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Flashcards in 9/5/17 Deck (50):
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Pathology

Study of morphological, biochemical, and functional changes in cells, tissues, and organs that underlie disease

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Pathogenesis

Sequence of cellular, biochemical, and molecular events that follow exposure of a cell or tissue to injury

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Causes of cell injury

Oxygen depravation: common
Ischemia- lack of blood flow
Hypoxia- deficiency of oxygen
Anoxia- lack of oxygen

Chemicals or drugs

Physical injury

Infectious agents

Immune response: autoimmune diseases, allergies

Nutritional imbalances

Genetic derangement

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Cell adaptation to injury

Intracellular accumulation

Cell size (hypertrophy)

Cell number (hyperplasia)

Cell Differentiation (metaplasia)

Atrophy

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Hypertrophy

Increase in cell size

Entails gene activation and protein/organelle synthesis

Tissues incapable of cell cycle exhibit hypertrophy instead of hyperplasia, heart muscles from high BP

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Hyperplasia

Increase in cell number

Produce new cells from stem cells

Can become pathological and progress to dysphasia then cancer

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Aplasia

Failure of cell division during embryogenesis

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Hypoplasia

Decrease in cell production during embryogenesis resulting in smaller tissues/organs

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Atrophy

Decrease in stress or stimulus results in decreased organ/tissue size/mass

Due to decreased hormonal stimulation, disuse, or decreased blood supply

Occurs via decrease in-
1. Cell size: ubiquitin-proteosome degradation of the cytoskeleton, especially intermediate filaments

2. Cell number: apoptosis

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Metaplasia

New or increased stress or chronic irritation that leads to alteration in cell type

Often one type of epithelium change to another

Due to stem cell reprogramming, may be reversible if stimulus removed

Could progress to dysplasia then cancer

Barrett's esophagus is an example

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Barrett's Esophagus

Normal squamous epithelium of the esophagus converted to nonciliated mucin producing epithelium to better cope with stomach acid into esophagus

Example of metaplasia

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Dysplasia

Disordered cellular growth

Usually for precancerous cells, could be reversible if remove stress or could progress to cancer

Cervical dysplasia is a precursor to cancer

Can arise from longstanding hyperplasia or metaplasia like Barrett's esophagus

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Reversible Cell Injury

Cell swelling: reduced oxidative phosphorylation leads to less ATP, ion conc. changes and water influx leads to swelling

Fatty change: lipid vacuoles appear in cytoplasm, mainly seen in cells involved in lipid metabolism like liver/heart
Seen in toxic, metabolic, or hypoxic injury

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Factors that cellular response to injury is dependent on

Cell type: heart cells more sensitive to low oxygen levels than bone

Type of injurious stimulus

Strength/intensity of stimulus

Duration of stimulus

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6 cellular mechanisms of injury

ATP depletion

Mitochondrial damage

Loss of calcium homeostasis (influx)

Oxidative stress from free radicals

Loss of selective membrane permeability

DNA and protein damage

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Cell injury: ATP depletion

For hypoxia and toxic (cyanide) injuries

Depleted oxygen supply or mitochondrial damage

Lower ATP leads to glycolysis, lowers pH

ATP needed for-
Protein synthesis: less production and unfolding may occur
Membrane transport
Membrane maintenance: fails due to impaired phospholipid turnover

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Mitochondrial Damage

Common and from hypoxia or toxic exposure

Damaged by increased cellular Ca2+, ROS, oxygen depravation

Lower ATP and high ROS production leads to necrosis, caused by low oxygen or toxins

Higher pro-apoptotic and lower anti-apoptotic proteins leads to leakage of mitochondrial proteins and apoptosis, caused by decreased survival signals and DNA/protein damage

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Loss of Calcium homeostasis

Normally low Ca2+, sequestered in mitochondria and ER

Caused by ischemia or toxins

Calcium released from intracellular storage, extracellular Ca2+ flux can then occur

Consequences of increased calcium:
1. Enhanced mitochondrial permeability, leads to failure of ATP production

2. Activates enzymes: phospholipases and proteases lead to membrane damage, endonucleases cause DNA damage, ATPases further deplete ATP supply

3. Induce apoptosis by activating capases

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Oxidative Stress

Important in many types of injury

Affects macromolecules in autocatalytic manner

Injury occurs when production increases or scavenging capacity decreased

Damages membrane lipids, proteins, and DNA

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Defects in membrane permeability

Loss of selective membrane permeability leads to invert damage in necrosis, not apoptosis

Mechanisms-
1. ROS: lipid peroxidation can propagate
2. Decreased phospholipid synthesis: lower ATP production
3. Increased phospholipid breakdown: phospholipase activity increases
4. Cytoskeletal abnormalities: protease damage

Defects in most important membranes-
1. Mitochondria: lower ATP production, cascade release
2. Plasma membrane: lose osmotic balance, Ca2+ influx, lose cytosolic contents (ATP)
3. Lysosomes: degradation enzymes released

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Two factors to initiate apoptosis

