Cellular Processes Flashcards
Steps cells response to stress/injury:
Homeostasis > stress
ADAPTATION> Cellular alterations
if can’t adapt>INJURY> (reversible) recover
if can’t recover>death:necrosis/apoptosis
What are cellular adaptations?
- hyperplasia
- hypertrophy
- atrophy
- metaplasia
Hyperplasia
More cells! > increase mass of tissue
- in cells undergoing division
- reversible
- growth factors > increase proliferation of mature cellsand production of new cells
Ex of physiologic hyperplasia
- hormonal hyperplasia - breast tissue, endometrium in preg
- compensatory hyperplasia: RBC during trauma and blood loss
Ex of pathologic hyperplasia
Too much hormones:
- endometrial hyperplasia
- prostatic hyperp
- ductal hyperp of breast
- HPV>squamous cell proliferation
Hypertrophy
- BIGGER cells > increae mass
- NO cell division
- reversible
- growth factors > increase production of proteins and cell components
Ex of physiologic hypertrophy
- hormonal: myometrium during preg
- compensatory: skeletal muscles with excercise
Ex of pathologic hypertrophy
- cardiac muscle in trying to pump harder
- bladder muscle in tryign to overcome obstruction
Atrophy
ex:
-decrease in size and # of cells > decrease mass
-reversible
-increase protein degrad and decrease production
ex:
-normal embryogenesis processes
-reversal of physiological hyperplasia/hypertrophy
-not using limbs
-loss of innervation, blood supply, nutrition, hormones
-pressure on tissue
metaplasia
- mature cell change to another type in response to stress
- adaptative and questionable reversible
- cytokines, growth factors > alter transcription factors > change differentiation of cells
Ex of physiologic metaplasia. describe
- ONLY ONE: squamous metaplasia of cervix (columnar>squamous) due to exposure to vagina at puberty
- increase risk of infection + cancer (HPV)
- screening and vaccination impt. if highly dysplastic (HSIL) > remove to prevent cancer
Ex pathologic metaplasia
- squamous metaplasia of bronchus (columnar > squamous)
- Barrett’s metaplasia of esophagus (squamous > columnar)
- interstinal metaplasia of stomach (stomach>intestinal)
- squamous meta of bladder (transitional > squamous)
What is altered cellular constituents?
- not adaptations.
- sign of damage
- usually excessive accumulation due to:
1. increase synthesis/decrease degrad of normal content
2. abnormal protein production
3. exogenous material not transported/degraded/metabolism
Ex of pathologic altered cell constituents
4
- steatosis of liver due to alcohol
- Gaucher’s disease - enzyme failure > lipid
- Alzheimer’s - folded protein accumulate
- parkinson’s - abnormally folded proteins accumulate
What are amyloids
- abnormally folded protein > B-sheet
- resistant to degradation
- seen in kidney obstruction, inflammation, Alzheimer’s
What are prions?
- PrP protein abnormally foleded into B sheets
- aggregate and resistant to protease
- PrPSc protein is infectious, self-replicative > induces others to go into Bsheets. can jump species
ex: CJD, kuru, mad cow
Dysplasia?
- cellular alterations > disordered growth
- premalignant but not cancer!
- maybe reversible
Neoplasia?
- NEW growth
- tumour lost normal control
- benign or malignant
- irreversible
What is endometrial hyperplasia?
Cause
Clinical
Tx
-increased proliferation of endometrial glands next to stroma Cause: excess estrogen. (anovulation, PCOS, obesity, tumours, HRT) Clinical: -common -bleeding -incrase risk of endometrial cancer Tx: -treat underlying -PROGESTERONE to shut down endometrium -hysterectomy
What is benign prostatic hyperplasia?
Cause
Clinical
Tx
-proliferation of epithelium and stromal cells in periurethral area
Cause: increase dihydrotestosterone with age (stromal cells)
Clinical:
-common, asymptomatic, peeing problems, enlarged prostate, infection risk due to bladder obstruction
-NO incraesed risk of cancer
Tx:
-decrease fluid intakes
-meds: 5-alpha reductase inhibitor (decrease DHT); alpha blocker (decrease muscle tone, loosen prostate for urethra opening)
-surgery to open urethra
What is Barrett’s esophagus?
