Altered Cellular and Tissue Biology (ch 2)

Atrophy

Decrease in cell size that results in decreased tissue or organ size

What causes atrophy?

• Decreased workload/disuse

• Loss of innervation

• Decreased blood supply

• Inadequate nutrition

• Loss of endocrine stimulation

• Aging

What cellular processes contribute to atrophy?

• Decreased protein synthesis

• Increased protein degradation

• Autophagy of cellular components

Hypertrophy

Increase in size of individual cells resulting in enlargement of the affected organ/tissue

What causes hypertrophy?

increased

• Workload

• Mechanical stress

• Hormonal/growth factor stimulation

Ex: HTN causes enlargement of cardiac muscle cells

Hyperplasia

Increase in the number of cells caused by increased cellular proliferation

Two major types of physiologic hyperplasia

1. Hormonal

2. Compensatory (liver regenerates after partial removal)

metaplasia

reversible replacement of one mature differentiated cell type by another mature cell type better able to tolerate the stress

normal respiratory epithelium is replaced by squamous epithelium from chronic cigarette smoke

metaplasia

dysplasia

abnormal changes in cell size, shape, and organization

disordered cellular growth

two major forms of cell death

• necrosis

• apoptosis

necrosis

pathologic cell death associated with cellular swelling, membrane disruption, leakage of cellular contents and inflammation

apoptosis

programmed cell death involving controlled destruction and removal of individual cells, generally without significant inflammation

BPH (benign prostatic hyperplasia)

hyperplasia resulting from changes in hormone balance

mechanism of cell injury

• ATP depletion

• mitochondrial damage

• loss of calcium homeostasis/ increase intracellular Ca2+

• oxidative stress from reactive oxygen species (ROS)

• membrane damage

• protein/DNA damage

why is ATP depletion harmful to cells

decrease ATP causes failure of energy-dependent cellular processes, especially membrane ion pumps, leading to disrupted ion balance, cell swelling, and eventually cell death if severe/prolonged.

Why does ATP depletion cause cell swelling?

decrease ATP —> failure of Na+/K+ ATPase —>water follows Na+—>cellular swelling

How does ATP depletion affect cellular metabolism?

Cells shift from aerobic metabolism to anaerobic glycolysis, causing:

• decrease glycogen

• increase lactic acid

• decrease intracellular pH

What is the most common cause of hypoxic cellular injury?

Ischemia - inadequate blood supply to tissue

Why does hypoxia cause ATP depletion?

oxygen is required for mitochondrial oxidative phosphorylation

*decrease O2 —> decrease oxidative phosphorylation —> decrease ATP —> cellular dysfunction/ injury

mitochondrial damage

• decrease ATP production

• increase reactive oxygen species

• loss of mitochondrial membrane potential/permeability changes

• release of proteins that can activate apoptosis

Why is increased intracellular Ca++ damaging ?

Ca++ activates destructive enzymes :

• phospholipases —>damage cell membranes

• proteases —> damage proteins/ cytoskeleton

• endonucleases —> damage DNA

• ATPases —> worsen ATP depletion

reactive oxygen species (ROS)

• hypoxia triggers the mitochondrial complex to produce ROS

can damage: lipids, proteins, DNA

difference between hypoxia and ischemia

• hypoxia - decrease oxygen to tissues

• ischemia - decrease blood flow to tissues

A coronary artery becomes completely occluded. What causes myocardial cell injury downstream?

Ischemia —> decrease oxygen —> decrease oxidative phosphorylation —> decrease ATP —> ion pump failure —> cellular injury —> irreversible injury/ cell death if blood flow isnt restored

What is ischemia-reperfusion injury?

Additional tissue damage that occurs when blood flow and oxygen are restored to previously ischemic tissue

Why can reperfusion worsen cellular injury?

• sudden generation of reactive oxygen species (ROS)

• increase intracellular Ca++

• inflammation

• mitochondrial damage/dysfunction

additional cell injury or death

What is a free radical?

A highly reactive molecule or atom with an unpaired electron in its outer orbital

What are important reactive oxygen species involved in cellular injury?

• superoxide

• hydrogen peroxide

• hydroxyl radical

What is oxidative stress

an imbalance in which the production of ROS exceeds the bodys antioxidant defenses, resulting in cellular damage

How can ischemia followed by reperfusion lead to additional cell injury?

