9/5/17 Flashcards
Pathology
Study of morphological, biochemical, and functional changes in cells, tissues, and organs that underlie disease
Pathogenesis
Sequence of cellular, biochemical, and molecular events that follow exposure of a cell or tissue to injury
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
Cell adaptation to injury
Intracellular accumulation
Cell size (hypertrophy)
Cell number (hyperplasia)
Cell Differentiation (metaplasia)
Atrophy
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
Hyperplasia
Increase in cell number
Produce new cells from stem cells
Can become pathological and progress to dysphasia then cancer
Aplasia
Failure of cell division during embryogenesis
Hypoplasia
Decrease in cell production during embryogenesis resulting in smaller tissues/organs
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
- Cell number: apoptosis
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
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
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
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
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
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
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
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
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
- Activates enzymes: phospholipases and proteases lead to membrane damage, endonucleases cause DNA damage, ATPases further deplete ATP supply
- Induce apoptosis by activating capases
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
Defects in membrane permeability
Loss of selective membrane permeability leads to invert damage in necrosis, not apoptosis
Mechanisms-
- ROS: lipid peroxidation can propagate
- Decreased phospholipid synthesis: lower ATP production
- Increased phospholipid breakdown: phospholipase activity increases
- Cytoskeletal abnormalities: protease damage
Defects in most important membranes-
- Mitochondria: lower ATP production, cascade release
- Plasma membrane: lose osmotic balance, Ca2+ influx, lose cytosolic contents (ATP)
- Lysosomes: degradation enzymes released
Two factors to initiate apoptosis
Too much DNA damage beyond repair mechanisms
Improperly folded proteins
How reversible injury becomes irreversible
Unsure
- Inability to reverse mitochondrial dysfunction (ATP)
- Membrane damage to lysosomes, mitochondria, and plasma membrane
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
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
Features of necrosis
Damage to cell membranes, loss of ion homeostasis, lysosomal enzymes released, breakdown cell, inflammatory reaction
Unregulated
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
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
Effect of low ROS conc. and/or chronic overproduction of oxidants
Activate various cellular pathways
Stimulate cell proliferation
Damage lipids, proteins, and DNA
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
- Lipid peroxidation products: form adducts/crosslinks with DNA and proteins, direct toxicity, disrupt membrane dependent signaling
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
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
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
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
Reasons for atrophy
Decreased functional demand
Hypoxia
Starvation or malnutrition
Decreased trophic factors
Persistent cell injury: chronic pressure, inflammation, or disease, also aging
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
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
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
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
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
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
2 Main Causes of Hypertrophy
Increased functional demand
Increased tropic factors
3 Concepts in Cellular Changes
- Cells that rent capable of proliferating (skeletal/cardiac myocytes) do hypertrophy without proliferation, cells that can proliferate do hypertrophy and hyperplasia
- Cells incapable of proliferation do atrophy without apoptosis, do both atrophy and apoptosis if can proliferate
- Adaptive cellular changes are reversible when chronic stress or physiologic stimuli is removed
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
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
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
Nuclei Acid Nomenclature
Nuclei Acid: polymer of DNA/RNA nucleotides
Nucleotides: nitrogenous base, sugar, and 1-3 phosphates
Nucleoside: nitrogenous base and sugar
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
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
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
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
