Lecture 1: Cellular Aspects of Disease

What is a disease?

An acute or chronic illness that one acquires or is born with

What is etiology?

The cause of disease, what puts the disease in motion

What are the types of etiology in diseases?

Biological, Physical, Chemical, Genetics

Pathogenesis

How the disease progresses over time

What are biologic causes of disease

Bacteria, Viruses, Yeasts/Fungi, Parasites

What are physical causes of disease

Trauma, Burns, and Radiation

What are chemical causes of disease?

Poisons, Alcohol, and Medications

What are the genetic causes of disease?

Autoimmune diseases and congenital abnormalities

What is pathogenesis?

How the disease develops over time

What is cellular adaptation?

The reversible change a cell can make in size, number, or metabolic activity to survive and function when faced with environmental stress or shifting demands

What is gene expression, and how does it connect to atrophy and hypertrophy?

Gene expression means the cell is turning certain genes on or off to change what proteins is made.

In hypertrophy, genes that increase protein production and cell growth are turned on more, causing the cell to get bigger

In atrophy, genes that promote protein breakdown may be turned on, while genes that code for protein production may decrease, so the cell gets smaller

What controls and regulates the cells ability to adapt and why?

Daily stressors in the environment will cause the cell to “need to adapt” and this influences gene expression

Do genes change during cellular adaptation?

No, actual genes do not change during cellular adaption, cells only change which genes are used

What happens when a cellular stressor is stimulus is removed?

The cell will often return to normal size, structure, and function

What is atrophy?

The wasting away, shrinking, or loss of size and strength in body part, tissue, or organ

What happens to organelles during cellular atrophy?

Organelles are broken down and the cell shrinks, this decreases its metabolic activity

What happens to cell efficiency during atrophy?

Cell efficiency decreases because cell becomes smaller and fewer organelles to perform normal functions

How can atrophy affect tissue?

Atrophy causes tissue to shrink, lose mass, and experience a reduction in both size and number of useful cells

What is physiologic atrophy?

Physiologic atrophy is a normal decrease in the size of cells or tissues that occurs as part of normal development of aging

What is an example of physiologic atrophy?

The normal, programmed shrinkage of ovaries after menopause

What is pathologic atrophy?

Pathologic atrophy is abnormal decrease in cell size caused by disease, injury, or reduced use.

What are the five causes of atrophy?

1. Disuse - decreased workload

2. Denervation - loss of nerve supply

3. Inadequate Nutrition - starvation or malnutrition

4. Loss of hormonal stimulation - decreased estrogen after menopause

What is disuse atrophy?

Disuse atrophy is when muscles are not being used enough so the muscle cells begin to break down which causes muscle loss

What is denervation atrophy? Provide an example

Denervation atrophy is the loss of nerve supply to an affected area. An example of this is ALS (amyotrophic lateral sclerosis) and the disease progressively damages and kills motor neurons

What causes atrophy from loss of endocrine stimulation? Provide an example

When growth-promoting hormones that maintain the size and function of the target hormone dependent tissues stop being produced, atrophy occurs. An example of this is menopause leads to decreased estrogen production that causes atrophy to parts of the female reproduction system

What happens when atrophy is caused by inadequate nutrition?

When cells do not receive enough nutrients, calories, or protein to maintain their normal size

What is ischemia?

Ischemia is reduced blood flow to a tissue or organ, meaning the cells receive less oxygen and nutrients

What are the two main processes that cause cells to shrink during atrophy?

Decreased protein synthesis and increased protein degradation

What is the effect of decreased workload on muscle?

Decreased workload leads to decreased oxygen consumption and decreased protein synthesis, resulting in muscle atrophy

What is proteolysis

Proteolysis is the breakdown of proteins into smaller peptides or amino acids

What does proteasome mean

A large protein complex that acts like the cell’s shredder. Its job is to break down proteins that have been tagged with ubiquitin into smaller pieces

What does ubiquitin mean

Its a small protein that acts like a “destroy me” tag that is attached to proteins that need to be broken down.

Where doe the ubiquitin-proteasome system take place?

Inside the cell, especially in the cytoplasm and nucleus

What is step 1 of the Ubiquitin-Proteasome system?

Ubiquitin-activating enzyme uses ATP to activate a ubiquitin molecule and holds onto it

What is step 2 of the Ubiquitin-Proteasome system?

The ubiquitin attaches to the target protein and facilitates the attachment of the proteasome to the protein

What is step 3 of the Ubiquitin-Proteasome system?

