Bio217 F2013 Unit 1

Bio 217 Pathophysiology Class Notes Professor Linda Falkow

• Unit 1: Introduction to Pathophysiology Cellular Biology

– Chapter 1: Cellular Biology Chapter 1 – Chapter 2: Genes & Genetic – Chapter 3: Altered Cellular & Tissue Biology – Chapter 4: Fluids & , Acids & Bases

Cellular Functions Cell Structure & Function

• Movement • Nucleus

• Conductivity – DNA • DNA replication ______• Metabolic absorption – Cell division • Secretion • Excretion • Cytoplasm • Respiration – Cytosol • Reproduction – Cytoplasmic • Communication

Eukaryotic Cell Eukaryotic Cell

• Nucleus • Nucleus

1 Bio217 F2013 Unit 1

Eukaryotic Cell Organelles • Cytoplasm • ______– synthesis

• ______– Rough ER – site of protein synthesis – Smooth ER - site of lipid synthesis

• ______– from the endoplasmic reticulum are packaged in the ______

Eukaryotic Organelles Plasma Membrane • Lysosomes – Contain enzymes – Role in autodigestion as a result of cellular injury • Lipids • Peroxisomes • Hydrophilic and hydrophobic • Phospholipids, glycolipids, and cholesterol – Contain oxidative enzymes

– Produce H2O2 • Carbohydrates • ______• Glycoproteins – Participates in oxidative phosphorylation (ATP production) • Proteins • Cytoskeleton – Integral, peripheral, transmembrane – “Bones and muscles” of the cell – Functions – Microtubules and Microfilaments

Membrane Fluidity Plasma Membrane (______) • Plasma membrane protein functions

2 Bio217 F2013 Unit 1

Adenosine Triphosphate Cellular Energy 1. Digestion • Created from the chemical energy contained in organic molecules 2. Glycolysis & • Used in synthesis of organic molecules, oxidation muscle contraction, and active transport • Stores and transfers energy 3. Citric Acid Cycle

Membrane Transport Membrane Transport

• Passive transport Passive Diffusion Facilitated Diffusion – Diffusion (simple and facilitated) • Concentration gradient [high  low] – Filtration • Hydrostatic pressure – Osmosis • Movement of water – Tonicity • Isotonic, hypertonic, and hypotonic

Active Transport Membrane Transport (Na-K Pump)

• Active transport – Active transport pumps (Na/K Pump) – Transport by vesicle formation • Endocytosis – Pinocytosis – Phagocytosis – Receptor mediated • Exocytosis

3 Bio217 F2013 Unit 1

Membrane Transport The Cell Cycle

– ______(G1 phase, S phase, G2 phase) plus ______

G1- cell activities and centrioles replicate

S - DNA replicates

G2 – protein synthesis, preparation for mitosis Exocytosis

Types of Tissue Influences on the Cell Cycle • Epithelial tissue – Simple vs. stratified squamous • Cellular division rates – Transitional – Cuboidal – Complete cell cycle 12-24 hours – Simple vs. stratified columnar – Mitosis 1 hour – Pseudostratified ciliated

• Growth factors (cytokines) • Connective tissue – PDGF – Dense regular or irregular – EGF – Loose and dense connective tissue – IGF-I – Elastic and reticular connective – Cartilage, bone, vascular, and adipose

Types of Tissue Concept Check

• Muscle tissue • 1. What are the main parts of the eukaryotic – Smooth cell? – Striated (skeletal) – Cardiac A. Lipids, CHO, proteins

B. Minerals and water • Nerve tissue C. Organelles – conduct nerve impulses D. Cytoplasm and membrane-bound nucleus – Neuroglia provide support activities

4 Bio217 F2013 Unit 1

3. Which of the following statements 2. Which of the following cellular functions regarding transport across membranes is does NOT occur in all cell types? TRUE?

A. Diffusion requires a significant energy input. A. Respiration B. Mediated transport involves a receptor with B. Excretion a high degree of specificity. C. Active transport moves molecules down a C. Metabolic absorption concentration gradient. D. Secretion D. Facilitated transport expends energy.

