Pathphys exam 1

pathology

the causes of disease and the changes in cells, tissues, and organs that are associated with the development of disease

etiology

the origin of a disease, including the underlying causes and modifying factors

pathogenesis

steps in disease development

reversible injury

Homeostasis is restored

irreversible injury

leads to cell death

types of cellular stress

1. oxidative stress

2. ER stress and UPR

3. Disruption of calcium homeostasis

How does ROS get cleared?

enzymatically and/or by antioxidants

What enzymes help clear ROS ?

1. glutathione peroxidase

2. catalase

oxidative stress occurs when?

ROS accumulation

What is the purpose of chaperones in the ER?

ensure proper folding of newly synthesized proteins

Misfolded proteins in the ER activate what?

UPR, unfolded protein response

UPR (unfolded protein response) occurs when?

accumulation of misfolded proteins in the ER

UPR increases what?

1. chaperone expression

2. protein degradation

UPR decreases what?

protein synthesis

High levels of misfolded proteins trigger?

apoptosis via mitochondrial intrinsic pathway

When does ER stress occur?

accumulation of misfolded proteins

3 ways that misfolding proteins can cause disease?

1. Creating a deficiency of an essential protein (loss of function)

2. Inducing apoptosis

3. Gaining a toxic function

what is the ubiquitin-proteasome system?

cells garbage disposal

ubiquitin ligases does what?

tag proteins that are damaged

Proteasome

endopeptidase complex - the cells trash can

proteolysis?

protein breakdown

what is the importance of Ca2+ ?

second messenger

High intracellular Ca2+ cause?

1. disrupts multiple signaling pathways

2. activates enzymes that damage cellular components

What enzymes are activated when Ca2+ levels are high?

1. Proteases

2. phospolipases

What cellular components are damaged by high levels of Ca2+?

1. plasma membrane

2. cytoskeleton

4 different types of cellular adaptations?

1. hypertrophy

2. hyperplasia

3. atrophy

4. metaplasia

Physiologic adaptations

the responses of cells to normal stimulation by hormones or endogenous chemical mediators, or to the demands of mechanical stress

Pathologic adaptations

responses to stress that allow cells to modulate their structure and function, and thus escape injury, but at the expense of normal junction

Cellular Adaptation

cell changes itself to survive stress. These changes are reversible if stress is removed

HyperTROPHY

increased in cell size that leads to increased organ size, but no increase in cell number

Hyperplasia

increase in number of cells in an organ

Atrophy

reduced size of an organ or tissue caused by reduction in the size and number of cells due to both pathologic and physiologic causes

Metaplasia

a change in which one adult cell type is replaced by another adult cell type

when does metaplasia typically arise?

reprogramming of stem cells

2 types of reversible cell injury

1. cellular swelling

2. fatty changes

3 signs that the cell injury is irreversible

1. Mitochondria cannot be recovered

2. Altered structure and loss of function of plasma and intracellular membranes

3. Loss of structural integrity of DNA and chromatin

types of membrane damage

1. mitochondrial

2. plasma

3. lysosomal

Mitochondrial membrane damage causes ____

formation of mitochondrial permeability transition pore

Plasma membrane damage causes

loss of osmotic balance, influx of fluids and ions, loss of cellular contents

Lysosomal membrane damage causes

leakage of enzymes into cytosol

The guardian of the genome

p53

What does p53 do?

causes cell cycle to arrest to allow DNA repair to occur before replication

pathologic calcification

result of abnormal deposition of calcium salts

Dystrophic calcification

deposition of crystalline calcium phosphate in membrane-bound vesicles

- found in injured or dead tissue

- seen in atherosclerosis and tuberculosis

Metastatic calcification

associated with hypercalcemia and can occur in normal tissues

Aging is a consequence of

alterations in genes and signaling pathways

DNA damage over time causes?