Too much DNA damage beyond repair mechanisms

Improperly folded proteins

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How reversible injury becomes irreversible

Unsure

1. Inability to reverse mitochondrial dysfunction (ATP)

2. Membrane damage to lysosomes, mitochondria, and plasma membrane

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Necrosis Types

Death of large groups of cells often followed by inflammation, due to underlying pathology and never physiology

Types-
Coagulative: preserves cell/organ shape, nucleus gone, typical of ischemic infarction in any organ besides brain

Liquefactive: tissue liquified by digestive enzymes for dead cells, seen in pancreas, rain, and abscess

Gangrenous: coagulative necrosis becomes mummified, may get secondarily infected and liquefactive necrosis occurs

Caseous: cheese-like combo of liquefaction and coagulative necrosis, typical of granulomatous inflammation in TB or fungi

Fat: becomes chalky White due to calcium saponification, breast trauma and pancreatitis lipase activity

Fibrinoid: necrosis of blood vessel wall, fibrin leaks out of vessel, seen in vasculitis, extreme high BP

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Apoptosis

ATP-dependent, genetically programmed, involves single cells or small groups

Morphology: cell shrinks, cytoplasm is pink (eosinophilic), nucleus condenses, not accompanied by inflammation

Mediated by capases

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Features of necrosis

Damage to cell membranes, loss of ion homeostasis, lysosomal enzymes released, breakdown cell, inflammatory reaction

Unregulated

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Generation of ROS

Superoxide: oxygen with a free radical, produced by the ETC, inactivated by superoxide dismutase to form hydrogen peroxide

Hydrogen peroxide: made by auto-oxidation in mitochondria and oxidases in peroxisomes, converted to a hydroxyl radical by the Fenton Reaction involving Fe2+ or Cu2+

Hydroxyl radical: made by Fenton Reaction or from hydrolysis of water by ionizing radiation

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Endogenous sources of ROS

ER, cytoplasm, peroxisomes, PM, mitochondria, and lysosomes

Mitochondria: major source of ROS, makes superoxide via Complex I and III, may play a role in aging and Parkinson's

Peroxisomes: acyl-CoA oxidase of its beta oxidation generates hydrogen peroxide that's converted to water via catalase

NADPH Oxidase System: makes superoxide to regenerate NADP+ from NADPH, located in lysosomes of immune phagocytes, gp91 and p22 bound to membrane and three others (p67,40,47) come to bind
Chronic granulomatous disease- mutation in one of the 5 proteins, life threatening bacterial/fungal infections and granuloma formation, phagocytes can't destroy catalase bacteria

Cytoplasmic Source: hypoxanthine becomes xanthine and uric acid via xanthine oxidase, generates hydrogen peroxide and superoxide, inhibit this enzyme to prevent gout

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Effect of low ROS conc. and/or chronic overproduction of oxidants

Activate various cellular pathways

Stimulate cell proliferation

Damage lipids, proteins, and DNA

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Lipid Peroxidation

Unsaturated lipid reacts with hydroxyl radical to form a lipid radical, which reacts with oxygen to form a lipid peroxyl radical, which reacts with an unsaturated lipid to regenerate another lipid radical and make lipid peroxide

Lipid peroxide breaks down to smelly aldehyde

Terminates when 2 lipid radicals react

Consequences-
1. Membrane structure changes: alter fluidity and channels, alter membrane bound signal proteins, increase ion permeability

2. Lipid peroxidation products: form adducts/crosslinks with DNA and proteins, direct toxicity, disrupt membrane dependent signaling

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Protein Oxidation

Hydroxyl radicals attack Cys, Met, Arg, His, and Pro in membrane and cytoplasmic proteins, leads to degradation via autophagosome or protesomes which decreases structural integrity and increases permeability

Can create mixed disulfide bonds

Increased susceptibility to proteolysis

Oxidation of catalytic sites can be LOF that lead to GOF

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DNA oxidation

DNA adducts, strand breaks, modified bases (T and G most common)

Increased risk for neoplastic changes

Stimulates DNA repair that can deplete ATP, induce error prone polymerase

Mutations

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Preventative Antioxidants

Anti-inflammatory agents

Nitric oxide synthase inhibitors

Metal chealtors: metallothionein, transferrin, lactoferrin

NADPH oxidase inhibitors

Xanthine oxidase inhibitors

Water soluble: glutathione, vitamin C, uric acid
Fat soluble: vitamin E, CoQ, beta carotene (retinoids)

Proteins: superoxide dismutase (intracellular and PM), glutathione peroxidase, albumin

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Catalytic Reduction Pathway of Peroxides

Hydrogen peroxide converted to water by catalase in peroxisomes

Hydrogen peroxide converted to water in mitochondria/cytoplasm by glutathione peroxidase, which then needs glutathione reductase and NADPH, regenerate NADPH by PPP

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Reasons for atrophy

Decreased functional demand

Hypoxia

Starvation or malnutrition

Decreased trophic factors

Persistent cell injury: chronic pressure, inflammation, or disease, also aging

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Atrophy: decreased functional demand