-pathologic metaplasia squamous > columnar due to exposure to gastric acid CAUSE: -gerd CLINICAL: -red goblet cells in esoph -gerd symptoms -risk of dysplasia>adenocarcinoma Tx: -treat gerd -screen for dysplasia -resection/radiation
What is intestinal metaplasia of stomach?
-stomach tissue > intestinal cells b/c of hpylori exposure
(hpylori doesn’t like intestine so stomach adapted to fight back)
-gastritis
-loss of parietal cells > issues
-ulcer risk
-cancer risk: gastric cancer, gastric lymphoma
Tx:
-eradicate hpylori
-screen for dysplasia
-surgical resection
What is cell INJURY?
6 mechanisms?
- can’t adapt to stress; damaging exposure; instrinsic abnormality
- decrease ATP production, membrane damage, increase cyto Ca, increase reactive O species, DNA damage, protein misfolded
Reversible vs irreversible injury?
Reversible:
- mild/no dna, protein, membrane damage
- short
- less specific
Irreversible > death
- severe damage to dna, protein, membrane
- can’t produce atp
- prolonged
- specific biomolecular pathway damaged
Injury mechanism 1 - ATP depletion
- metabolite pump issues, anchoring protein issues: influx of water, Ca, efflux K
- swelling, loss of microvilli, blebs - respiration issues
- anaerobic > change pH > clumping of chromatin = dense - ribosome detachment > decrease protein syn > lipid deposition
Injury mech 2: Cytosolic calcium
> enzyme activation:
-phospholipase breakdown membrane
-lipase > necrosis and saponification
-endonucleases, DNAases > nuclear breakdown
-caspases > apoptosis
mitochondrial more permeable > loss of H potential, ATP production issues, apoptosis
=membrane damage, nuclear damage, decreaase ATP
Injury mech 3: Mitochondria damage
-caused by increase Ca or direct damage
-increase mitoc permeabililty
> loss of H potential > no ATP prod > NECROSIS
>leakage of cytochrom c > caspases > APOPTOSIS
Injury mech 4: Free radicals
how do they damage dna, membrane, proteins
-react with other compounds > autocatalytic. hard to stop
-many sources: phosphorylation, energy, inflammation, nitric oxide, drugs, metals
-oxidation leads to:
>fatty acids: per oxidation > membrane damage
>proteins: crosslinking, denaturation, enzymes
>DNA: crosslinking, breaks, mutations
-removed by enzymes, antioxidants, sequestrants
Injury mech 5: Membrane permeability
- loss of ATP in mitochon
- osmotic loss > inflammation
- lysosome digestion-membrane leakage with inflammation=NECROSIS
Injury mech 6: DNA and protein damage
-apoptosis vs necrosis
- if dna/protein damage alone > APOPTOSIS
- irreparable damage + membrane damage > NECROSIS and apoptosis
What is necrosis? what are the cellular features
- pathological
- irreversible cell injury with membrane leakage + inflammatory response
1. coagulation of proteins > cyto eosinophilia - swelling of organelles
2. coagulation of dna > nuclear basophilia
3. coagulated phospholipis > myelin figures in cytoplasm
4. activation of endonucleases and dnases > nuclear changes
What is pyknosis
karyorrhexis
karyolysis
- pyknosis: nucear shrikage and basophilia
- karyorrhexis: fragmentation of dna
- karyolysis: fading of nucleus
from activation of endonucleases and DNAases
Coagulative vs liquefactive necrosis?
tissue morphology based on hydrolytic enzymes: Coagulative: -preserved architecture -hypereosinophilia -loss of nuclei -delayed entry of neutrophils ex: infarct
Liquefactive:
- destruction
- hypereosinophilia
- loss of nuclei
- PUS: neutrophils and debris localized
caseous vs fibrinoid necrosis?
tissue morph based on etiology of injury:
CASEOUS: cheeselike, amorphous, debris
-granuloma: macrphages with inflammation
-due to indigestible stimulus
ex: TB
FIBRINOID: immune mediated destruction - fibrin deposit
ex: vasulitis
What is fat necrosis?
ex?
what is saponification?
