5070 Deck 1: infarction/stress intro to pathophysiology

Intro to pathophysiology

what two systems are involved in the body’s response to stress? What do they do?

SNS- releases epi, norepi

HPA axis- releases glucocorticoids (mainly cortisol)

what does HPA axis stand for ?

hypothalamic pituitary adrenal axis

what is a major result of the neurohormonal response?

increase in blood glucose

what does hypothalamus release during fight or flight response to activate the SNS?

CRH- corticotropin releasing hormone

durign the fight or flight response. the activated SNS does what?

stimulates the adrenal medulla to release NE and epi

in HPA axis, hypothalamus secretes what?

CRH

what does CRH in HPA elicit?

anterior pituitary to release ATCH

what does ATCH from anterior pituitary in HPA axis elicit?

stimulates adrenal cortex to release glucocorticoids (mainly cortisol)

what is the HPA feedback loop considered?

negative

what is widespread, multi-system effects of chronic stress considered?

allostatic overload

cell differentiation

maturing and specialization for a specific function

hypertrophy

increase in cell size

triggered by mechanical and/or trophic signals

atrophy

decrease in cell size

associated with damage or disuse

hyperplasia

increase in cell number

increased rate of cell division

metaplasia

replacement of well-differentiated mature cell type by another well-differentiated cell type

new type can withstand stressor better

dysplasia

deranged or disorderly cellular growth

variations in shape/size/arrangement

can lead to cancer

what is an example of hyperplasia

wart/skin tag

what is an example of dysplasia

skin cancer

when there is increased organ workload, what do the cells usually do?

hypertrophy

hyperplasia

how long after surgery removing 2/3 of liver does it regain to its original size?

1 week

alzheimer’s is an example of what type of cellular growth?

atrophy

inflammation is a mechanism of what that can happen to a cell?

injury

when inflammation is for this amount of time, it can cause what?

chronic amounts of time

significant cellular tissue injury

what are three ways that chronic inflammation causes cellular and tissue injury?

fibrosis, scarring

generation of ROS

infiltration of WBC, constant cell signaling generating more inflammation

inappropriate and widespread acute inflammation is what?

highly damaging to cells, can be fatal

definition of ischemia

inadequate blood flow to part of the body

if ischemia is present, how does mitochondria respond?

cannot process oxygen normally

what is ischemia normally caused by?

a blood clot blocking a vessel

sometimes blood vessel compression

hypoxia is a manifestation of what? and what does it do? what does it cause?

ischemia

compromises ATP production due to loss of oxidative phosphorylation

leads to large energy deficits for cell functions

what does lack of blood flow caused by ischemia cause regarding waste products?

buildup of waste products that aren’t removed

what does ischemia cause regarding energy supply?

loss of constant energy supply to tissues in the form of glucose

what does ischemia lead to eventually?

cell death

where in the body does ischemic cell death commonly occur?

heart, brain, periphery, etc

decreased ATP leads to what 3 things at the cellular level?

dysfunction of Na/K pump

increases anaerobic glycolysis

causes detachment of ribosomes from the ER

when the Na/K pump is affected by decreased ATP, this causes the cell to retain what? and lose what?

sodium

potassium

what does increased intracellular sodium do? what can this cause?

attracts water

can cause cell to burst

pressure ulcers are caused by ischemia how?

sustained pressure over bony prominence leads to compression of blood vessels

is ischemia reversible?

possibly

infarction definition

the permanent (irreversible) loss (death) of cells caused by an extended period of ischemiai

ischemia, in an extended period of time can lead to what?

infarction

excess intracellular calcium leads to what? how does this happen?

cell death

through activation of many calcium-dependent intracellular degradative enzymes that break down plasma, proteins, DNA, RNA

where in the body is excess intracellular calcium found notably?

brain

under healthy conditions, ROS produced by the mitochondria are ______ by enzymes and peptides. they are converted to what?

neutralized

non-toxic molecules

glutathione is what?

an important antioxidant and free radical scavenger

what does Glutathione most often do?

convert hydrogen peroxide to 2 molecules of water

what is GSH?

glutathione

if ROS are produced in large amounts, what can occur?

normal detoxification pathways are overwhelmed

cell damage/death

how do neutrophils and macrophages utilize ROS?

generate them to kill invading bacteria

what does ROS from chronic inflammation have the ability to do?

cause tissue damage

what is superoxide dismutase (SOD)

enzyme that catalyzes superoxide free radical to hydrogen peroxide

what is the pathway of GSH neutralization of ROS ?