For casts, prolonged bed rest, or inactivity

Leg diameter is smaller and has larger fat layer

Inactive skeletal muscle has higher amounts of ECM between myocytes

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Atrophy: decrease oxygen supply

One kidney enlarges to compensate, can be due to atherosclerosis

Brain: enlarged lateral ventricles, larger sulci between gyri, and overall shrinkage away from frontal bone

Can be due to chronic cerebral ischemia

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Atrophy: Decreased Trophic Stimulation

Occurs when nerve to skeletal muscle is cut or loss of hormonal/growth factor stimulation to cell/tissue

Bell's palsy: asymmetry of face, cut facial nerve leads to denervation of a muscle, scattered atrophic angulated fibers eventually form groups

Endometrium is proliferation and has numerous branched glands upon estrogen stimulation, gets fewer glands during menopause

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Atrophy: Chronic Increased Pressure

Hydrocephalus: increase in CSF in cerebral ventricles due to an obstruction, increased fluid pressure dilates ventricles and causes atrophy of surrounding cerebral tissue

Very Unhappy Looking CT scan, enlarged ventricles

Decubitus ulcers (bed sores): atrophy of skin/subcutaneous tissue overlying bony prominences of sacrum, ankles, knees, and elbows from chronic pressure due to lack of movement

Can be superficial or extend to the bone, preventable by rotating the patient

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Atrophy: Chronic Inflammation

Chronic gastritis of the stomach lining

Normal: thick epithelial layer with numerous branching tubular glands, close to each other with little connective tissue between glands

Atrophy: glands are smaller and fewer of them due to apoptosis, amount of connective tissue between them increases in size, little black dots of immune cells like macrophages

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Atrophy: Chronic Disease

Cachexia: significant skeletal muscle and adipose tissue atrophy independent of nutritional intake, negative protein balance and increased glucose utilization due to an elevated adrenergic state

Many cancer patients have it, TB, AIDS

Cancer cachexia mediated by cytokines that induce protein ubiquination-proteasome activity

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2 Main Causes of Hypertrophy

Increased functional demand

Increased tropic factors

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3 Concepts in Cellular Changes

1. Cells that rent capable of proliferating (skeletal/cardiac myocytes) do hypertrophy without proliferation, cells that can proliferate do hypertrophy and hyperplasia

2. Cells incapable of proliferation do atrophy without apoptosis, do both atrophy and apoptosis if can proliferate

3. Adaptive cellular changes are reversible when chronic stress or physiologic stimuli is removed

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Pathologic Hypertrophy

Hypertension: cardiac muscle has increased functional demand to pump blood through narrowed vesicles

Would be physiologic if from exercise

Thicker ventricle wall, larger myocardial muscle cells, larger nuclei

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Physiologic Hypertrophy

Gravid Uterus: Hypertrophy and hyperplasia of smooth muscle cells in the wall of the uterus in response to estrogen during pregnancy

Hypertrophied smooth muscle has greater distance between nuclei compared to normal smooth muscle cells

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Hypertrophy Mechanisms

Hypertension: mechanical stretch sensors activated and lead to binding of growth factors and agonists to their receptors

STP activates TFs that stimulate re-introduction of the fetal genes for contractile proteins (myosin) and growth factors (ANF, atrial naturetic factor) with autocrine effect

Increased mechanical performance and decreased work load

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Nuclei Acid Nomenclature

Nuclei Acid: polymer of DNA/RNA nucleotides

Nucleotides: nitrogenous base, sugar, and 1-3 phosphates

Nucleoside: nitrogenous base and sugar

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Pyrimidine Synthesis

Need Gln and Asp

Oritic Acid and UMP

Rate limiting step: Carbamoyl phosphate synthetase II (CPS-II)

Create nitrogenous base and then add sugar (activated ribose 5-phosphate)

Makes UMP, TMP, and CTP

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Purine Synthesis

Gly, Gln, And Asp

IMP

Rate limiting: Glutamine-PRPP Amidotransferase (GPAT)

Create sugar and then add nitrogenous base via AAs

Makes AMP and GMP

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Nucleotide a Salvage Pathway: Purines

Base to Nucleotide-
Adenine, hypoxanthine, guanine have ribose 5-phosphate added by phosphoribosyltransferase, makes AMP, IMP, and GMP

Degradation-
AMP, IMP, and GMP broken down by adenosine deaminase and xanthine oxidase, form uric acid (water insoluble)

Adenosine to inosine to hypoxanthine to xanthine to uric acid, guanine to xanthine to uric acid

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Nucleotide Salvage Pathways: Pyrimidines

Base to Nucleotide:
Uracil and thymine to nucleoside by adding ribose 1-phosphate and phosphorylation of the nucleoside

Need nucleoside phosphorylase and nucleoside kinase

Make CMP, UMP, and TMP from nucleoside


Nucleotide Degradation:
CMP, UMP, and TMP to CO2, H2O, urea, beta-alanine, and beta-alanine aminoisubutyrate

Need dihydropyrimidine dehydrogenase, dihydropyrimidinase