- not really necrosis
- degrad of fats > free fatty acids deposition
- ex: acute pancreatitis: lipase released and break down
- saponification = free fatty acids + calcium
What is gangrene? dry vs wet?
- gangrenous necrosis: limb that lost blood supply > necrosis
- dry: coagulative necrosis. typical
- wet: b/c of infection > liquefactive because enzymes of bacteria + neutrophils present
Apoptosis?
features?
physio vs patho?
- regulated cell death WITHOUT membrane leakage and inflammation
- reduced cell size, cytoskeletal breakdown, fragmentation of nucleus
- physio: maintain steady state. eliminate cells we don’t need.
- patho: eliminate damage beyond repair while limiting collateral damage (no host rxn)
Apoptosis: Intrinsic vs extrensic pathway?
Intrinsic: mitochondrial
- damage or loss of survival signal > activation of proteins that block Bcl2 (normally anti-apoptotic protein on mitochond)
- leaky channels (Bax/Bak) > cytochrome c leakage > CASPASES > endonucleases and proteases > break down DNA and cytoskeleton > membrane bleb off = apoptotic body with receptor for macrophages to rid
Extrensic: Death Receptor
-FasLigand binds Fas death receptor > CASPASES > endonucleases and proteases > break down DNA and cytoskeleton > membrane bleb off = apoptotic body with receptor for macrophages to rid
How to see diff bt necrosis and apoptosis on electrophoresis?
- smear pattern - nonspecific = necrosis b/c endonucleases and DNAases
- ladder pattern - fragments = apoptosis b/c only endonuc
Necrosis vs apoptosis? (6)
- swelling vs shrinking
- pyknosis > karyorrhexis > karyolysis vs fragmentations
- membrane leakage vs intact
- cellular digestion and leaking vs intact/apoptotic bodies
- inflammation in necrosis!
- always patho vs apoptosis can be physic/patho
Theories about aging
- ext changes, alterations in tissues, decrease response ability, increase risk of disease
- accumulated cell damage due to oxidative stress, dna damage+mutation, mitochon damage, abnormal proteins, cellular senescence +telomeres
replicative senescence
- decreased replication until an arrest state = non dividing
- Hayflick limit: ~50 times of replication for normal somatic cells
- but role in aging still unclear
- not seen in germ cells and stem cells
telomeres
short repeat DNA at ends of chromosomes
- prevent fusion and ensure complete replication
- shortened with every replication cycle (5’ end of dna shortened b/c polymerase can’t completely copy the 3’ end). shortened until no more. can’t replicate a normal protein = stop cell.
- telomerases maintain length > continue replication (seen in cancer)
aging and caloric restriction?
sirtuins?
- 1930s, mice on restricted diet lived 40% longer
- hard to study on humans. side effects: hunger, depression, low energy, libido
- activated via sirloins: increase expression of gene > resistance to cell stress, increase insulin sensitivity, glucose met
where may sirtuin be found?
RESVERTATROL - in red wine (need high quantity)
but alcohol has other issues
Aging and gene mutations?
- mutations to lower level of GH, IGF1 > resistance to injury in animals
- in humans not sure…
What is acute inflammation?
- rapid, non-specific tissue rxn
- neutrophil-mediated
- vasodilation, vascular permeability, leukocytes!
Cardinal features of inflammation?
“red hot painful bump that can’t do much”
- red hot painful swelling
- loss of fnc
Stimuli for acute inflammation
-infarction, infection, toxin, trauma
- endothelial retraction due to nitric oxide, histamine
- direct endothelial damage: burns, toxins
- leukocyte-induced endothelial injury: inflammation from something else?
- transcytosis - VEGF induced leaking?
Rxns of blood vessels in acute inflamm?
transudate vs exudate?
