemical
What are the 3 nuclear changes in necrosis?
→ Chromatin condensation/shrinkage
→ fragmentation of the nucleus
→ dissolution of chromatin by DNAse
What are the 2 cytoplasmic changes in necrosis?
→ Opacification : denaturation of proteins with aggregation
→ complete digestion of cells by enzymes cause the cell to liquefy (liquefactive necrosis)
What are the 2 biochemical changes in necrosis?
→ Release of enzymes such as creatine kinase or lactase dehydrogenase which can be measured in the lab → myoglobin released
What happens in astrocytoma?
As tumour grows the surrounding vascularisation, the blood vessels become further from the middle
Such that as cancer progresses- it is important that they are able to induce their own vascularisation to supply themselves with blood as they grow
What features of this cell demonstrate necrosis?
→ No dark staining in the nucleus because the DNA is degraded
What is the function of necrosis and why?
→ Removes damaged cells from an organism
→ failure to do so leads to chronic inflammation
What is the function of apoptosis?
→ Selective process for the deletion of superfluous infected or transformed cells
List 8 examples of apoptosis?
→ Cell death in embryonic hand to form fingers
→ apoptosis induced by growth factor deprivation
→ DNA damage mediated apoptosis
→ cell death in tumours
→ cell death in viral diseases
→ cell death induced by cytotoxic T cells
→ death of neutrophils during an acute inflammatory reponse
→ death of immune cells
What is apoptosis involved in?
Embryogenesis Metamorphosis Normal tissue turnover Endocrine-dependent tissue atrophy A variety of pathological conditions
Describe apoptosis step by step.
- Programmed cell death of one or a few cells.
- Events are irreversible and energy (ATP) dependent.
- Cells shrink as the cytoskeleton is disassembled.
- Orderly packaging of organelles and nuclear fragments into membrane bound vesicles.
- New molecules are expressed on vesicle membranes that stimulate phagocytosis without an inflammatory response.
3 Differences between apoptosis and necrosis
Necrosis-multiple cells at once
apoptosis- selected cells
Necrosis- reversible and no ATP
apoptosis- irreversible and ATP
Necrosis- no orderly packaging apoptosis- orderly packaging of organelles…
Apoptosis- clean way of disposing cellular contents
What are 3 factors that promote survival?
→ Growth factors
→ Cell-cell or cell-matrix contacts
→ cytokines
What are 4 factors that promote cell death?
→ Disruption of cell-cell contact or cell-matrix
→ lack of growth factors
→ DNA damaging agents
→ death domain ligands
What are the two types of apoptosis?
→ Intrinsic
→ Extrinsic
What are the 5 causes of intrinsic apoptosis?
→ DNA damage p53 dependent
→ interruption of the cell cycle
→ inhibition of protein synthesis
→ viral infection
→ change in redox state
What are the 3 extrinsic causes of apoptosis?
→ Withdrawal of growth factors (IL-3)
→ extracellular signals (TNF)
→ T cell or NK (granzymes)
What are the 3 types of changes of apoptotic cells?
cytoplasmic changes
nuclear changes
biochemical changes
What are cytoplasmic changes in apoptotic cells?
- Shrinkage of cell. Organelles packaged into membrane vesicles.
- Cell fragmentation. Membrane bound vesicles bud off.
- Phagocytosis of cell fragments by macrophage and adjacent cell.
- No leakage of cytosolic components.
What are the nuclear changes in apoptotic cells?
- Nuclear chromatin condenses on nuclear membrane.
2. DNA cleavage.
What are the biochemical changes in apoptotic cells?
- Expression of charged sugar molecules on outer surface of cell membranes (recognised by macrophages to enhance phagocytosis)
- Protein cleavage by proteases, caspases
What are caspases?
Cysteine proteases that play a central role in the initiation of apoptosis
Where do caspases cut?
→ between cysteine and aspartate residues
Describe the activation of caspase Y
→ The caspases are released in their inactive form -inactive procaspase Y
→ This is activated and cleaved by an active caspase X
→ After cleavage a small and large subunit are formed which makes a simer and forms active caspase Y
→ Caspase X is also expressed in an inactive form
Describe the caspase cascade?
→ In response to triggering apoptosis you have active initiator caspase 8 or 9
→ these activate other caspases which cleave cytosolic proteins containing cysteine or aspartate
What is the function of the effector caspases?
→ Actin cytoskeleton breakdown and cell collapse
→ nuclear lamins are also cleaved
What microscopic changes does caspase activation lead to?
→ morphological changes such as shrinkage
→ chromatin condensation
→ DNA fragmentation
→ plasma membrane blebbing
What do blebs contain?
→ intact organelles such as mitochondria
How do blebs get broken down?
→ They are coated in sugar and digested by macrophages
Which bands are : normal, necrotic and apoptotic and why?
→ Normal DNA is heavy so it gets stuck at the top (lane 1)
→ There is laddering in apoptotic cells because the nucleosomes are intact (lane 2)
→ necrotic cells have no laddering because the fragmentation of necrotic cells is random and there are no nucleosomes
What are the 3 characteristics of apoptosis?
→ single or a few cells are selected
→ programmed cell death
→ irreversible once initiated
What happens to the organelles and nuclear fragments in apoptosis?
→ orderly packaged into membrane bound vesicles
What are the nuclear microscopic changes in apoptosis?
→ DNA cleavage
→ Nuclear chromatin condenses on nuclear membrane
