Pathophysiology Unit 1

lectures 1-8

what is pathology?

the study of the causes of diseases and abnormalities in cells, tissues, and organs

what is etiology?

the study of how a disease starts, including its causes and contributing factors

what is pathogenesis?

the process by which a disease progresses and develops

what is homeostasis?

the healthy/normal state of the body or cell

what is cellular adaptation?

a cellular response to stress that allows the cell to establish a new state of homeostasis

what happens when a cell can successfully adapt to stress?

the cell establishes a new homeostasis and remains viable

what happens when the stress exceeds the cell’s adaptive threshold?

cell injury occurs

what are the two possible outcomes of cell injury?

reversible injury or irreversible injury leading to death

what happens during reversible cell injury?

if the damaging stimulus is removed, the cell can reestablish homeostasis and recover

what happens during irreversible cell injury?

the cell cannot recover and eventually dies

what are the three major types of injurious cellular stress?

oxidative stress, ER stress, and disruption of calcium homeostasis

what is oxidative stress?

a state in which excessive reactive oxygen species (free radicals) damage cellular components

what types of cellular molecules can ROS damage?

DNA, proteins, lipids

why are reactive oxygen species dangerous?

they are unstable and react with cellular components, causing damage

how can oxidative stress become a positive feedback loop?

cell injury can increase ROS production or decrease clearance, which causes more cellular damage and then potentially more ROS production

what are some causes of ROS production?

radiation, hypoxia, aging, injury/inflammation, ischemia

are ROS always abnormal?

no, ROS are normally produced in redox reactions

why does the cell need to maintain a balance involving ROS?

ROS has normal physiological roles, but too much cause cause oxidative stress

what two things can happen during cell injury that increase oxidative stress?

ROS production can increase OR ROS clearance can decrease

what helps regulate and remove ROS?

antioxidants and antioxidant enzymes

what are two important enzymes involved in clearing ROS?

glutathione peroxidase and catalase

what is ER stress?

stress caused by an accumulation of misfolded proteins

where do misfolded proteins accumulate during ER stress?

in the cytosol

what normally helps proteins fold correctly?

molecular chaperones

what protein (molecular chaperone) senses misfolded proteins during ER stress?

IRE1

what is the unfolded protein response (UPR)?

an adaptive cellular response to misfolded proteins

what are the three major things the UPR does

it recruits chaperones, decreases protein synthesis, and increases protein breakdown

is the UPR initially adaptive or destructive?

initially adaptive

what happens if the ER stress becomes severe?

it can activate mitochondrial/intrinsic apoptosis

what type of protein is activated severe ER stress to promote apoptosis?

BH3

what happens after BH3 activation during severe ER stress?

capases are activated, leading to cell death

what are the causes of protein misfolding?

mutations, aging, viral infections, pH changes, redox changes, hypoxia, and ischemia

what are three ways protein misfolding can cause disease?

loss of protein’s orignial function, induction of apoptosis, or gain of abnormal function

what disease is used as an example of protein misfolding?

cystic fibrosis

what is the purpose of the ubiquitin-protease system?

to identify and break down proteins that need to be removed, including misfolded proteinswhat

what molecule tags a protein for degradation?

ubiquitin

what enzyme adds ubiquitin to a protein?

a ubiquitin ligase

what happens after a protein is ubiquitinated?

it is targeted to the proteasome

what does the proteasome do?

breaks down the tagged protein so its components can be recycled

what happens if the ubiquitin-proteasome system fails?

abnormal proteins can accumulate inside cells

what are two examples associated with abnormal protein accumulation?

polyglutamine repeat diseases and parkinson’s (from parkin)

how does intracellular Ca2+ concentration normally compare with extracellular Ca2+ concentration?

intracellular Ca2+ is normally much lower

why is calcium important for cells?

it is necessary for cellular functions and acts as a major secondary messenger

why can excessive intracellular Ca2+ be toxic?