1. superoxide

2. SOD neutralization to OH

3. OH neutralization with GSH

   1. water product

when cells are injured, they leak what? this is the basis of many what?

cell contents

lab tests

abnormal organelle function is linked to what?

cell death

which organelles (2) are likely to initiate apoptosis?

rough ER

mitochondria

apoptosis

programmed cell death

where does protein synthesis occur?

in the rough ER

what cellular organelle does quality control on protein surveillance? what happens if proteins are misfolded?

rough ER

STOPS transcription/translation, produces chaperone proteins to fix the problem

what can the rough ER do if unfolded proteins accumulate and cause stress?

initiate apoptosis if it is stressed

where is homeostasis maintained?

smooth ER

what maintains normal low levels of intracellular calcium

the ER membrane calcium ATPase

what are 2 functions of the mitochondria

atp production

calcium storage

what happens with damage occurs to the mitochondria? what does it signal?

outer membrane leaks proteins

proteins enter the cytoplasm

this signals apoptotic pathway of cell death

is apoptosis a normal cellular function?

yes

how is apoptosis regulated?

tightly- a ‘death program’

cell division = cell death in health cell

what does apoptosis protect agains?

damaged/infected cells

development of cancer

from where can apoptosis be signaled from?

intrinsic- inside the cell

extrinsic- outside the cell

extrinsic signal for apoptosis could be from what 2 signals

absence of survival signal from neighboring cells

presence of death signal

extrinsic and intrinsic signals for apoptosis activate what enzymes? what do they do?

caspases

begin cascade of apoptosis

what is the process of apoptosis?

cell shrinks, cytoskeletal collapse, DNA breaks

apoptotic bodies form

cell surface is changed, cell rapidly phagocytosed

leakage of cellular content

necrosis

rapid form of cell death during chronic/acute injury

what does necrosis induce

inflammation, pain/swelling that perpetuates tissue damage

necrosis causes membrane, swelling, rupture and cellular dissolution which causes what?

causes leakage of cellular contents

is necrosis clean?

no it is messy

during necrosis, is the plasma membrane affected? what happens?

yes it is disrupted

membrane potential lost, cell contents leak

during apoptosis, what happens to plasma membrane?

it stays intact

apoptotic bodies separate from cell with membrane intact

in apoptosis, what happens to cellular contents?

release in apoptotic bodies

phagocytized by neighboring cells/macrophages

small amounts may be measureable in serum

is there adjacent inflammation in necrosis? what does this lead to?

yes

swelling and pain

is there adjacent inflammation in apoptosis?

no

is necrosis pathologic?

yes, invariably

is apoptosis physiologic?

yes- means of eliminating unwanted/unneeded cells

what is the third pathway of cell death?

autophagy

autophagy definition? is it tightly regulated?

self-eating, through lysosomal mechanisms

yes tightly regulated

what does autophagy play a role in?

housekeeping-removing/recycling protein aggregates and damaged organelles

what does autophagy promote?

cell survival and tissue homeostasis

what is a trigger for autophagy? what does it help the cell to do (if some cases, it results in the opposite)?

cellular nutrient depletion/deprivation

survive under stressful conditions

what key substance cannot be produced by mitochondria in regions of ischemic or infarcted tissue?

ATP

what key cellular functions are disrupted when this key substance cannot be produced?

sodium potassium pump disrupted

proper oxygenation/glucose to damaged cells

ATP production

carbon dioxide can’t be taken out