1. telomere dysfunction and cellular senescene

2. mitochondrial dysfunction

Mechanisms of cellular aging

1. dna damage

2. specific signaling pathways

3. persistent inflammation

purpose of telomeres

- Protect chromosome ends from fusion and degradation

- ensure complete replication of chromosome ends

Senescence

cell is alive but has entered a permanent nondividing state

necrosis

enlarged (swelling)

apoptosis

programmed pathway by which cells degrade their own nuclear DNA and nuclear and cytoplasmic proteins, causing cellular and nuclear fragmentation and chromatin condensation

Is the plasma intact or disrupted in necrosis?

disrupted

Is the plasma intact or disrupted in apoptosis?

intact

During cell death, which will have cellular content leakage?

necrosis

Does necrosis or apoptosis cause inflammation?

necrosis

Is necrosis pathologic or physiologic?

always pathologic

Is apoptosis pathologic or physiologic?

both

pyknosis

DNA condensation and nuclear shrinkage

karyorrhexis

nuclear fragmentation

karyolysis

digestion of DNA

membrane blebs

Fragments of apoptotic cells break off and form apoptotic bodies

sequence apoptosis

1. cell shrinks

2. DNA/chromatin condenses and fragments

3. cell membrane develops membrane blebs

4. cell breaks into little apoptotic bodies

5. phagocytes clean them up no inflammation

Mitochondrial permeability is controlled by which proteins?

Bcl-2

sequence mitochondrial pathway

1. Mitochondrial permeability changes

2. Pro-apoptotic proteins are released

3. cytochrome-c released into cytosol

4. activates caspase cascade

5. apoptosis

what is the extrinsic pathway controlled by?

death receptors

What are the 2 death receptors?

TNF receptor family and Fas

sequence extrinsic pathway

1. Death signal binds receptor

2. death receptors come together (cross-link)

3. death domains recruit adapter proteins

4. caspases activated

5. apoptosis

Caspase cascade does?

degradation of cellular proteins and nuclear fragmentation

- no inflammatory response

2 main cell deaths

necrosis and apoptosis

other mechanisms of cell death

1. pyroptosis

2. necroptosis

3. ferroptosis

pyroptosis

mediated by inflammasome

Necroptosis

induced by TNF with necrotic and apoptotic features

ferroptosis

dependent of cellular iron levels

autophagy

When an autophagosome joins with lysosomes so that lysosomal enzymes can digest cellular components for the cell to reuse.

(self-eating)

Does hypoxia or ischemia still have blood flow?

hypoxia

ischemia-reperfusion injury

restoration of blood flow to ischemic tissue but can cause extra ROS, ca2+, and inflammatory damage

Hypoxia and ischemia both deprive the cells of?

oxygen

Direct-acting toxins

combine directly to cellular proteins or organelles

latent toxins

chemical must be converted to a reactive metabolite that acts on target cells to exert toxic effect, usually by cytochrome P-450 in the liver

2 examples of direct acting

1. mercury poisoning

2. chemotherapy drugs

main example of latent

acetaminophen poisoning

non-coding regulatory RNAs

genes that are transcribed but not translated (microRNAs, long coding RNAs)

transpsons

mobile genetic elements

telomeres and centromeres

structural regions of DNA

epigenetics

modifications to DNA, histones, or chromatin structure that alter gene expression without changing the DNA sequence itself

3 types of epigenetic mechanisms

1. covalent modifications of DNA

2. post-translational modifications of histones

3. 3D chromatin structure

Single nucleotide polymorphisms (SNPs)

Variations at a single nucleotide position.

Where can SNPs occur?

coding and non-coding regions

Non-coding SNPs may alter?

the regulation of gene expression

Coding SNPs may change the sequence of ______

a protein

do "neutral" SNPs change anything?

No, they have no effect on gene fucntion or phenotype

Copy number variations (CNVs)

segments of DNA that are duplicated or deleted

Point mutations

substitution of a single nucleotide base by a different base

2 types of point mutations

1. missense

2. nonsense

missense mutation

changes an amino acid

nonsense mutation

creates a stop coding

mutation

changes the actual DNA sequence

frameshift mutation

Insertion or deletion of 1-2 base pairs alters the reading frame of the DNA strand

CRISPRs

clustered regularly interspaced short palindromic repeats