pathophyis ch. 1-4\

Pathophysiology

Diseases disrupt normal body function

Prokaryotic

No membrane-bound organelles

chromosomes = singular, circular

Ex: bacteria & archaea

Eukaryotic

Membrane-bound organelles; histones

Ex: human cells, animal cells, plant cells

Differentiation

Stem cells to specific types of cells w/ specific functions

Cellular Functions

Movement, conductivity, metabolic absorption, secretion, excretion, respiration, reproduction, communication

Totipotent

Embryonic

Limitless self-renewal

Give rise to cells in the body

Grow into any cell type in the body

Adult stem cells

Tissue

Differentiated w/ limited renewal

Generated new cells within tissue (can only make three cell specific types/copies of them selves

Self renewal

Cells maintain their number

Asymmetric division

One daughter cell enters differentiation while others remain the same

Plasma membrane disorder

Cholera- releases toxins, enters intestinal cell → adenylate cyclase →cystic fibrosis transmembrane conductance regulator → chloride into lumen → osmotic force draws water into lumen → diarrhea

Plasma membrane function

Selective barrier, detects chemical signals, anchors cell to adjacent structures, “fluid mosaic model”

Phospholipid bilayer

Hydrophilic (polar) head | faces outward

Hydrophobic (nonpolar) tail | faces inwards

Heterogeneous & asymmetric

Contains cholesterol + glycolipids + glycoproteins + integral/peripheral/transmembrane/channel proteins

Simple Diffusion

Small, non polar molecules moving passively (no energy)

Facilitated Diffusion

Uses a carrier or channel proteins, along the gradient (uses energy)

Active Transport (via carrier)

Requires energy to move against the gradient

Cytoplasm

Cytosine, cytoskeleton, organelles

Cytosol

Intracellular fluid (majority water w/ proteins)

Cytoskeleton

Network of protein filaments → maintain/change cell shape + maintain polarity + organize organelles

Organelles

Specific cellular machinery suspended in cytosol

Actin microfilament

Elastic support of membrane

Cell motion (w/ myosin)

Intermediate filament

Strength, permanent structure, helps ID tumor origin

Microtubule

rigid structure, cell division (spindles), transport, cilia

What filament is affected when someone is diagnosed with Alzheimers?

Microtubule

Tau protein disfunction → loss of microtubule assembly/stability → neurons can’t communicate/die

What filament is affected when someone is diagnosed with Nemaline myopathy?

Actin microfilament

Actin gene mutation → inclusions in muscle fibers → congenital muscle weakness

What filament is affected when someone is diagnosed with Keratinopathies/White Sponge Neves?

Intermediate filament

Keratin gene mutation (K4 or K13) → irregular filaments → white, spongy patches on buccal mucosa

Mitocondria

double bilayer membrane → smooth outer + highly folded inner and self replicated → circular DNA

Powerhouse of the cell + regulatory of apoptosis + generates reactive oxygen species

Mitochondria disorder

Leber Hereditary Optic Neuropathy: point mutation in mRNA

Kearns-Sayre syndrome: deletion of a segment of mtDNA (muscle weakness, blindness, kidney problems, dementia)

Rough ER function/pathway

produces polypeptides → enter rough ER lumen → folds into 3D shapes + glycosylation + transported to Golgi → transport inside or outside cell

produces membrane components (integral & peripheral proteins) for membrane-bound organelles and plasma membrane

ER disorder

Cystic Fibrosis: mutation causes CFTR chloride channel protein to misfold slightly in the rough ER → “overprotected” rough ER destroys it before it reaches the membrane

Golgi Apparatus (flat pancakes) function

Modification, sorting, and packing (MSP) for export + synthesizes certain carbohydrates

Golgi Apparatus disorder

Achondrogenesis Type IA (AR): Golgi Apparatus microtubules disturbed in multiple tissues, nonsense mutation of Trip II gene → loss GMAP-210 protein

• very short limbs, narrow chest, soft skull, poor spine/pelvis ossification

Lysosomes

organelle for intracellular digestion of damaged cellular structures, ingested food particles, and unwanted matter (bacteria), contains digestive enzymes called acid hydrolyses

Lysosome disorders

Pompe Disease: enzyme defect = alpha-glucosuidose; excessive glycogen storage → damages muscle fibers → progressive muscle weakness, respiratory failure, sever cardiomyopathy