___ 5. Anaphase a. centrioles separate

• 4. Which can transport substances against ___ 6. Chromatin b. single stranded DNA in the concentration gradient? non-dividing cell ___ 7. Metaphase c. site of protein synthesis A. Active transport B. Osmosis ___ 8. Mitochondria d. chromatids separate C. Facilitated diffusion D. Dialysis ___ 9. Ribosome e. powerhouse of cell

___10. Prophase f. chomatid pairs align

5 Bio217 F2013 Unit 1

DNA

Genes and Genetic Diseases • Pentose sugar (______) • Phosphate molecule Chapter 2 • Four ______bases – Pyrimidines: Cytosine and Thymine – Purines: Guanine and Adenine • Double helix model • ______

Proteins Mutation • Any inherited alteration of genetic material – aberrations • One or more polypeptides – Base pair substitution • One base pair is substituted for another

• Composed of amino acids • Frameshift mutation – ______amino acids – Insertion or deletion of one or more base pairs – Causes a change in the entire “reading frame” – Directed by sequence of bases (codons) • Mutagens – Increase frequency of mutations – Radiation and chemicals

Mutation Transcription - DNA serves as template for formation of _____

6 Bio217 F2013 Unit 1

Translation - Process by which RNA directs the synthesis of a ______• Somatic cells (____) – Contain 46 chromosomes (23 pairs) • Gametes (__) – Contain 23 chromosomes

 Meiosis • Formation of haploid cells from diploid cells  Mitosis • Forms ______cells

Chromosomes Karyotype • Ordered display of chromosomes (metaphase) • Autosomes – The first 22 of the 23 pairs of chromosomes in males and females

• Sex chromosomes – Remaining pair of chromosomes – In females (____) – In males (_____)

Chromosome Aberrations Chromosome Aberrations • Euploid cells have a multiple of the normal number of chromosomes (“eu” Gk. = good ) • Aneuploidy – n and 2n cells are euploid forms – Somatic cell that does not contain a multiple of 23 chromosomes • Polyploid - when a euploid cell has more – Cell containing three copies of one than the diploid number chromosome is trisomic (trisomy) • Triploidy - three copies of each chromosome – Monosomy is one copy of any chromosome, (3n=69) often lethal • Tetraploidy: - four copies of each (4n=92 total) • “It is better to have extra than less” • Triploid or tetraploid fetuses never survive

7 Bio217 F2013 Unit 1

Chromosome Aberrations Nondisjunction

• Disjunction – Normal separation of ______during cell division • Nondisjunction – Usually the cause of aneuploidy – Failure of homologous chromosomes to separate normally during cell division

Autosomal Aneuploidy Down Syndrome

• Down syndrome (______) – Best known example of aneuploidy – 1:800 live births – Mentally retarded, low nasal bridge, epicanthal folds (eyes), protruding tongue, poor muscle tone – Risk increases with maternal age >35

Sex Chromosome Aneuploidy Sex Chromosome Aneuploidy • Turner syndrome (45, X) • Klinefelter syndrome (47, XXY) – Females with only one ______– Individuals with at least two Xs and – Characteristics one Y chromosome • Absence of ovaries (sterile) – Characteristics • Short stature (~ 4'7") • Male appearance • Webbing of the neck • Develop female-like breasts • Edema • • Underdeveloped breasts; wide nipples Small testes • High number of aborted fetuses have • Sparse body hair this karyotype • Long limbs • X is usually inherited from mother

8 Bio217 F2013 Unit 1

Abnormalities in Abnormalities in Chromosome Structure Chromosome Structure • Chromosome breakage • Breakage or loss of DNA – If breakage does occur, physiologic • Cri du chat syndrome mechanisms usually repair the break, – “Cry of the cat” but often heals so that chromosome structure – Deletion of short arm of chromosome 5 is altered – Low birthweight, metal retardation, and

microcephaly – Clastogens - harmful agents such as: – ionizing radiation – chemicals – viruses