The proteasome recognizes the ubiquitin-tagged protein and breaks it down into small pieces

What is hypertrophy?

Hypertrophy is an increase in the size of individual cells, causing the tissue or organ to become larger

What is the main cause of hypertrophy?

An increased workload or stimulation on a cell

What is the main purpose of hypertrophy?

To help cells handle an increased workload or demand by becoming larger and increasing their functional capacity

Where is hypertrophy common?

Cardiac muscle, skeletal muscle, and renal tissue

What are the three types of hypertrophy?

Physiologic Hypertrophy - normal increase in cell size, such as muscles growing with exercise

Compensatory Hypertrophy - cells enlarge to compensate for increased demand or loss of tissue

Pathologic Hypertrophy - abnormal enlargement caused by disease, such as heart enlargement from chronic high blood pressure

What are the four initiating events of hypertrophy?

1. Increased workload/stress

2. Hormone Stimulation

3. Growth Factor Stimulation

4. Activation of genes that increase protein production

What is the effect of hypertrophy stimuli on the cell?

Hypertrophy stimuli cause the cell to increase gene expression for protein synthesis, leading to more structural proteins and organelles created

What cells can undergo hyperplasia?

Cells that are capable of dividing can undergo hyperplasia, like skin and liver cells

What are the types of hyperplasia and an example of each?

Physiologic Hyperplasia - a normal increase in number of cells often due to hormones or increased demand.

Pathologic Hyperplasia - abnormal increase of cells thats caused by excessive hormones or excessive growth factors

Ex. BPH, prostate cells increase caused an enlarged prostate

What are common stimuli for hyperplasia?

Hyperplasia stimuli active genes that control cell growth and division, causing cells to enter the cell cycle and proliferate

What is metaplasia?

Metaplasia is a reversible change where one mature cell type is replaced by another cell type that is better able to tolerate stress

What are the main initiating events for metaplasia?

The main initiating events for metaplasia are chronic irritation, chronic inflammation, and hormonal or chemical stimulation

What is an example of metaplasia caused by cigarette smoke?

A common example is in smokers where normal ciliated columnar epithelial cells are replaced by stratified squamous epithelial cells

What is an example of metaplasia caused by GERD (gastroesophageal reflux disease)?

In GERD, the normal squamous cells of the lower esophagus can be replaced by columnar, intestinal type cells that can better tolerate stomach acid

What is steatosis?

Steatosis is the abnormal accumulation of fat, mainly triglycerides, inside cells

What is the most common cause of steatosis?

The most common cause of steatosis is metabolic dysfunction associated with obesity

What is dysplasia?

Dysplasia is deranged cell growth, resulting in various sizes, shapes, and levels of organization

What is dysplasia often associated with?

Often associated with chronic inflammation, it may be reversible and its often a precursor to cancer

What is an example of dysplasia?

An example of dysplasia is seen in the changes of the cervix with Human Papilloma Virus, often seen as a precursor to cancer and can lead to cervical cancer

Describe the transition from dysplasia to invasive cancer

Dysplasia is the beginning stage, and becomes invasive cancer when the cancer cells pass the basement membrane

What is carcinoma in situ

Carcinoma in situ is when the cancer cells have not penetrated the basement membrane

What are the three sources of Intracellular Accumulations

1. Normal Body Substances

2. Abnormal Endogenous Products - comes from within the body

3. Exogenous Products - comes from outside the body

What is an example of an Abnormal Endogenous Product?

Lysosomal Storage Disorders ex. Tay-Sachs

What is an example of an Exogenous Product?

Exposure to coal mines leading to black lung

What does protein accumulation mean in disease?

Protein accumulation is the abnormal buildup of proteins inside cells or tissues because they are produced too much, folded incorrectly, or not broken down properly

What is an example of abnormal protein accumulation in Alzheimer disease?

In Alzheimer disease, abnormal proteins accumulate as:

1. Beta-amyloid plaques outside neurons

2. Tau neurofibrillary tangles inside neurones

How can protein accumulation damage cells?

Enzymes produced to break down proteins can cause collateral damage, and increased protein in the cytoplasm can push against organelles and cause dysfunction

What are the two forms of iron storage in tissue?

Ferritin and Hemosiderin

What is ferritin?

Ferritin is a protein that stores iron inside cells and releases it when the body needs it

What is hemosiderin?

Hemosiderin is an iron storage pigment that forms when there is excess iron in cells or tissues

What is the appearance of hemosiderin?

Hemosiderin appears as a course, golden-brown pigment inside cells

What is the hemosiderosis?

