Chapter 3 - Cellular Adaptation, Injury, and Death

Atrophy

decrease in cell size resulting in reduction of tissue or organ size

Physiological Atropy

normal, expected adaptation

• can occur because of decreased cell activity, reduced hormone stimulation, and aging-related changes

ex) the thymus after puberty, decrease in muscle mass with aging (carcopenia, decrease in muscle cell, lose myofibrils), and uterine shrinkage after menopause (decreased estrogen production during menopause causes decrease in size of the reproductive organs)

Thymus Involution Process

physiological atrophy

• the thymus is the primary organ of the immune structure

• during childhood, the thymus is at its largest size, during puberty, the thymus receives oxidative stress and low-grade chronic inflammation

• when the body matures and ages, the thymus shrinks and tissue is replaced by adipose tissue

this causes:

• increasing ROS

• decreasing antioxidants (SOD, catalase)

• increase in autoimmune diseases

• increase in production virgin T lymphocytes

• decreased structural organization

• increased susceptibility to infections

• increased immunosenescence and inflammaging

Pathological atropy

not normal, caused by disease or abnormal conditions

• results from decreased workload (disuse), pressure, decreased blood supply, poor nutrition, loss of hormonal stimulation, and nervous stimulation (damage to CNS or nerve when muscle stimulates impulse; neurodegenerative diseases)

examples: prolonged bed rest or immobilization, muscle loss from nerve injury

How do cells adapt during pathological atrophy?

by decreasing protein synthesis

increasing protein breakdown

activating autophagy (self-eating, cellular breakdown)

Hypertrophy

increase in cell size resulting in enlargement of tissue or organ

Physiological atropy

normal, expected

• ex) muscle growth from working out

Pathological hypertrophy

occurs due to disease or abnormal stress

ex)left ventricular hypertrophy from hypertension (leads to heart failure)

left ventricular hypertrophy

when patient’s have high BP, this causes a higher back pressure

• the heart needs to compensate for this back pressure by pumping harder.

• This causes the myocardial tissue in the heart to grow, leaving less room for the ventricle to be filled with blood

• this causes the heart can’t pump sufficient amount of blood

Hyperplasia

increase in cell # caused by increased rate in cellular division

Compensatory physiologic hyperplasia

allows organs to regenerate (regenerates to compensate for lost tissue)

• ex) regeneration of the liver after partial removal

Hormonal physiological hyperplasia

replaces lost tissue or supports new growth

• ex) during pregnancy, breast tissue increases due to estrogen stimulation

Pathological Hyperplasia

results from excessive or abnormal hormonal stimulation or effects of growth factors on target tissue

• ex) enlargement of the prostate in benign prostatic hyperplasia (BPH)

Dysplasia

deranged cellular growth; not true cellular adaptation but rather atypical hyperplasia (abnormal cellular growth)

• does not indicate cancer but is a sign of pre-cancer (if it goes untreated it can turn into cancer)

• usually occurs in places with epithelial tissue (lining of tissues such as the cervix, colon, skin, or airways)

Cervical Dysplasia

abnormal cells on the cervix of the uterus, often linked the HPV infection

• a pap-smear can detect early cervical cancer (secondary prevention), a positive test requires treatment

• HPV is a risk factor of cancer

Metaplasia

the reversible replacement of mature cells by another less mature cell type

• it is an adaptive response to chronic irritation, inflammation, smoking, and acid reflux

• metaplasia can develop into dysplasia

Barrett Esophagus

chronic acid reflux (heart burn) that causes the normal squamous lining of the esophagus to change into a intestinal (columnar) cell type

• the heart burn causes irritated of the epithelial lining of the esophagus

What is similar about dysplasia and metaplasia?

for most cases, it is pathologic because it involves severe irritation and inflammation

Cellular injury

damage thay occurs when cells are exposed to stress or harmful agents beyond their ability to adapt

Reversible injury

cells recover if the stress is removed

Irreversible injury

cells die

Common causes of cellular injury

lack of oxygen (hypoxia), free radicals, toxic chemicals, infectious agents, physical and mechanical factors, immunologic reactions, genetic factors, nutritional imbalances, and physical trauma