Tay-Sachs Disease: enzyme defect = beta-hexosaminidase A; accumulation of GMS gangliosides (lysosomes can digest it → no exocytosis of residual material)

Peroxisomes

contain oxidases; use O2 to carry out chemicals reactions → produce hydrogen peroxide

oxidize toxic chemicals to less toxic compounds, breakdown fatty acids into smaller molecules for energy or anabolic reactions, synthesize certain phospholipids critical to plasma membranes of nervous system cells

Peroxisomes disorders

Mutation of ABCD1 gene → defect in peroxisome membrane transporter (ALDP) → accumulation of a very long chain of fatty acids (VLCFA) in the brain and adrenal cortex

Proteasomes

degrade cytosolic proteins into small fragments (amino acids)

target- denature, misfolded proteins, or macromolecules whose lifespan needs regulation

mechanism- ubiquitin: proteasome system — ubiquitin covalently binds to the target protein & polyubiquitin molecules are unfolded and funneled into a polymeric proteasome complex (a cylinder w/ multiple protease activity that “shreds” the protein into peptide fragments)

Stress

a state produced by change in the environment

Stressor

A threat to the steady state/homeostasis

Adaptation

the body’s adjustment/response to change

Cell injury

occurs when a cell is unable to maintain homeostasis in the face of injurious stimuli or is unable to adapt

Normal cell (homeostasis)

[Stress] → Adaptation → (inability to adapt) → cell injury

Normal cell [Injurious stimulus]

Cell injury → mild/transient → reversible injury → back to normal cell

Cell injury (severe/progressive)

Irreversible injury → cell death (necrosis or apoptosis)

Increased load

Adaptation hypertrophy (adapted myocyte)

Cell injury (not corrected)

reversibly injured myocyte → if uncorrected = cell death

Reversible

early, mild damage; correctable if harmful stimulus is removed

1) Generalized swelling of cell and organelles: ATP depletion → failure of NA+ (out)/K+ (in) ATPase; no ATP = water goes in → swelling occurs

2) Fatty chain in metabolically active organs: intracellular triglyceride deposits

Irreversible

Once occurs damage crosses the “point of no return”

1) Irreversible mitochondrial dysfunction: cannot restart oxidative phosphorylation → permanent loss of ATP generation

2) Severe membrane damage → especially lysomal membranes → enzymatic self-digestion

Causes of cell injury

Hypoxia, physical agents, chemical agents and drugs, infectious agents, immunologic reactions, genetic abnormalities, nutritional imbalances

Mitochondrial damage

ATP affected; ROS increased → damage (necrosis)

Membrane damage

damage to lysosomal membranes → leakage of enzymes → necrosis

damage to plasma membrane → impaired transport, leakage of cellular contents → necrosis

Damage to DNA

radiation/mutations → nuclear damage → cell cycle arrest OR activation of caspases (APOPTOSIS)

Disturbance in calcium homeostasis

injury → cell/ER leaks calcium → cytosolic CA 2+ is harmful

increased Ca2+ = activation of cellular enzymes (phospholipase, protease, endonuclease, ATPase) → membrane damage, nuclear damage, decreased mitochondrial permeability transition

Endoplasmic reticulum stress

mutations, cell stress, infections → misfolded protein accumulation → unfolded protein response

small amt. misfolded- mild ER stress = adaptive UPR: increased chaperones, decreased protein synthesis, increased protein degradation

large amt. misfolded- severe ER stress = terminal UPR: apoptosis

Oxidative stress

accumulation of O2 derived free radicals

Free radicals

single unpaired e- in the outer shell

very unstable

autocatalytic-self programming, turn on more free radicals

Reactive oxygen species (ROS)

produced not normally during oxidative phosphorylation

types: superoxide (O2), hydrogen peroxide (H2O2), hydroxyl radical

Removal of free radicals (antioxidants)

block or inactivate

binding to storage/transport proteins (transferrin, ferritin)

enzymes: catalase, superoxide dismutase (SOD), glutathione peroxidase

Oxidative stress

antioxidants < free radicals = excess of free radicals

leads to oxidative damage of lipids, proteins, nucleic acids → tissue injury & inflammation

Causes of Oxidative Stress

Normal metabolic processes (mitochondrial respiration/energy generation)

Ionizing and UV radiation

Transition metals (copper and iron)

Chronic inflammation

Chemical or drug toxicity

Ischemia (reperfusion injury; vessel obstructed → flow restored → cells altered upon return flow)