Genetics Genetics • Homozygous • Genotype (“what they have”) – Loci on a pair of chromosomes have – The genetic makeup of an identical genes • Phenotype (“what they demonstrate”) – Example • O blood type (OO) – The observable, detectable, or outward • Heterozygous appearance – Loci on a pair of chromosomes have • Example different genes – Individual with the A blood type could be AA or – Example AO. Genotype = ______• AB blood type (A and B genes on pair of loci) Phenotype = ______

Genetics Genetics

• If two alleles are found together, the allele • Carrier that is observable is dominant, and the – A carrier is one that has a gene but one whose effects are hidden is recessive is phenotypically normal – For a person to demonstrate a recessive • ____ = homozygous disease, the pair of recessive genes must • ____ = heterozygous be inherited • ____ = homozygous – Example • Ss = sickle cell anemia carrier • Alleles can be codominant • ss = demonstrates sickle cell disease

9 Bio217 F2013 Unit 1

Single-Gene Disorders Expressivity - variation in phenotype • Autosomal dominant disorder • Examples: – Abnormal allele is dominant, normal allele is – von Recklinghausen’s disease recessive, and the genes exist on a pair of autosomes (Neurofibromatosis type 1) – Autosomal dominant • Huntington’s disease (Hh) – Long arm of chromosome 17 – Dementia, uncontrollable movements – Disease varies from spots (caf-au-lait) on – Evident after age 40 the skin to malignant neurofibromas, – results in death scoliosis, gliomas, neuromas, etc.

Autosomal Recessive Consanguinity

• Mating of two related individuals  • Cystic fibrosis inbred offspring – Defect on Ch 7 • Dramatically increases the recurrence – Cl ion transport defect  salt imbalance  risk of recessive disorders thick mucus – Affect respiratory and digestive systems – Individuals live to ~ age 30

Sex-Linked Disorders Sex-Linked Disorders

• The Y chromosome contains only a few • Male-pattern baldness dozen genes, so most sex-linked traits are located on the X chromosome – Occurs mostly in men (autosomal dominant) (X-linked) – Can occur in women (autosomal recessive)

• Sex-linked (X-linked) disorders are usually • Color-blindness expressed by males because females – Affects 8% of males; 0.5% females have another X chromosome to mask – Unable to distinguish red from green the abnormal gene

10 Bio217 F2013 Unit 1

Sex-Linked Disorders Concept Check

1. Which of the following statements is TRUE?

A. Protein synthesis takes place in the cytoplasm. B. DNA is replicated in the cytoplasm. C. RNA is double-stranded. D. RNA contains the same bases as DNA.

2. Which term best describes an allele with an Altered Cellular and observable effect? Tissue Biology

A. Homozygous Chapter 3 B. Heterozygous C. Dominant D. Recessive

Cellular Adaptation Cellular Adaptation

• Physiologic (normal) vs. pathogenic Atrophy – decrease in cell size (diseased states) Hypertrophy – increase in cell size – Atrophy – Hypertrophy Hyperplasia – increase in cell – Hyperplasia numbers (incr. in cell div.)

– Metaplasia Metaplasia – one cell type – Dysplasia converts to another cell type

Dysplasia – abnormal changes in cells (vary in size, shape, etc.)

11 Bio217 F2013 Unit 1

Cellular Adaptation Cellular Injury

• Reversible

• Irreversible

Cellular Injury (Hypoxic Injury due to ) Cellular Injury Mechanisms

• Hypoxic injury – Ischemia - ______

– Anoxia - lack of ______( due to blood clot) – Cellular responses • Decrease in ATP, causing failure of Na-K pump and sodium- exchange • Cellular swelling • Vacuolation (formation of vacuoles)

– If O2 restored  Reperfusion injury  free radicals

Cellular Injury Mechanisms Cellular Injury • Chemical injury (poisons)

– Carbon tetrachloride (CCl4) - forms free radicals by liver – Lead -- environmental or occupational sources -- affects nervous system, hemopoiesis, kidneys – Carbon monoxide (CO) -- causes hypoxic injury due to increased affinity for Hb