Hemosiderosis is the excess accumulation of hemosiderin (iron) in tissues

What are common causes of hemosiderosis?

Common causes of hemosiderosis include

1. Repeated blood transfusions

2. Chronic breakdown of red blood cells

3. Excess iron absorption

4. Repeated or chronic bleeding

5. Chronic venous congestion - especially in the lungs

How can hemolysis lead to hemosiderosis?

Hemolysis breaks down red blood cells and releases hemoglobin, which contains iron

What is bilirubin?

Bilirubin is a yellow-green pigment in bile derived from hemoglobin

What is jaundice?

Jaundice is the yellowing of tissue due to increased bilirubin in the blood

What are common causes of increased bilirubin and jaundice?

1. Hemolysis

2. Abnormal metabolism of bilirubin in the liver

3. Obstruction of the bile duct causing bilirubin retention

What pigment is derived from hemoglobin?

Bilirubin

Where can calcium accumulate?

In injured and dead tissue

What is metastatic calcification?

Metastatic calcification is the abnormal deposition of calcium in normal functioning tissue due to high blood calcium levels (hypercalcemia)

What commonly causes metastatic calcification?

The most common causes of metastatic calcification are conditions that cause hypercalcemia such as:

1. Hyperparathyroidism

2. Bone Destruction from tumors

3. Excess Vitamin D

4. Chronic Kidney Disease

Where do metastatic calcium deposits commonly occur?

Metastatic calcium deposits commonly occur in:

1. Kidneys

2. Lungs

3. Stomach

4. Blood Vessels

What is dystrophic calcification?

Dystrophic Calcification is the deposition of calcium in damaged or dead tissues even when blood calcium levels are normal

What are examples of dystrophic calcification?

Examples of dystrophic calcification include:

1. Atherosclerotic plaques

2. Damaged or aging heart valves

What is the mechanism of dystrophic calcification?

Cell Injury or death can cause the calcium to bind to damaged cell membranes and proteins, this causes calcium phosphate crystals to form and deposit in the tissue

What is urate?

Urate is the excessive metabolism of purines or decreased excretion of urate by kidnes, resulting in high concentrations of uric acid in the blood

What could cause sodium urate crystals to form?

When levels of uric acid become excessive, especially in the joints and kidneys

What is gout?

Gout is a form of inflammatory arthritis caused by uric acid crystals building up in a joint

Where does gout commonly occur?

Cooler areas of the body, far away from warmer blood areas:

Fingers, Toes, Ears

What is Tay-Sachs Disease:

The most common lysosomal storage disorder where the body lacked the enzyme Hexosaminidase A

What is the genetic defect of Tay-Sachs disease?

Deficiency of the enzyme that breaks down fatty acids in nerve cells cause the accumulation of fatty acids in nerve cell lysosomes, this nerve cell accumulation causes the Central Nerve System (CNS) to have nerve toxicity

What are the clinical manifestations of Tay-Sachs disease?

Onset by 6 months of age

Neuro - exaggerated startle reflux, seizures, dementia

Death usually occurs at age 5

How much ATP does aerobic respiration produce?

36 ATP

What are the byproducts of aerobic respiration?

CO2 and H2O

How much ATP does anaerobic respiration produce?

2 ATP

What is the byproduct of anaerobic respiration?

Lactic Acid

What is the most common cause of hypoxic injury?

Ischemia

What is the initial effect of ischemia?

The initial effect of ischemia is decreased oxygen delivery to the tissue, which reduces aerobic respiration and ATP production

What fuel does anaerobic respiration use during ischemia?

During ischemia, anaerobic respiration initially uses glucose stored in glucose stores in the cells to produce ATP

What happens to glycogen stores during prolonged ischemia?

During prolonged ischemia, glycogen stores become depleted because the cell keeps using glycogen for anaerobic ATP production

What happens to ATP after glycogen stores are depleted?

After glycogen stores in the cell are depleted, ATP production drops sharply because the cell no longer has enough fuel for anaerobic metabolism

What are the variables to cell injury that determine where injury is reversible?

1. Severity of the insult

2. Blood Supply

3. Nutrition

4. Regenerative Capacity

What happens if ischemia is not corrected?

If ischemia is not corrected, ATP depletion and cell injury worsen, eventually causing irreversible cell injury and cell death, usually by becrosis

What is collateral damage during ischemic injury?

Collateral damage during ischemic injury is injury surrounding health cells and tissues caused by substances released from damaged or dying cells - such as enzymes, free radicals, and inflammatory chemicals