Nitric oxide (NO) → peroxynitrite

Necrosis (cell size, nucleus, plasma membrane, cellular contents, adjacent inflammation)

Enlarged

Pyknosis, karyorrhexis, karyolysis

Disrupted

Enzymatic digestion; may leak out

Frequent

→ inflammation

Apoptosis

Reduced

Fragmentation into nucleosome-sized fragments

Intact; altered structure (lipid orientation changes)

Intact; may be released in apoptotic bodies

No

→ programmed cell death

Coagulative

proteins inside the cell are destroyed/denatured → tissue architecture preserved for some days → firm texture → leukocyte lysosomal enzymes eventually break down necrotic cells

Liquefactive

Enzymatic digestion of dead cells → liquid viscous mass (rupturing membrane disrupts tissue → becomes “jello”)

Caseous

“Cell death and debris” - cheese like → dead ccells disintegrate + granulomatous inflammation → soft, granulomatous tissue

Fat

focal area of fat destruction released lipases break down TG → release FA → FA combine w/ calcium → chalky white areas (saponification)

Fibrinoid

blood vessel necrosis; antigen-antibody complexes deposited in arterial walls (could cause problems)

Gangrenous

clinical term for death of soft tissue (often limbs) from several hypoxic injury/lack of O2 to limb

Wet- ischemia + bacterial infection → liquefactive necrosis → swelling, blistering, wet, cold, black

Dry- ischemia → coagulative necrosis → dry shriveled brown/black skin

Apoptosis

pathway in which cells activate enzymes (caspases) that degrade the cell’s own DNA and nuclear/cytoplasmic proteins → programmed cell death

Causes of apoptosis: Pathologic

injury is beyond repair, limits collateral tissue damage

• DNA damage (radiation, cytotoxic anticancer drug)- directly or via free radicals → prevents survival of mutated DNA

• Accumulation of misfolded proteins (ER stress)

• Virally infected cell itself or cytotoxic T lymphocytes

Causes of apoptosis: Physiologic

cells are deprived of necessary survival signs or receive a pro-apoptotic signal

• Removal of supernumerary cells during development (webbed fingers)

• Involution of hormone-dependent tissues on hormone withdrawal (ovulation = “expect” pregnancy → organ shrinks when estrogen is removed)

• Cell turnover in proliferating cell populations (not all cells that travel to a body part survives)

• Death of hosts cells that have served their purpose

Initiation phase of apoptosis

activation of some caspases (marker for apoptosis) → unleashes a cascade of other caspases

Execution phase of apoptosis

terminal caspases trigger cellular fragmentation

Mitochondrial (intrinsic) pathway

Anti-apoptotic protein: BCL2, BCL-XL, MCLI

• found in outer mitochondrial membrane, cytosol, ER membranes

• keep mitochondrial membrane impermeable - ensures cytochrome C does not leave the cell

• growth factors and other. survival signals activate these proteins

Pro-apoptotic proteins: BAX & BAK

• both ensure mitochondrial membrane permeability

Regulator/sensor (initiator) proteins: BH3 only — BAD, BIM, BID, Puma

Death (extrinsic) pathway

Receptor-ligand interactions (Fas, TNF receptor) → adaptor proteins → initiator caspases → executioner caspases

Apoptosis summary

No survival signals + DNA damage + ER stress + BH3 only proteins up-regulate + mitochondrial leakage (cytochrome C) → activate caspase cascade

Necroptosis

mixed features of apoptosis & necrosis; caspase-independent → cell lysis → inflammation

bone growth

steatonepatitis, pancreatitis, neurodegenerative disease (Parkinsons)

Autophagy

self-degradative process that helps balance energy sources at critical times - “cell volunteer to give up their contents so other cells can thrive”

conserved, ancient process by which a cell eats its own contents; allowed starved cells to survive

Pyroptosis

a form of apoptosis accompanied by release of the fever-inducing cytokine

IL-1 → induces inflammation, fever, and apoptosis

Ferroptosis

Intracellular iron-dependent induced by lipid peroxidation → disrupts plasma membrane function

Occurs when too much iron is present (iron levels must be tightly regulated-destroys the cell is excess)

Autophagy MEMORIZE

vesicle called autophagosome surrounds organelle or cytosolic structure

Phagosomes matures and fuses w/ lysosome → degradation of contents

Hypertrophy