PATH 201 - LECTURE 3

what is response to cell injury specific to

cell type

what type of cell death is this and how do u know

• irreversible

• loss of cell nuclei

• fragmentation of cells

• leakage of contents

what are the two types of cell death

• necrosis and apoptosis

what type of cell death is termed cell suicide

apoptosis

what type of cell death is termed cell homicide

necrosis

what happens to a normal cell following irreversible cellular stress

• necrosis

• cell death

what happens once a cell has undergone necrosis

• cell swells

• membrane ruptures

• its cellular contents begin to leak out which triggers inflammation attracting neutrophils and macrophages

• dead cell is broken down by autolysis or heterolysis

• debris is cleared by macrophages

describe autolysis

digestion by the cells own lysosomal enzymes

describe heterolysis

digestion by enzymes released from inflammatory cells such as neutrophils and macrophages

what are 3 changes that the nucleus undergoes in a necrotic cell

• nuclear fading

• nuclear shrinkage

• nuclear fragmentation

describe nuclear fading

• chromatin dissolution due to action of DNAses and RNAses

describe nuclear shrinkage

• DNA condenses into a shrunken basophillic mass

describe nuclear fragmentation

nuclei membrane ruptures and nuclei undergo fragmentation

what are the morphological types of necrosis

• coagulative

• liquefactive

• caseous

• fatty

• gangrenous

describe coagulative necrosis

• the tissue architecture is retained

where do we see coagulative necrosis

heart and kidneys

what is coagulative necrosis generally due to

hypoxia

describe liquefactive necrosis

• cellular destruction and pus formation

what is liquefactive necrosis often caused by

• bacterial/fungal infection

• brain ischaemia

describe caseous necrosis

combination of coagulative and liquefactive necrosis

cheesy appearance

describe fatty necrosis

• caused by lipases

where do we normally see fatty necrosis

• pancreas and breast

what is gangrenous necrosis in response to

• severe hypoxia and subsequent bacterial infection

what type of response does necrosis trigger

• inflammatory response

what does an inflammatory response triggered by necrosis lead to

clearing of necrotic material and healing

describe apoptosis

• it is programmed cell death

is apoptosis always pathological

• no it can be physiological aas well

describe what happens to the cell during apoptosis

• cell shrinkage

• chromatin condensation

• cytoplasmic blebs and apoptopic bodies

• phagocytosis of apoptopic bodies by adjacent cells

• membranes and organels preserved

does apoptosis trigger an inflammatory response

no

describe what happens to the nucleus of a cell during apoptosis

fragmentation into nucleosome sized fragments

compare what happens to the cellular contents in apoptosis versus necrosis

• in apoptosis the cell contents remain intact

• in necrosis enzymatic digestion occurs and contents leak out of the cell

describe what happens to the plasma membrane in apoptosis compared to necrosis

• plasma membrane is disrupted in necrosis

• it remains intact but altered structure in apoptosis

which type of cell death affects groups of cells

necrosis

which type of cell death is active

apoptosis

which type of cell death is always pathological

necrosis

which type of cell death causes an increase in cell size

necrosis

which type of cell death does not cause inflammatory response

• apoptosis

what are 3 major molecular mechanisms of cell injury

• ATP depletion

• reactive oxygen species

• misfolded proteins

• DNA damage

• inflammation-mediated injury

what normally causes ATP depletion in a cell

• hypoxia - lack of oxygen

• most ATP using oxidative phosphorylation (ADP>ATP)

• lack of oxygen means no ATP

what is the consequence of ATP depletion on the cell

• initially it will cause reversible cell stress

• if it continues over a prolonged period, it will led to cell death

• type is necrosis

what causes ROS to increase

• hypoxia, chemicals, radiation, inflammation

what does ROS do to the cell

• damages lipids, proteins, DNA > necrosis

• can also trigger apoptosis

describe what causes misfolded proteins

• mutations

• aging

• infections (viral)

• hypoxia

• ischaemia

what happens when we have misfolded protiens

• they accumulate in the ER

• we get ER stress

• if the problem cannot be rectified

• cell undergoes apoptosis

what does misfolded proteins cause (disease wise)

• causes neurodegenreative disease such as

• huntingtons

• parkinson

• alzheimer

describe what causes DNA damage

• ROS

• radiation

• chemicals

• etc

what mechanism does the cell have against DNA damage

• the cell detects it through intracellular sentinels

• stabilisies p53 which causes the cell cycle to stop

• the DNA attempts to repair itself

• if not - apoptosis of the cell

describe inflammation mediated injury

• In infections and autoimmune disease, inflammatory cells attempt to eliminate microbes or abnormal targets. However, they also release

• cytokines

• proteolytic enzymes

• ROS

• can be damaging and cause necrosis or apoptosis

what is apoptosis’s role during embryogenesis

• when we are developing we have webbed fingers and toes - apoptosis removes this webbing

what is an example of hormone dependant apoptosis

during mentruation we get thickening of the endometrium, if there is no implantation, it is shed - the shedding is done by apoptosis

what is apoptosis’s role in cell division

• cell division is not a perfect process

• apoptosis takes care of any cells that were mistakes

at what points in the cell cycle is cells checked for DNA damage

• between G1 and S phase

• between G2 and mitosis

describe the checkpoint before S phase

• if DNA damage is detected

• p53 (tumour supressor) accumulates>p21

• p21 inhibits cyclin CDK complexes which stops the cell moving into the G1 phase

where does DNA damage cause cells to accumulate

• in G1, because the checkpoint happens jsut before entry into S phase

• if damage is detected, they are not able to go through

what are the two pathways of apoptosis

• extrinsic

• intrinsic

describe the intrinsic pathway of cell apoptosis

• cell injury is detected by BH3 sensors in the cytoplasm of the cell

• cascade down to Bcl-2 effectors (Bax, Bak) which affect mitochondria

• mitochondria leaks cytochrome C and other pro-apoptopic proteins

• cytochrome c leads to activation of initiator caspases and then executioner caspases

describe the extrinsic pathway of cell apoptosis

• ligand-mediated

• adaptor proteins within the cell feed into initiator caspases when a ligand binds

• initiator caspases go downstream and activate executioner caspases

what happens when executioner caspases are activated

• endonuclease activation and breakdown of the cytoskeleton which creates the membrane blebs

what are the receptors associated with apoptosis

• TNF-R family

• Fas

what are the ligands associated with apoptosis

FasL expressed on T cells

what caspase mediates the intrinsic pathway

caspase 9

what caspase mediates the extrinsic pathway

caspase 8

what are caspases

• proteases that mediate apoptosis

how are caspases activated

• inactive procaspases have cleavage sites

• they must be cleaved, and they can then come together and be activated

what controls the intrinsic apoptopic pathway

• proapoptopic entities such as BAX and BAK

• antiapoptopic entities such as BCL-2

what does malfunction of apoptosis lead to

disease

what causes cancer

• malfunction in pro and anti apoptopic genes

what is cervical cancer caused by

• inactivation of p53 (tumour suppressor protein that accumulates with DNA damage) by human papilloma virus