Cell Injury, Death And Adaptation Flashcards by Denisse Tiangco

Implicated for accelerated proteolysis in catabolic conditions (cachexia in CA, TB)

Drives atrophy by decreasing cell size
Posted in intermediate filaments of cytoskeleton
Proteasome recognizes and tags them for degradation

Ubiquitin Proteosome Pathway

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REVERSIBLE change in which one adult cell type (epi or mesen) is replaced by another adult

Metaplasia

Replacement better able to withstand environment

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Metaplasia occurs by

reprogramming stem cells to differentiate along a different pathway vs phenotypic transdifferentiation change

But inc propensity for malignant transformation

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Inc cell and organ size in resp to inc workload in cells incapable of cell division

Hypertrophy

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Hypertrophy esp in cardiac tissue are induced by

1) mechanical trigger

2) trophic chemical trigger

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Inc cell number in response to 1) hormone 2)compensation

in cells with abundant tissue stem cells

Hyperplasia

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Dec cell organ and size due to dec nutrient and disuse

Inc protein degradation dec protein synthesis

Atrophy

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First lost after stress and noxious influence in the cell

Cellular function

Lag with morphologic change and cell death

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Irreversibility in cell damage occurs (2)

1) inability to correct mitochondrial dysfunction (lack of oxphos and ATP generation) despite resolution
2) profound disturbance in membrane function

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targetting membrane of this organelle promotes progression to necrosis

Lysosome

Enzymatic dissolution by hydrolases

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Barbiturates cause tolerance in the long run bec

Hypertrophy of ER and inc CYP450 activity in liver

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Morphologic changes in reversible injury (2)

Cellular swelling

Fatty change

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Small clear vacuoles within cytoplasm which pinched off from SER

Hydrophic change

Vacuolar degeneration

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Failure of energy dependent ion pumps in plasma mem leading to inability to maintain ionic and fluid homeostasis

Cellular swelling

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Occurs in hypoxic injury, toxic or metabolic charac by appearance of lipid vacuoles in cytoplasm

Fatty change

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Intracellular changes assoc with reversible injury (4)

1 plasma membrane blebbing and loss of microvilli
2 mitochondrial swelling
3 dilation of ER
4 eosinophilia due to dec cytoplasmic RNA, nuclear alteration chromatin clumping

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Loss of basophilia of chromatin in necrotic cell

Karyolysis

due to DNase

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Nuclear shrinkage and inc basophilia in necrotic cells

Pyknosis

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Fragmentation of pyknotic nucleus in necrotic cell

Karyorrhexis

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Necrotic cells become calcified by

Necrotic cell -> myelin figure -> degraded to fatty acid -> FA with calcium salt -> calcified

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Architecture preserved with tissues having firm texture
Structural proteins and enzymes denatured halting proteolysis of dead cell
Infarcts, solid organs

Coagulative necrosis

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Focal bacterial, fungal infection stimulating leukocytic digestion of tissue
Completely digested -> liquid viscous mass
Creamy yellow pus
Brain

Liquefactive necrosis

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Limb losing blood supply undergoing coagulative necrosis

Bacterial superimposition -> coagulative necrosis (modified)

Gangrenous necrosis

Wet gangrene

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Cheese like friable yellow like
Collection of lysed cell with pink appearance complete obliteration of architecture
Enclosed in an inflammatory border
Focus of inflammation:

Caseous necrosis

Granuloma

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Focal areas of fat destruction resulting from release of pancreatic lipase liquefying fat cells FA combine with Ca to form chalky white areas (saponification)

Fat necrosis

Deposition of immune complex with fibrin in walls of arteries producing : Seen in PAN

Fibrinoid

Inc eosinophilia Nuclear shrinkage, fragmentation, dissolution (pyknosis, karyorrhexis, karyolysis) Breakdown of plasma and organelle membrane Abundant myelin Leakage and digestion of enzyme to cell content

Necrosis

Principal targets and biochem mech of cell injury (4)

1) mitochondria (ATP and ROS generation) 2) calcium homeostasis disturbance 3) plasma and lysosomal membrane damage 4) DNA damage and protein misfolding

Restoring of blood flow to ischemic but viable tissue results in death of cells undergoing irreversible injury

Ischemia-reperfusion injury

Ischemia reperfusion injury occurs due to (2)

Generation of ROS | Inflammation bec of influx of leukocytes and plasma protein and complement

