Exam 1: Cell Injury and Cell Death Flashcards

Question

Free Radical Generation

Answer 1

* **Redox rxns during normal metabolism** * Small amount of partially reduced intermediates generated * Superoxide anion, hydrogen peroxide, hydroxyl ions * **Absorption of radiant energy (UV, X-rays) and ionizing radiation** * Hydrolyzes water ⇒ free radicals * **Activated WBCs generate ROS during inflammation (respiratory burst)** * **Enzymatic metabolism of exogenous chemicals/drugs** * **Transition metals (Fe, Cu)** can donate or accept free electrons during rxns * Can catalyze formation of TOS * Binding to storage/transport proteins reduces reactivity * **Nitric oxide** can act as a free radical

Answer 2

* Inherently unstable ⇒ **decay spontaneously** * Cells have non-enzymatic & enzymatic mechanisms to remove free radicals * _Non-enzymatic_ * **Antioxidants** ⇒ prevent formation or inactivate/scavange free radicals * Vit E, A, and C * Glutathione * Free Fe and Cu * _Enzymatic_ ⇒ enzymes act as free radical scavening systems * Catalase, superoxide dismutase, glutathione peroxidase

Answer 3

1. **Lipid peroxidation in plasma/organellar membranes** * Attack double bonds in unsaturated FAs of membrane lipids * Generates peroxide * Results in autocatalytic chain reaction ⇒ propagation * Causes membrane damage 2. **Oxidative modification of proteins** * Damage enzyme active sites * Disrupt conformation of structural proteins * Enhance degradation of misfolded proteins 3. **Lesions in DNA** * Single or double stranded breaks in DNA * Crosslinking of strands * Implicated in cell aging and malignancy

Answer 4

* _Mechanisms of injury:_ * **ROS** ⇒ lipid peroxidation * **↓ phospholipid synthesis** * **↑ phospholipid breakdown** * Products accumulate & have detergent effect on membranes * **Cytoskeletal abnormalities** * Due to proteases affected by ↑ cytosolic calcium * _Results in damage to:_ * Mitochondrial membranes ⇒ apoptosis * Plasma membranes * Lysosomal membranes

Answer 5

* Cell initiates suicide program if: * DNA damage too severe to be corrected * Level of misfolded proteins too high * Results in death by apoptosis

Answer 6

* Ischemia results from hypoxia due to ↓ blood flow * Usually due to blockage in arterial flow * Can be due to reduced venous drainage * Worsens hypoxia by also affecting anerobic energy generation * Reversible if oxygen flow restored in time * Organs respond differently to hypoxia d/t differences in metabolic activity

Answer 7

Cell death will begin in: * Neurons ⇒ 3-5 minutes * Myocardia ⇒ 20-30 minutes * Renal tubule cells ⇒ 30-60 minutes * Hepatocytes ⇒ 1-2 hours * Skeletal muscle ⇒ many hours * CT ⇒ many hours

Answer 8

* Direct toxicity * Chemicals injure cells by combining with molecular components * Ex. mercuric chloride poisoning, cyanide, chemotherapy * Conversion to toxic metabolites * Usually done by cytochrome P-450 mixed function oxidases * Ex. carbon tetrachloride, acetaminophen

Answer 9

Irreversible cell injury

Answer 10

* Inability to reverse mitochondrial dysfunction * Lack of ox phos and ATP generation * Profound disturbances in membrane function

Answer 11

* End result of progressive cell injury * Many pathologic causes ⇒ ischemia, infection, toxins * Can be a normal process ⇒ embryogenesis, maintaining homeostasis * Two pathways ⇒ necrosis & apoptosis

Answer 12

* **Always pathological** * Ischemia, toxins, infections, trauma * **Results from cell membrane damage** * Loss of ion homeostasis * Cell contents leak into EC space ⇒ **inflammatory response** * Lysosomal enzymes enter cytoplasm & digest cell ⇒ necrosis

Answer 13

Takes many hours for histologic or gross changes to be visible. * _Cytoplasmic changes_ * **↑ eosinophilia** * Loss of RNA * Denatured proteins * **Vacuoles** * **Myelin figures** * From damaged cell membranes * Degraded into FA, may calcify * _Nuclear changes_ * **Karyolysis** ⇒ nuclear fragmentation * **Pyknosis** ⇒ nuclear contration * **Karyorrhexis** ⇒ fragmentation of pyknotic nuclei * _Plasma membrane destruction_ * Enzymes & proteins leak out into ECM and blood * Detectable in blood within 2 hours of necrosis

Answer 14

* Typically caused by ischemia or infarction * **Dead tissue structure preverved for several days** * Area called an **infarct** * Injury denatures enzymes ⇒ no proteolysis of dead cells ⇒ **see eosinophilic cells without nuclei** * Dead cells eventually cleared by WBCs via phagocytosis and lysosomal digestion * Typically seen with MI's

Answer 15

* Results from focal bacterial or fungal infections * PMNs and Mφ degrade necrotic material and pathogen ⇒ pus * Seen in CNS s/p hypoxic injury