– Ethanol (C2H5OH) --  nutritional deficiencies & liver disorders -- conversion to acetaldehyde  fat deposits, liver enlargement and necrosis, CNS depressant – Mercury (Hg) -- dental amalgams, fish, vaccines -- controversy over health effects

– Social or street drugs - THC, C10H15N (meth), cocaine, opiates

12 Bio217 F2013 Unit 1

Unintentional and Unintentional and Intentional Injuries Intentional Injuries • Blunt force injuries • Sharp injuries – Application of mechanical energy to the – Incised wounds body resulting in the tearing, shearing, – or crushing of tissues Stab wounds – Contusion (bruise) vs. – Puncture wounds hematoma (collection of blood) – Chopping wounds – Abrasion (scrape) – Laceration (tear in skin or tissue) – Fractures (bones break)

Unintentional and Unintentional and Intentional Injuries Intentional Injuries

Stab Wounds

Avulsed Laceration

Patterned Abrasion

Unintentional and Intentional Injuries Infectious Injury • Asphyxial injuries – Caused by failure of cells to receive or use oxygen • Pathogenicity of a microorganism • Suffocation • Disease-producing potential –Choking asphyxiation – Invasion and destruction • Strangulation – Toxin production –Hanging, ligature, and manual strangulation – Production of hypersensitivity reactions • Chemical asphyxiants –Cyanide and hydrogen sulfide • Drowning –Cerebral hypoxia unconsiousness

13 Bio217 F2013 Unit 1

Immunologic and Manifestations of Cellular Injury Inflammatory Injury • Phagocytic cells • Cellular accumulations (infiltrations) – Water • Immune and inflammatory substances – Lipids and carbohydrates – Histamine, antibodies, lymphokines, – Glycogen complement, and proteases – Proteins • Membrane alterations  K+ leakage from cell – Pigments • Melanin, hemoproteins, – Calcium – Urate

Oncosis (Hydropic Degeneration) - swelling (degeneration by water) Manifestations of Cellular Injury

Cellular Death Cellular Death • Necrosis – Cellular changes after local cell death and the Stages of Necrosis process of cellular autodigestion (self-digestion) 4 types of Necrosis: – Coagulative – Liquefactive – Caseous – Fatty Gangrenous necrosis is large area of tissue death, Pyknosis – nucleus shrinks and Karyolysis – nucleus become dense mass of genetic fragments  “nuclear dust” not a separate type of cell death. material

14 Bio217 F2013 Unit 1

Necrosis Necrosis • Coagulative necrosis – result of hypoxia due to ischemia • Liquefactive necrosis – Kidneys, heart, and adrenal glands – Due to ischemic injury to brain cells (neurons and neuroglia) – Proteins denature  coagulation – Hydrolytic enzymes digest cells – Caused by bacterial infection Coagulative Necrosis of • Staphylococci, streptococci, and Escherichia coli Myocardium of LV (heart): note anemic infarct and necrosis of papillary muscle Liquefactive necrosis of brain

Necrosis Necrosis • • Caseous necrosis Fat necrosis – Breast, pancreas, and other abdominal organs – Tuberculous pulmonary infection – Due to action of lipases – Combination of coagulative and liquefactive necrosis

Granuloma with Central Caseous Necrosis: Fat Necrosis of Pancreas typical of pulmonary TB - note necrotic adipocytes

Necrosis Gangrenous Necrosis

• Gangrenous necrosis – Death of tissue from severe hypoxic injury • Dry vs. wet gangrene – Gas gangrene • Clostridium

15 Bio217 F2013 Unit 1

Apoptosis Necrosis vs.