Ischemia:

• decrease oxygen

• decrease ATP and mitochondrial dysfunction

• cell becomes vulnerable

Reperfusion

• sudden oxygen restoration

• increase ROS and increase Ca++ and inflammation

• membrane/protein/DNA damage

• additional cellular injury

examples of antioxidant defenses against ROS

enzymes like

• superoxide dismutase

• catalase

• glutathione peroxidase

convert reactive species into less harmful molecules

oxidative stress = ROS production —> antioxidant defenses

lipid peroxidation

ROS attack polyunsaturated fatty acids in cell membranes, causing membrane damage and increased permeability

how do ROS damage DNA

ROS can cause DNA strand damage and alterations that may result in mutations and contribute to cell death or malignant transformation

What enzyme converts superoxide to hydrogen peroxide

superoxide dismutase (SOD)

What enzyme help convert hydrogen peroxide into harmless products

• catalase

• glutathione peroxidase

how does the body enzymatically detoxify ROS?

• decrease superoxide dismutase

  • hydrogen proxide

• decrease catalase/glutathione peroxidase

  • H2O and O2/ harmless products

two mechanisms by which chemicals cause cellular injury?

1. directly damage cellular components

2. be metabolized into toxic/ reactive metabolites that cause cellular damage

• Xenobiotic = foreign chemical

• exposure (inhalation, ingestion, skin)

• absorption —> bloodstream

• metabolism —> primarily liver

• can result in either detoxification/elimination OR cellular injury

What is particulate matter and why is PM2.5 harmful?

• a mixture of solid particles and liquid droplets suspended in air

• its very small size allows it to travel deep into the lungs

Lead poisoning

Lead —> interferes with Ca++/cellular processes —> neurotoxicity —> developing children are especially vulnerable

What is primarily affect by lead poisoning?

Nervous system

hematopoietic system

kidneys

CV system

How does lead cause cellular injury?

Lead interferes with multiple cellular processes

• Ca++ -dependent processes
  Cell membrane function

• Mitochondrial function

• Neurotransmitter function

• Heme synthesis

particularly damaging to the nervous system

Potential manifestations of lead exposure in children

• learning/cognitive problems

• behavioral problems

• developmental effects

• neurologic dysfunction

What is the primary pathway for ethanol metabolism

• Ethanol

• decrease alcohol dehydrogenase (ADH)

• Acetaldehyde

• decrease aldehyde dehydrogenase (ALDH)

• Acetate

How does chronic alcohol metabolism contribute to oxidative stress

• chronic ethanol metabolism increases activity of the microsomal ethanol-oxidating system (MEOS/CYP2E1) which generates reactive oxygen species (ROS) —>

• oxidative stress —> lipid peroxidation —> cellular injury

progression of alcohol-related liver disease

• fatty liver (steatosis)

• alcoholic hepatitis

• fibrosis/cirrhosis

fetal alcohol syndrome abnormalities

• growth restriction

• CNS/neurodevelopmental abnormalities

• facial abnormalities

  • short palperbral fissures

  • smooth/flattened philtrum

  • thin upper lip

how does carbon monoxide cause hypoxic injury?

CO binds to hemoglobin with 200x greater affintiy than oxygen, reducing oxygen delivery to tissues

HAPE (high altitude pulmonary edema )

hypoxia —>pulmonary vasoconstriction —> increase pulmonary pressure —> pulmonary edema

HACE (high altitude cerebral edema)

cerebral edema —> ataxia + altered mental status

pathophysiology mechanisms

• hypoxia

• decrease oxidative phosphorylation

• decrease ATP

• Na+/K+ - ATPase fails

• Na+ accumulates inside cell

• H20 follows Na+

• CELLULAR SWELLING

Dystrophic vs metastatic calcification

• Dystrophic: damaged tissue + normal serum Ca++

• Metastatic: normal tissue: high serum Ca++

hemosiderosis

• a transient, localized deposition of iron.

• condition in which excess iron is stored as hemosiderin (yellow/brown pigment derived from hemoglobin) in the cells of many organs and tissues

• common in people with repeated blood transfusions or prolonged parenteral administration of iron, excessive ETOH ingestion

coagulative necrosis

• dead tissue retains its basic shape/architecture for several days. It is most commonly caused by ischemia or infarction

• results from protein denaturation

Coagulative = clot like + ischemia

liquefactive necosis

• dead cells are digested by enzymes turning the tissue into a liquid/viscous mass

• common with: brain infarction and bacterial infections/abscesses

liquefactive = liquid

Caseous necrosis

• soft, white, “cheese-like” form of necrosis classically associated with tuberculosis

• combination of coagulative and liquefactive necrosis

CASEous = cheese

gangrenous necrosis

• coagulative necrosis involving multiple tissue layers, commonly from severe loss of blood supply to an extremity.

dry gangrene

• coagulative necrosis (skin changes to dark brown or black)

• Primarily ischemic

wet gangrene

• occurs when neutrophils invade the site. Usually in internal organs causes site to become old, swollen, and black with foul odor

• bacterial infection is added —> liquefactive changes