Cellular Injury leads to cell death by these steps:

1. Decreased ATP production

2. Failure of AT mechanisms (Na+/K+ pump fails, causing accumulation of Na+ inside the cell causing the cell to swell)

3. Cellular swelling (water follows solute)

4. Detachment of ribosomes from ER

5. Cessation of protein synthesis

6. Mitochondrial swelling from Ca2+ accumulation

7. Leakage of digestive enzymes from lysosomes; auto digestion of intracellular structures and breakdown of proteins

8. Lysis (dissolution/separating) of the plasma membrane

Hypoxia

lack of oxygen

Ischemia

decreased blood flow to tissue leading to hypoxia

Ischemia-Reperfusion Injury: Ischemia phase

when the cells switch to anaerobic metabolism: decreased ATP production

• this causes ion pumps to fail: cell swelling, and calcium buildup

Ischemia-Reperfusion Injury: Reprefusion phase

when the blood returns

• sudden oxygen influx leads to a burst of reactive oxygen species (ROS)

• oxidative stress: radicals (ROS) cause memrbane damage and permeability transition pore

Ischemia-Reperfusion Injury: when is it the mechanism of injury?

in:

• tissue transplantation

• ischemic syndroes: myocardial, hepatic

Myocardial infraction

BV is blocked, myocardium gets no blood/oxygen causing heart failure (when BV is blocked, there is no blood flow to tissue)

Anoxia: What happens when a thrombus (abnormal clot) blocks a BV

anoxia: a total depletion or absence of oxygen supply to the body's tissues and organs

anaerobic metabolism occurs due to hypoxia, there is decreased ATP stores causing the AT mechanisms (Na+/K+ pump) to fail, sodium retention inside the cell, cell swelling, ribosomes detach from rough ER, protein synthesis stops, etc.

Reprefusion

produces free radicals that are harmful to cells

• this leads to a necrotic cell

Free Radicals and ROS

cause oxidative stress when there is an increase of different reactive species

causes detrimental oxidation of:

lipids, nucleic acids, proteins, and mitochondria

When lipids undergo oxidative stress from free radicals and ROS, what happens?

loss of membrane integrity, increased permeability, cell swelling and necrosis (premature death of cells and living tissue in the body)

When proteins undergo oxidative stress from free radicals and ROS, what happens?

enzyme inactivation, protein fragmentation

When nucleic acids undergo oxidative stress from free radicals and ROS, what happens?

gene mutations

When the mitochondria undergos oxidative stress from free radicals and ROS, what happens?

dysfunction and inefficient antioxidants (as the body gets more free radicals, antioxidants becomes useless)

SOD (review)

specific type of antioxidants that are produced by the mitochondria

Chemical or toxic injury

causes direct toxicity to the cell causing destruction of the plasma membrane

Reactive free radicals and lipid peroxidation (review)

causes indirect damage (indirect damage is increased production of the free radicals in the cell)

Lead

affects the CNS and PNS

Carbon Monoxide

directly reduces the oxygen-carrying capacity of the blood, and promotes tissue hypoxia

• CO binds to certain receptors

Ethyl Alcohol

results in major nutritional deficiencies, especially folate (natural water-soluble B vitamin that helps your body make red blood cells and repair DNA)

Mercury

affects the NS and kidneys

Cellular accumulations (infiltrations)

cells attempt to catabolize “stored” substances that cause metabolite accumulation in cell

water: cellular swelling (when Na+/K+ pumps fail)

lipids and carbs: liver tries to accumulate triglycerides (affects liver) (e.g., fatty liver)

glycogen: observed in genetic disorders: Glycogen storage disease (von gierke disease)

Uric acid: causes gout (produces severe pain and irritation

Von Gierke Disease

glucose-6 phosphatase deficiency; causes glycogen accumulation in liver and kidneys (hypoglycemia)