Cell death where cells activate enzymes that degrade its own nucleur DNA and cytoplasmic proteins

Apoptosis

Apoptosis does not elicit inflammatory response bec

Membranes remain intact and fragments are cleared before contents have leaked

Apoptosis is induced in pathologic conditions (4) by

1) DNA damage 2) misfolded protein accumulation 3) cell injury in infection 4) Pathologic atrophy

Reduced cell size Fragmentation into nucleosome Intact altered structure and orientation of lipid Intact cellular contents released into apoptotic bodies No inflammation

Apoptosis

Cysteine proteins that cleave proteins after aspartic residues activated in apoptosis

Caspases

Survival and death of cell depends on

Permeability of mitochondria

Permeability of mitochondria is controlled by

20 proteins prototype BLC 2

Apoptosis mitochondrial pathway

Lack of survival signals (DNA damage, protein misfolding) -> activation of sensors Bax and Bak channels inhibiting BCL-2 -> leak of cytochrome c and proteins -> capsase activation

Loss of CFTE leading to defect in chloride transport

Cystic fibrosis

Loss of LDL receptor leading to hyperchole

Familial hypercholesterolinemia

Lack of lysosomal enzyme leading to storage of GM2 gangliosides in neuron Hexosaminidase B2 unit

Tay Sachs

Absence of alpha 1 | Antitrypsin in lungs causing destruction of elastic tissue -> emphysema

Alpha 1 antitrypsin deficiency

Eliminates self reactive lymphocytes and damage by cytotoxic T lymphocytes Initiated by engagement of death receptors (TNF)

Death receptor extrinsic pathway

Mechanisms of intracellular accumulation (4)

1 abnormal metabolism (fatty change) 2) protein misfolding and transport (intracellular accum of defective protein) 3) enzyme deficiency (substrate accumulation, storage disease) 4) ingestion of indigestible material (exogenous material accumulation)

Most common exogenous pigment

Carbon Anthracosis

Wear and tear pigment Brownish yellowish granular Marker of past free rad injury (age or atrophy) Lipid perox

Lipofuscin

Golden yellow to brown from hg due to excess iron

Hemosiderin

Deposition of calcium at sites of cell injury and necrosis (dead cell)

Dystrophic

Deposition of Ca at normal tissue by hypercalcemia inc PTH

Metastatic

Results from accumulating cell damage (ROS), reduced capacity to divide (replicatice senescence), reduced ability to repair damaged DNA

Cellular aging

Defective DNA repair mech reversed by calorie restriction

Accumulation of DNA damage

Reduced capacity of cell to divide secondary to progressive shortening of chromosomal ends (telomeres)

Replicative senescence

Progressive accumulation of metabolic damage, role of growth factors promoting aging

Other causes of aging

Hemosiderin-laden alveolar macrophage

Heart failure cell

Earliest symptom of LSHF

Dyspnea ``` Cardiomegaly Tachycardia S3 Rales MR systolic murmur ```

Early latent phase syphilis is until

1 year after infection Mucocutaneous lesion recurrence

Untreated syphilis patients enter an asymptomatic period

Latent phase 1/3 will develop new sx in 5-20 years

Progression from latent phase develops into

Tertiary syphilis (late symptomatic phase) Lesions in CV, CNS other organs

In tertiary stages, spirochetes are And patients are

Less likely to be demonstrated Less likely to be infectious Common in HIV and promotes its transmission (bec ulceration)

Pathognomonic microscopic syphilitic lesion

Proliferative endarteritis with plasma cell-rich infiltrate

Responsible for endothelial cell activation and proliferation Hallmark of endarteritis Leading to perivascular fibrosis and lumen narrowing

Host immune response

3 instances of Hypoxia | Most important cause of injury

Ischemia Hypoxemia Decreased capacity of blood to carry oxygen

Decreased blood flow Atherosclerosis CVD (Brain 3-5mins) Skeletal muscle (CS)

Ischemia

Low partial pressure of oxygen in the blood (PaO2 less than 60mmHg, SaO2 <90%) COPD Interstitial fibrosis

Hypoxemia

RBC incapable of carrying right amount of oxygen Methemoglobinemia Anemia (dec in RBC mass, PaO2 normal, SaO2 normal) CO poisoning (binds hgb 100x affinity compared to O2, PaO2 normal, SaO2 dec) Cherry red appearanc of akin because of co tightly bound to Hb Early sign of exposure = headache