Answer 16

(Clinical term) * Limb ischemia ⇒ _coagulative necrosis_ ⇒ **dry gangrene** * Superimposed bacterial infection ⇒ _liquefactive necrosis_ ⇒ **wet gangrene**

Answer 17

* 'Cheese-like' central necrotic area of a granuloma * Seen in tuberculosis and some other infectious * Caseation appears pink, amorphous, and granular

Answer 18

* **Focal areas of destruction** * Usually specific to the **release of pancreatic lipases** or **trauma to the breast** * Fat reacts with calcium ⇒ **saponification** ⇒ soap * Appears chalky-white grossly * Shows outlines of necrotic fat cells microscopically

Answer 19

**Deposition of chalky white material in areas of fat necrosis.** * Results from combo of FA's released from intracellular stores + extracellular calcium * Ex. dystrophic calcification * Serum calcium is normal

Answer 20

* **Programmed cell death** ⇒ highly regulated * **Serves many normal functions** * **Activated by either an intrinsic or extrinsic pathway** * Relies on sequential activation of proteases through cleavage or caspase cascades * **No inflmmatory reaction triggered**

Answer 21

Serves many normal functions: * **Response to DNA or protein damage** * **Embryologic development** * Ex. Webs between fingers * **Tissue remodeling** * **Normal turnover** * **Involution of hormone-dependent tissues** * **Cell loss in proliferating cell populations** * Ex. lymphocytes that don't express useful antigen receptors * **Elimination of self-reactive lymphocytes** * **Death of neutrophils after activation**

Answer 22

* **After exposure to toxins** * **Death of cells with mutations or DNA damage** * Removes potentially cancerous cells * **Improperly folded proteins** * Caused by mutations or free radical damage * Accumulates in ER ⇒ ER stress ⇒ apoptosis * **Death of infected cells** * Viral infections ⇒ adenovirus, HIV * Host immune responses ⇒ hepatitis * **T-cell mediated mechanisms** * Kill tumor cells * Reject transplants * **Atrophy in parenchymal glands when ducts obstructed**

Answer 23

* Degradation of cellular DNA and proteins * Organelles tightly packed ⇒ **cell shrinkage** * **Chromatin condensation** * Aggregates under nuclear membrane * Nucleus may break up * **Formation of cytoplasmic blebs & apoptotic bodies** * Membranes remain intact * **Phagocytosis of apoptotic cells or cell bodies** before materials leak out ⇒ **no inflammatory response**

Answer 24

* **Results from activation of enzymes** * **Caspases** * Inactive proenzymes * Must undergo enzymatic cleavage for activation * Cleaved caspases are a marker of apoptotic cells * **Activation depends on balance between pro- and anti- apoptotic signals** * **Two phases:** 1. **Initiation** ⇒ some caspases become active 2. **Execution** ⇒ other caspases trigger degradation of cellular components

Answer 25

**"Mitochondrial pathway"** * Major mechanism * Results from ↑ permeability of outer mitochondrial membrane * **Releases pro-apoptotic molecules into cytosol** * **Cytochrome C** ⇒ initiates apoptosis * **BCL2 family** ⇒ controls release * _Some anti-apoptotic_ ⇒ BCL-2, BCL-XL, MCL-1 * _Some pro-apoptotic_ ⇒ BAX and BAK * _Some are sensors_ ⇒ regulate the balance * **Path activates initiator caspase-9**

Answer 26

**"Death Receptor-Initiated Pathway"** * Triggered by activation of death receptors on plasma membrane of some cells * **Death receptors** * Members of TNF receptor family * **'Death domain'** site required * Protein-protein interactions delivers apoptotic signals * **Type I TNF receptor (TNFR1)** ⇒ best known * **Fas (CD95)** **receptor** ⇒ found on many cells * Binds **Fas ligand (FasL)** * Found on T cells that recognize self-Ag * Eliminate self-reactive lymphocytes * Found on some cytotoxic T-cells * Kill virus-infected and tumor cells * Fas-FasL binding brings together Fas molecules * **Forms binding site for FADD** (Fas-associated death domain) * FADD binds inactive **Caspase-8** via death domain ⇒ activation * **Path activates initiator caspase-8 and caspase-10**

Answer 27

Intrinsic and extrinsic initiation pathways converge at the activation of **executioner caspases**: * **Executioner caspases ⇒ caspase-3 and caspase-6** * Acts on cellular components * Results in: * Cleavage of DNA * Degradation of nuclear matrix * Degradation of proteins * Etc. * **Apoptotic bodies removed by phagocytes** * May be recruited by cell surface markers on apoptotic bodies * **Thrombospondin** * **C1q**

Answer 28

Defective apoptosis ⇒ increased cell survival: * **Survival of abnormal cells** * **TP53 mutations** * Defective DNA repair * ↑ susceptibility to accumulation of mutations * ↑ cancer risk * Most common genetic abnl found in human cancers * **Failure to remove self-reactive and dead cells** * **↑ risk of autoimmune disorders**

Answer 29

Increased apoptosis ⇒ excessive cell death * Neurodegenerative diseases * Apoptosis due to mutations and misfolded proteins * Ischemic injury * E.g. MI and stroke * Death of virus infected cells

Answer 30

* Cell digests its own constiuents * Protects against nutriend deprivation * Performs intracellular "quality control' * Involved in elimination of intracellular infections * Rodels cellular components to meet needs

Answer 31

1. Chaperone-mediated autophagy 2. Microautophagy 3. Macroautophagy

Answer 32

Direct translocation across lysosomal membrane by chaperone proteins.