• glucose-6 phosphatase is responsible for breaking down glycogen into glucose

child has a doll-like face, enlarged liver (hepatomegaly) and kidneys, and distended abdomen (b/c of enlarged liver)

hypoglycemia causes seizures, coma, and intellectual disability

Pathologic calficiation

abnormal deposition of calcium salts

Dystrophic calcification

calcium deposition occurs in dead or damaged tissues despite normal serum calcium levels

• calcium conc. in blood normal damaged tissues accumulate calcium

ex) when fatty plaques are developing in arteries, they become calcified due to calcium accumulation

Metastatic calcification

calcium deposition (accumulation/settling down) occurs in normal tissues due to hypercalcemia

Hypercalcemia

increased blood calcium concentration, causes calcium to go into tissues

Necrosis

uncontrolled death of cells or tissues in a living organism, usually caused by injury or prolonged/severe inflammation

• includes inflammatory changes leading to autolysis

• pathologic

• commonly classified based on the morphologic appearance of dead tissue

Apoptosis

programmed, controlled cellular death that the body uses to remove unwanted, damaged, or old cells without harming nearby tissue

• physiologic

Type 1 → programmed cellular death (RBCs are replaced by new RBCs)

Type 2 → autophagic cell death (cell self-eating)

Pyknosis

shrinking of the nucleus (the nucleus becomes smaller, dark, and dense)

• one of the processes of necrosis

Karyorrhexis

fragmentation of the nucleus

• DNA is broken into pieces

• one of the processes of necrosis

Karyolysis

nuclear dissolution and chromatin lysis

• DNA is digested by enzymes

• nucleus and nuclear envelope disappear

• one of the processes of necrosis

Coagulative necrosis

cells are transformed into a gray, firm mass

• protein denaturation result from activation of enzymes

• common in kidneys, heart, and adrenal glands

Liquefactive necrosis

hydrolytic enzymes form liquid-filled cyst or form puss

• common in neurons and glial cells in the brain

• basically means dead cells and tissues become liquid

Caseous necrosis

cells transformed into cheese-looking substance that is walled off

• TB pulmonary infection

• combination of coagulative and liqueative necrosis

• dead cells turn into a yellow, gray substances

Fat necrosis

occurs exclusively in adipose tissue

• common in breast, pancreas, and other abdominal structures

• lipases breakdown lipids into fatty acids

Gangrenous necrosis

considerable mass of tissue undergoes necrosis

• gangrene can be classified as dry, wet, and gas

Dry Gangrene

tissue becomes dry and shrinks, the skin wrinkles, and the color changes to dark brown or black

• caused by severe loss in blood supply (ischemia) without significant bacterial infection

• shows symptoms of dehydration

• no bacterial infection

Wet Gangrene

occurs when dead tissue becomes infected by bacteria, leading to rapid tissue breakdown and swelling

• secondary infection

Gas gangrene

special type that results from bacterial infection of tissues by one of several clostridium bacteria (bacteria that is present in dirt, can produce toxins that cause necrosis and produce gas (hissing sound) inside wound)

Apoptosis

programmed cellular death

• controlled and selective, injured dead and aged cells

• controls tissue regeneration

Dysregulated apoptosis

excessive or insufficient

• pathologic

can lead to cancer, autoimmune disorders, neurodegenerative diseases, and ischemic injury

Autophagy

cellular self-eating

• cells digest their own damaged parts, organelles, or misfolded proteins to clean self and generate energy

• this is a survival mechanism (damaged mitochondria can leak toxic ROS)

• by digesting broken parts of cell, autophagy acts as an internal anti-aging system

Aging

result of accumulation of damaged macromolecules

Programmed aging theories

aging follows biological schedules encoded by genes

• lifespan is regulated by genes

• cells follow predetermined replication limits

Damaged or error theories

aging results from accumulated damage over time

• increase in free radicals effects on cells

• structural alternations

Cellular adapatation

the bodies response to escape and protect itself from injury

• the reversible change a cell makes in size, number, phenotype, or metabolic activity to survive stress and maintain function