Edema b/c of increase hydrostatic and decrease colloid P
- Transudate: low protein, low cellularity, low specific gravity. THUS NO underlying inflammation but a P issue
ex: CHF, liver disease, kidney disease - Exudate: high protein, high cellularity, high specific gravity THUS leaky from underlying inflam
rxn of leukocytes in acute inflamm
- injury > tissues release:
1. > cytokines: IL1, TNF > endothelial cells express SELECTINS = low aff adhesion to rolling leukocyte
2. > chemokines > change configuration of INTEGRINS = high aff adhesion to endothelial
3. Diapedesis: migration of abc through endothelium
4. Chemotaxis: wbc follow chemokines to offending agent
5. Kill via Phagocytosis or Phagolysosome or reactive oxygen species
Mediators of inflammation?
- Preformed: granules, rapid
- Histamine
- Serotonin
- lysomoal contents in leukocytes - Synthesized: delayed
- Arachodoic acid metabolites: prostaglandins, thromboxane, leukotrienes
- Nitric Oxide
- Cytokines: TNF, IL1 - Plasma derived
- complements
- coag factor XII > coagulation, fribrinolysis
- kinin system > bradykinin
Morphological hallmarks of acute inflamm?
- dilation of vessels
- engorgemnt of blood
- exudation of wbc, fluid
WBC involved in inflammation?
- neutrophils - early; more lysosomal enzymatic killing - secrete into tissue - can cause more damage
- Macrophages - higher phagocytosis to remove debris and REPAIR
- Monocytes
Role of histamine in inflammation?
-in mast cells
-degranulated when injury, IgE on mast cells, complement activation, cytokines, leukocyte peptide activation
> VASODILATION, ENDO PERM via contraction
Role of serotonin in inflamm
-in platelets and neuroendocrine cells
-degradunlated when there is platelet aggregation/antigen-ab complex formed
>ENDO PERM
Enzymes in inflamm wbc?
- in neutrophils and macrophages
- proteases, collagenases, elastases, phospholipase, plasminogen activator
- leads to C3, C5 complement cascade > further inflamm
How do anti-inflammatory drugs work?
steroids
aspirin
- Steroids indhibit PHOSPHOLIPASES that lead to arachidonic acid production. Nonspecific, block early in rxn.
- Aspirin and other NSAIDS block COX > decrease prostaglandins (vasodilator) adn thromboxane (vasoconstrictor)
What do prostaglandins, thromboxane, leukotrienes do in inflamm?
PGE>vasodilation
TXA2>vasoconstriction
Leukotrienes > ENDO PERM and vasoconstriction, leukocyte adhesion, chemotaxis
Nitric Oxide in inflamm?
-synthesized from endothelials and macrophages
>KILLING, VASODILATION, ANTI-INFLAMM (reduces adhesion of platelets and leukocytes)
*enos vs inos
-both pro and anti=inflammatory rxns
TNF and IL1 in inflamm?
- activate leukocytes
- fibroblasts for repair
- adhesion to endothelium. pro-coag adn anti-coag balnance
- systemic effects: fever, leukocytosis, more proteins from liver, sleep need
Complements in inflamm?
- Alternative: microbes
- Classical: antibody-mediated
- lectin: mannose-binding
3 pathways > activation of C3, C5
>recruitment, chemotaxis
>phagocyte binding
>formation of membrane attack complex (C5) to kill
>activate LIPOXYGENASE of arachadonic pathway = anti-inflamm = VASOCON, ENDO PERM, bronchospasm
Hageman factor in inflamm?
-Factor XII released from liver
-intrinsic clotting pathway
>thrombin: fibrin
>activates COX2 = pro-inflamm = VASODIL, ENDO PERM
>Kinin cascade > BRADYKININ = PAIN
What is serous inflammation?
- mild injury
- minimal vas perm
- more fluid than leukocytes
What is fibrinous inflammation?
- lots of vas perm
- fibrin (b/c of leakage)
- local proinfl stimulus
- common in pleura, pericardium
What is supprative inflammation?
- lots of leukocytes
- pus (neutrophils)
- pyogenic organisms
What are the morphological patterns of acute inflamm?
- serous
- fibrinous
- supprative
What is chronic inflammation?
- inflammation, tissue damage, and repair co-existing
- adaptive immunity trying to respond to continuous injury and dysregulated immune response
- due to viral infections, chronic infections, long injury, autoimmune
Macrophages in chronic inflamm?