Decreased oxygen carrying capacity

Uncommon bone disorder in which scar-like fibrous tissue develops in place of normal bone

Fibrous dysplasia

Most common cause of budd-chiari blocking the hepatic vein

Polycythemia vera

FiO2 (atm)-> PAlveolar -> Parterial pressure -> SaO2 RBCs In high altitude, FiO2

Do not be confused Decreases FiO2 -> PAO2 will decrease if PACO2 increases (hypoventilation, COPD); interstitial fibrosis (thickened alveolar sac)

Fe binds to O2 Fe2 to Fe3 PaO2 is normal, SaO2 is decreased Clasically seen in oxidant stressors such as sulfa and nitrate drugs

Methemoglobinemia

Impaired oxidative phosphorylation | Consequence

Dec ATP Na-K pump promotes cell swelling Ca pump active enzymes (promotes Ca in cytosol) Aerobic glycolysis -> shift to anaerobic glycolysis (low ATP, lactic acid, precipitates DNA and proteins)

Able to proliferate all the time Epidermis Hematopoietic cells Excretory ducts

Labile

Few divisions Capable of rapid division when activated Hepatocyte Renal tubular epithelial cells

Stable | quiescent

Incapable of cell division Responds to injury by repair or producing a fibrous of scar Neurons Myocardial cells Skeletal muscle

Permanent Nondividing Fibrosis Gliosis

associated change in fibrocystic change of breast can it progress to dysplasia?

Apocrine metaplasia blue dome cyst No this metaplasia does not transform into dysplasia

Low Vit A induces metaplasia in the lungs to become squamous Other uses

Maturation of immune system Conjunctiva and cornea: highly specialiazed Keratomalacia: thickening of surface epithelium Night blindness Vitamin A/Retinol Retinaldehyde: for normal vision Retinoic: normal morphogenesis

Only leukemia than can be treated with all trans retinoic acid (Vit A) chromosome translocation?

Acute Promyelocytic Leukemia | T 15;17

CT: bone, cartilage Metaplasia Ex: Inflammation of skeletal muscle results in metaplastic production of bone

Mesenchymal type of tissue can withstand stress Myositis ossificans

Cell consumes some components in vacuole and these fuse with lysosomes which contains hydrolytic enzymes Tagged with: Shrink and break the cytoskeleton

Autophagy Mannose-6-phosphate

What lysosomal storage disease is associated with defective phosphotransferase hence there is failure to transfer phosphate to mannose residues (No mannose 6 phosphate)

I cell inclusion cell disease

Hallmark of irreversible cell damage

Membrane damage

Plasma membrane damage

Mitochondrial membrane damage

Cytochrome C

Enzyme leak in cytosol, will synergize with calcium to digest the cell itself

Lysosomal membrane

Correct sequence of morphologic changes

``` Cell function Biochemical Ultrastructural Light microscopic Gross ```

Frequently overexpressed due to chromosomal translocations and resulting rearrangements in certain B cell lymphomas Controls release of pro-apoptotic proteins

BCL-2 family of proteins

Anti-apoptotic proteins

BCL2 BCL XL MCL1

Pro-Apoptotic

BAX BAK BAD

Sensors

``` BIM BID Puma Noxa BAD ```

Best known death receptors (Death Receptor Pathway)

Fas | TNFR 1

Mitochondrial intrinsic pathway | Critical Inititator

Caspase 9

Death Receptor Pathway extrinsic | Critical initiator

Caspase 8

Execution Phase

Caspase 3 | Caspase 6

Combinations of both Morpho (necrosis) plasma membrane damage, loss of AT, release of enzyme Genetically programmed signal transduction (apoptosis-like) -> CASPASE INDEPENDENT Grossly looks necrotic Biochemically apoptotic

Necroptosis

Receptor for necroptosis

RIP -> Receptor Associated Kinase 1

Programmed cell death accompanied by IL - 1

Pyroptosis

Immunoglobulin in plasma cells

Russel bodies

Premature aging is seen in Werner syndrome because of the enzyme defect?

DNA helicase Wherner

Caloric restriction increases longevity by

Reducing signal intensity IGF-1 pathway (dec IGF or GH) | Increasing sirtuins

Speeds up aging

Decrease in IGF-1 driven by caloric restriction promotes

slowing of aging

Prolongs longevity by expression of several genes that increase longevity Caloric restriction increases this protein

Sirtuins

Cell Injury, Death And Adaptation Flashcards

(101 cards)