Excess calcium disrupts cellular signaling and activates damaging enzymes

what types of injury can increase intracellular calcium?

toxins and ischemia

where can excess intracellular calcium be released from?

the ER and mitochondira

what are cellular adaptations?

reversible changes in cell number, size, phenotype, activity, or function in response to stress

what are physiological adaptations?

adaptations to normal physiological stimuli such as hormones or mechanical stress

what are pathological adaptations?

adaptations to abnormal stress that may involve sacrificing some normal cellular function

what is hypertrophy?

an increase in sell size

does hypertrophy increase cell number?

no

what type of cells or tissue commonly undergo hypertrophy?

cells that do not readily divide

what happens if the stress causing hypertrophy continues for too long?

the cells can become injured

what is hyperplasia?

an increase in cell number

what must cells be capable of doing for hyperplasia to occur?

must be able to divide

what often accompanies hyperplasia?

hypertrophy

what stimulates hyperplasia?

hormones and growth factors

is hyperplasia physiological or pathological

either

what is atrophy?

a reduction in cell size and number that causes an organ or tissue to become smaller

what are causes of atrophy?

decreased use, loss of innervation, decreased bloop supply, poor nutrition, decreased endocrine stimulation, and aging

what happens to protein production during atrophy?

protein production decreases

what happens to protein breakdown during atrophy?

protein breakdown increases

what cellular process can occur during atrophy to remove cellular components?

autophagy

what can happen with severe or prolonged atrophy?

apoptosis can occur

what is metaplasia?

replacement of one mature cell type by another that is better suited to the abnormal environmentit

is metaplasia physiological or pathological?

it is always pathological

how does metaplasia occur?

reprogramming of stem cells

what is a classic example of metaplasia?

smoking can cause columnar epithelium to be replaced by stratified squamous epithelium

why can metaplasia be harmful?

the new cell type may lose some of the orignial tissue’s normal function

why does persistent metaplasia increase cancer risk?

abnormal stimulation can increase the risk of malignant transformation

what are major causes or cell injury?

hypoxia, ischemia, toxins, infectons, abnormal immune reactions, genetic abnormalities, nutritional imbalances, and physical factors

what three characteristics of an injury determine the cellular response?

the type, duration, and severity

what factors determine whether a cell survives an injury?

cell type, metabolic state, adaptability, genetics

which cells can tolerate lack of oxygen for the shortest time and why?

neurons because they have the highest metabolic activity

how can genetic differences affect a person’s response to toxins?

genetic differences in cytochrome P-450 can alter how toxins are metabolized

what happens to ATP production during hypoxia?

ATP production decreases because oxygen is needed for aerobic metabolism

what happens when ATP-dependent ion pumps fail?

water enters the cell, causing cellular swelling

what happens to organelles during reversible injury?

organelles can swell and become injured

what can happen to lipids during reversible cell injury?

lipids can accumulate inside cells

what is vacuolar degeneration?

cellular swelling associated with accumulation of fluid/vacuoles

what can happen to the ER during reversible injury?

the ER can break down

what is fatty change/steosis?

accumulation of lipid vacuoles, especially triglycerides, within cells

What organ is usually associated with fatty change?

the liver because it deals with the metabolism of lipids

what happens to ATP production during irreversible injury?

ATP production fails

what other functions/structures are damaged during irreversible injury?

cell membranes, DNA, cellular structure, and cellular function

what are the causes of mitochondrial damage?

hypoxia, ischemia, mitochondrial toxicants, radiation, and increased intracellular Ca2+

what type of metabolism increases when oxygen is unavailable?

anaerobic metabolism

what does anaerobic metabolism produce that affects pH?

lactic acid, pH decreases

how does decreased pH affect cells?

it causes enzyme dysfunction

what happens to protein synthesis machinery with prolonged ATP depletion?

ribosomes are removed from rough ER and polysomes dissociate decreasing protein synthesis

what is the mitochondrial permeability transition pore (mPTP)?

a pore that opens in damaged mitochondria and allows ions to enter

what happens when the mPTP opens?

mitochondrial membrane potential is lost and pH changes

what happens to mitochondria structurally during severe mitochondrial damage?

they can fragment

what happens to ROS production after mitochondrial damage?

ROS production increases, contributing to oxidative stress

what can severe mitochondrial damage trigger?

apoptosis

what happens when the plasma membrane is damaged?

water enters and osmotic balance is lost

what happens when lysosomal membranes are damaged?

lysosomal enzymes leak into the cell and digest cellular components

what can cause DNA damage?

radiation, chemo, oxidative stress, and mutations

what can severe DNA damage cause?

apoptosis

what happens to p53 when DNA is damaged?

p53 accumulates