Answer 33

Inward invagination of lysosomal membrane for delivery.

Answer 34

Sequester and transport portions of cytoplasm in double-membrane bound autophagic vacuoles (autophagosome) to lysosomes. Primary mode of autophagy.

Answer 35

* Material accumulates in cytosol, organelles, or nucleus * May be reversible or irreversible * Can cause damage if extreme

Answer 36

1. **Inadequate removal of normal substances** * Due to defect in packaging or transport * Ex. Steatosis in liver 2. **Accumulation of abnormal endogenous substances** * Due to defective folding, packaging, or secretion 3. **Failure to degade metabolites** * Due to inherited enzyme deficiences * "Storage diseases" * **Deposit and accumulate abnormal exogenous substances** * Due to inability to degrade or excrete substances * Ex. carbon in macrophages

Answer 37

"Fatty change" * **Abnormal accumulation of lipids/TAGs in parenchymal cells** * Seen in liver and other organs * Causes: * Toxins * Protein malnutition * DM * Obesity * Anoxia

Answer 38

* Smooth muscle cells and macrophages filled with lipid vacuoles * Contains mostly cholesterol and cholesteryl esters * Forms plaques on blood vessel walls

Answer 39

Cholesterol accumulation in macrophages in subepithelial CT of skin and tendons.

Answer 40

Accumulation of cholesterol-laden macrophages in lamina propria of the gallbladder.

Answer 41

Lysosomal storage disorder leading to abnormal accululation of cholesterol in cells.

Answer 42

Appears as rounded eosinophilic droplets, vacuoles, or aggregates in the cytosol.

Answer 43

Protein resorption droplets in proximal renal tubules. Found in patients with protein loss via urine.

Answer 44

Russell bodies

Answer 45

Defective intracellular transport and secretion of critical proteins. Material builds up in ER of hepatocytes.

Answer 46

* Alcoholic Hyaline * Made of keratin intemediate filaments * Accumulates in the liver * Amyloid * Accumulates inside and between cells * Many organs affected

Answer 47

* Homogeneous, glassy pink material * Accumulates inside or between cells * Non-specific marker for cell injury * Extracellular hyaline can be seen in walls of arterioles with chronic HTN

Answer 48

* Stored in healthy cells * Can be deposited in excessive amounts w/ abnormalities in glucose or glycogen metabolism * Appears as clear vacuoles in cytoplasm * Stained with PAS * Accumulates in glycogen storage diseases

Answer 49

* Coal dust (anthracotic pigment) * Accumulates in lungs and lymph nodes * Excessive amounts can produce serious disease * Ex. Coal workers pneumoconiosis * Tattoos * Pigments phagocytosed by derml macrophages

Answer 50

* Lipofuscin * Melanin * Hemosiderin

Answer 51

* Golden brown fine granules * 'Wear and tear' pigment * Contains lipid and proteins from membranes * Does not cause injury * Increases with age * Often seen in liver and heart

Answer 52

* Golden-brown granules * Derived from hemoglobin * Forms where there is local or systemic excess of iron * Normally see small amounts in macrophages * Bone marrow * Spleen * Liver * Local excess can accumulate in areas of bleeding * Systemic excess causes deposition in many tissues ⇒ **hemosiderosis**

Answer 53

pathologic calcification

Answer 54

* Local deposition of calcium in dying tissues * Serum calcium levels normal * See fine, white clumps w/ gritty texture * Basophilic on H&E

Answer 55

* Deposition of calcium salts in normal tissue * See hypercalcemia * May affect GI mucosa, kidneys, lungs, and blood vessels * If very severe, can affect organ function

Answer 56

**Progressive decline in cellular function and viability.** Results from: * **Genetic abnormalities** ⇒ mechanistic alterations * **Accumulation of cellular and molecular damage** * Due to exposure to exogenous influences

Answer 57

* **DNA damage** * DNA repair mechanisms unable to correct all errors * Damage accumulates over time * Werner syndrome ⇒ see premature aging * **Cellular senescence** * Normal cells stop dividing after a fixed number of divisions * Telomeres shorten each time * Telomerase absent in most somatic tissues * Cancer cells have reactivated telomerase ⇒ proliferates indefinitely * Become arrested in a non-diving state ⇒ _senescence_ * **Defective protein homeostasis** * **Deregulated nutrient sensing** * Caloric restriction shown to increase lifespan * Associated with IGF-1