- in blood and extracellular spaces
- migration within 48hr of inflame
- M1: Proinflamm: reactive O2 species, proteases, cytokines, chemokines, coag, AA metabolites
- M2 REPAIR and anti-inflamm: growth factors, fibrogenic, angiogenic, remodelling collagens
IL and TNF in chronic inflamm?
- release by macrophages
- recruit and activate neutrophils > peristant inflammatory response
What is a granuloma?
- collection of activated macrophages surrounded by chronic inflammation/fibrosis
- looks like nodule
- formed b/c of high INF-gamma in presence of antigen that we can’t eradicate
ex: TB, leprosy, syphilis, sarcoidosis, crohn’s, parasites, foreign bodies
What are giant cells?
foreign body type vs Langhans type?
- aggragation of macrophages around something we can’t rid.
a) around a foreign body
b) immune type: around fibrotic tissue/area of inflamm
Outcomes of acute inflammation?
- Resolution: fnc restored.
- not too serious damage, and too much damage, cells can be regenerated (N/A for heart, CNS…) - Healing via Fibrosis: collagen deposit, fnc loss
- Abscess: pus formation > fibrosis
- Progress to Chronic Inflammation
Cardinal features of chronic inflamm?
- Non-neutrophilic inflammation
- architectural destruction
- fibrosis
What are immune-mediated causes of chronic inflammation?
ex?
- autoimmunity: excessive immune response > tissue damage > release of self-antigen
ex: lupus, rheumatoid arth - unregulated immune response
ex: IBD - hypersenstivity reactions
ex: asthma
What is primary vs secondary nutrition?
1: missing 1/more of the necc comp of diet
2. adequate but not getting benefits (insuff, malabsorp, use, loss…)
hormones in appetite and weight:
Leptin
Adipoleptin
Ghrelin
Leptin:
- from adipocytes
- binds hypothalamus > stimulate POMC/CART neurons»_space; REDUCE appetite, INCREASE expenditure
- loss of leptin fnc»_space;early onset obesity
Adipoleptin: angel against obesity -from adipocytes >fatty acids from muscle for oxidation >less fatty acids to liver >decrease glucose from liver
Ghrelin:
-gut hormone»_space; INCREASE food intake via hypothalamus
Insulin
Kwashiorkor vs Marasmus?
Protein-energy malnutrition: affects developing countries
Kwashiorkor: protein def in visceral comparment
-intake is not an issue: eat lots of carb but low protein
-more severe!
-hypoalbuminemia, edema, flaky paint skin lesions, hair loss
-liver steatosis, anoerexia, vitamin def, immune issues
Marasmus: protein and caloric def in somatic comparment
- starvation > body conservation
- thin!, anemia, vitamin def, immune def, poor wound healing
What is cachexia?
- AIDS, cancer pts
- loss of fat and muscle
- increase E expenditures
- due to TNF, IL, PIF cytokines from tumour
- death
Other malnutrition diseases?
- anorexia nervosa - starvation
- bulimia - binge then self-induce vomitting
Vit D deficiency
- maintain Ca and phosporus levels
- due to diet, sunlight, absorp, renal/hepatic issues
- def > HYPOCALCEMIA
ex: Rickets, osteomalacia>osteporosis
Vitamin B1 def
- thiamine in grains
- fnc: ATP synthesis, cofactor for other pathways, neural membrane and nerve conduction
- due to diet insuff, alcoholism, excess loss (v/diar)
ex:
Dry Beriberi: polyneruopathy, myelin degen
Wet Beriberi: heart issues
Wernicke-Korsakoff Syndrome: CNS lesions
Vit B12 def
-from: animal proteins, meat, eggs
-IF binds VitB12 > transport of Vit B12
»Megaloblastic anemia, neurological complications
What is hemochromatosis?
- iron excess»_space; hepatomegaly, iron deposits in organs, DM, pigmentation of skin, arrthymias, heart failure, testicular atrophy
tx: phlebotomy, treat damaged organs
1ary: inherited - more in men
- 2ary: overload, transfusion, intake, liver disease
Diet and chemoprevention?
unconclusive!
ex: Vit A - lung; Lycopene (tomatoes) - prostate; Vit D (lung, endometrium, breast, colon)