• Programmed cellular death • Physiologic (normal tissue turnover) vs. pathologic (exogenous injury)

3. Which of the following terms best describes Concept Check death of a cell from hypoxia, generally as a 1. Which of the following is the most common cause result of ischemia in the lower extremities? of cellular injury? A. Coagulative necrosis A. Free radical-induced injury B. Liquefactive necrosis B. Chemical injury C. Fat necrosis C. Hypoxia D. Gangrenous necrosis D. Dysplasia 4. Cellular swelling is: 2. Which cell adaptation is observed in the cervix? A. Irreversible A. Hyperplasia C. Dysplasia B. Hypertrophy D. Metaplasia B. Occurs early in all cell injuries C. Low intracellular Na is common D. None of the above

Match the manifestation with the characteristic:

___5. Necrosis due to Clostridia a. Rigor mortis ___6. Rigidity of muscles after b. Gas gangrene Fluids and Electrolytes, death c. Hyperplasia Acids and Bases ___7. Increased cell number d. Metaplasia ___8. Necrosis from lysosomal e. Liquefaction Chapter 4 release f. Apoptosis ___9. Replacement of one cell with another __10. Normal & pathologic cell self-destruction

16 Bio217 F2013 Unit 1

Distribution of Body Fluids Net Filtration

• Total body water (TBW) ~60% of body wt. • Forces favoring filtration – Intracellular fluid (ICF) ~2/3 of TBW – Capillary hydrostatic pressure (blood pressure) • Fluid within cells – Interstitial colloid osmotic pressure – Extracellular fluid (ECF) ~1/3 of TBW (water-pulling) • Interstitial fluid - intercellular and not in vessels • Forces favoring reabsorption • Intravascular fluid - plasma – Plasma oncotic pressure (water-pulling) • Blood colloid osmotic pressure • Other ECF: Lymph, synovial, intestinal, CSF, sweat, urine, pleural, peritoneal, – Interstitial hydrostatic pressure pericardial, and intraocular fluids

Edema Acidosis and Alkalosis • Accumulation of ______within the interstitial spaces • Four categories of acid-base imbalances • Causes: – Increase in capillary hydrostatic pressure – Respiratory acidosis—elevation of pCO as a due to venous obstruction or salt & water retention 2 ( thrombophlebitis, CHF) result of ventilation depression – Decrease in plasma colloid osmotic pressure due to decreased plasma proteins (kidney disease, – Respiratory alkalosis—depression of pCO2 hemorrhage, cirrhosis of liver) as a result of alveolar hyperventilation – Increases in capillary permeability due to trauma – Lymph obstruction due to removal of lymph nodes

Metabolic Acidosis and Alkalosis Acidosis Alkalosis

– – Metabolic acidosis—depression of HCO3 or an increase in noncarbonic acids

– – Metabolic alkalosis—elevation of HCO3 usually caused by an excessive loss of metabolic acids

17 Bio217 F2013 Unit 1

Respiratory Concept Check Acidosis Alkalosis 1. Which of the statements is TRUE regarding water balance?

A. Isotonic fluids cause increased cellular swelling. B. Hypertonic fluid causes increased cellular swelling. C. Hypotonic fluid causes cellular swelling. D. Hypernatremia causes cellular swelling.

• 2. Of the 60% of TBW made up of water, • 4. Aldosterone controls ECF volume by: about 2/3 is ______. A. CHO, fat, and protein catabolism B. Na reabsorption – A. ECF C. K reabsorption – B. ICF D. H O reabsorption – C. Intravascular fluid 2 E. B and D are correct – D. interstitial water

• 5. The release of ADH is NOT stimulated by: • 3. Total water loss per day by an adult is about: A. Stress – A. 0.8 L B. Hyponatremia – B. 1.2 L C. Hypernatremia – C. 2.2 L D. Increase in – D. 2.8 L

• 6. The pH of saliva is about 7 and the pH of gastric Match the imbalance with the appropriate juice is about 2. How many times more concentrated is the [H+ ] in gastric juice than in saliva? compensatory mechanism: A. 5 • 10. Respiratory acidosis a. Kidneys excrete H+, B. 50 C. 10,000 retain HCO3 D. 100,000 • 11. Respiratory alkalosis b. Kidneys excrete HCO3, retain H+ Match the acid base with the probable cause: • 12. Metabolic acidosis c. Hyperventilation

___7. Respiratory acidosis a. Excessive baking soda (blow off CO2) ___8. Respiratory alkalosis b. Severe anxiety (hyperventilation) ___9. Metabolic alkalosis c. Emphysema

18