Mechanism of Cell Injury and Death

give examples of cell changes that are reversible cell injury

1. plasma membrane alterations like blebbing, blunting, loss of microvilli 2. nuclear alterations 3. mitochondrial swelling 4. ER dilation 5. "myelin figures"

when the ER undergoes stress due to misfolded proteins, what are 4 adaptations?

1. there is a decrease in protein synthesis 2. there is increased chaperones to help fold proteins correctly 3. there is increased proteasomal degradation of the misfolded proteins 4. there is slower translation

caseous necrosis

degeneration and death of tissue with a cheese-like appearance

Irreversible cell injury can result in...

necrosis or apoptosis

karyolysis

nuclear fading leading to nuclear dissolution and a necrotic cell

karyorrhexis

nuclear fragmentation leading to nuclear dissolution and a necrotic cell

pyknosis

nuclear shrinkage leading to nuclear dissolution and a necrotic cell

how does coagulative necrosis look?

tissue has a firm texture since structure is intact

how does liquefactive necrosis look?

tissue turns into a viscous liquid with pus due to proteolytic enzymes eating away at tissue

atrophy

to waste away

biomarker for hepatocyte damage:

transaminases (ALT/AST)

Why does fat necrosis occur?

trauma to fat and pancreatitis-mediated damage of peripancreatic fat there are pancreatic enzymes released which result in liquefying the fat cells

biomarker for cardiac muscle cell damage:

troponin

fibrinoid necrosis occurs from

vascular damage due to immune reaction with blood vessels there are complexes of antigens/antibodies which are deposited onto the walls on blood vessels

when is the mitochondrial (intrinsic) pathway of apoptosis activated?

when there is loss of survival signals, DNA damage and accumulation of misfolded proteins there is leakage of PRO-apoptotic proteins which causes caspase activation leading to apoptosis

wet gangrene

a liquefactive-like necrosis due to degradative enzymes in bacteria

Initiator caspases

2, 8, 9, 10 cleave the inactive proenzyme form of effector caspases

Effector caspases

3, 6, 7 these caspases are the ones that cleave substrates in a cell

pathologic cardiac hypertrophy and how it relates to perfusion and susceptibility to injury

In cardiac hypertrophy, there is an increase in protein synthesis more than degradation. In a pathogenic hypertrophy (such as LVH), there is a decline in ejection fraction, weaker walls, stiffening and loss of elasticity to the structure. This can result in decreased perfusion of the tissue. Hypertrophy can also be associated with fibrosis and cellular dysfunction. More stress= more injuries

How does the production of ROS affect a cell?

It can lead to membrane damage due to lipid peroxidation, protein modifications that end in protein breakdowns and misfoldings, and DNA damage that results in mutations

metaplasia

Mature cell type is replaced by a different mature cell type

necrosis vs apoptosis

Necrosis: bad, damage to nearby cells caused by lysis Apoptosis: good; for normal functioning of cell. Cell shrinkage, caspase activation, cell stays intact

Death Receptor Mediated Apoptosis Pathway (FASL)

This is an extrinsic cell death pathway 1. FasL binds to FAS receptor causing activation of caspase 8 (caspase 8 activation also leads to blocking BCL pro-survival proteins) 2. Caspase 8 activates caspase 3 which results in apoptosis activation

Mitochondrial Mediated Apoptosis

This is an intrinisic cell death pathway 1. Injury to the mitochondria causes pro-death proteins (BIM, PUMA) to activate more pro-death proteins (Bax) on the mitochondrial membrane (and inhibits pro-survival proteins (Bcl2) to be activated 2. cytochrome c is released from the mitochondria and attaches to the APAF1 protein 3. cytochrome c attached to APAF1 causes activation of caspase 9 which activates caspase 3 4. caspase 3 activates apoptosis

How does ischemia lead to ischemia reperfusion injury?

When there is reperfusion (restoration of blood flow, it's thought electrons in the ETC that were waiting to flow to the next step, flow out of the ETC complexes and interact with O2 to create free radicals. This ROS burst can be very harmful since it makes many ROS.

two groups of ROS scavengers with examples

antioxidants (such as vitamin E and vitamin A, ascorbic acid, glutathione) enzymes (catalase, SOD, glutathione peroxidase)

define adaptations and give some examples

adaptation is the cell's ability to change it's response to the environment under times of stress the cell can undergo hypertrophy, atrophy and metaplasia as an adaptation

biomarker for bile duct epithelium damage:

alkaline phosphatase

dry gangrene

an area of the body loses its blood supply and undergoes necrosis (coagulative)

hyperplasia

increase in number of cells

liquefactive necrosis is seen in...

brain infarction, abscess, pancreatitis

fat necrosis occurs from deposition of

calcium

what are the concerns for having too much intracellular calcium?

calcium is an activator for several intracellular enzymes which can activate many cascades of signaling - phospholipases cause membrane damage - proteases cause breakdown of membranes and cytoskeletal proteins - ATPases cause ATP depletion - Endonucleases cause DNA fragmentation calcium also open the mitochondrial membrane permeability pore, releasing ATP and therefore depletes cellular ATP

caseous necrosis typically appears in which infections? (2)

granulomatous inflammation due to fungal and TB infections

hypertrophy

increase in cell size

Coagulative necrosis is caused by

ischemia that results in damage to structural proteins and enzymes typically it has a triangular shape with the tip of the triangle pointing to the area of infarct

Explain why hypoxia and ischemia causes cell injury

lack of oxygen results in no oxphos and therefore little ATP lack of ATP results in: - Na/K pumps not working as often and having ER swelling, blebbing, loss of microvilli - there is increased anaerobic glycolysis which results in increased lactic acid (and decreased pH) - decreased protein synthesis

necrosis is characterized by

leaking of cellular contents to local cells due to a damage membrane and local inflammation

fibrinoid necrosis can be seen in which two diseases?

malignant hypertension and vasculitis