Cell Injury Mech & Causes

Question 1

Mitochondrial Injury

Answer 1

Form channel in mem called MPTP (mitoch perm transition pore)

Loss of potention, reduced oxidative phosphorylation, reduce ATP and necrosis occurs

Apoptotic proteins sequestered b/t inner & outer mem (caspace + cyt c) are released

Question 2

Ca2+ influx

Answer 2

Increase in cytosolic Ca2+

Decrease ATP

Decrease phospholipids

Disrupt proteins

Nucleus chromatin damage & mem damage

Question 3

ROS

Answer 3

1. O2 therapy- lungs & eyes suffer from toxicity if exceeds 20%
2. inflammation- ROS from cells damage joints, kidneys, lungs & heart
3. chem toxicity- CCl4 forms ROS
4. radiotherapy- killing cells due to formation of OH radicals after H2O radiolysis
5. chem carcinogenesis- mutations formed by ROS

Question 4

Superoxide O2- radical

Answer 4

Leaks in mitoch ox phosphorylation when e- transferred to O2

Inflammatory response via phagocyte oxidase

Coverted to H2O2 & O2 by SOD

Question 5

hydrogen peroxide H2O2

Answer 5

Catabolism of superoxide by SOD

Produed by peroxisome oxidases

Conver H2O & O2 by catalase, glutothione peroxidase

Stim Fe uptake to form OH radical

Highly reactive when converted to OH radical in excess

Forms hypochlorite in neturophils- potent microbicidal & cell destroyer

Question 6

Rxns

Answer 6

Fenton

Fe2+ + H2O2–> Fe3+ + OH* + OH-

Harber- Weiss

O2- + H+–> H2O2–> O2 + H20 + OH*

Question 7

Hydroxyl Radical

Answer 7

Converted to H2O by glutathione peroxidase

Lipid peroxidation- loss of mem integrity

OH radical attack sulphur containing aa, prot fragment etc. , DNA strand breaks etc.

Question 8

Peroxynitrite ONOO-

Answer 8

Generated by NO synthase in many cellls

NO* + O2- –> ONOO-

Converted to HNO2 by peroxi redoxins

Attacks lipids, prot & DNA

Question 9

Removing Free Radicals

Answer 9

Antioxi block initiation/inactivation of free radicals

Fe/Cu catalyze formation of ROS

Enz like catalase, SOD & glutathione peroxidase scavenge

Question 10

Mem permeability Defects

Answer 10

Mem damage

• ROS
• decrease phospholipid syn
• increase phospholipid breakdown
• cytoskeletal abnorm

Consequences

• reduce ATP
• prot leakage
• enz leakage from lysosomes

Question 11

Damaged DNA/Prot

Answer 11

If damage is too severe- apoptosis

Irreversible changes like mitochondiral dysf or mem f disruption = necrosis

• CK MB & troponin- heart
• ALT & AST- liver
• Isoform alkaline phosphatase- bile duct
• amylase & lipase- pancreas

Question 12

Ionizing Radiation

Answer 12

Low= apoptosis, generate OH* some cells are damaged

High= necrosis to all cells!

Question 13

Ischemic Injury

Answer 13

Lack of blood, diminished O2, lack of O2

Anaerobic metabolism, less ATP produced so less E form metabolism.

Cell adapts for short while but for extended periods of time= irreversible & cell dies.

Question 14

Reperfusion Injury

Answer 14

• of the heart in a patient w/ MI following thrombolytic or stent therapy
• transient ischemia, results in tissue injury & molecular O2 brought in w/ reperfusion
• Mitoch produces free radicals that combine w/ O2 from reperfusion
• Form ROS in parenchymal cells, endothelium & leukocytes
• TNFa, IL-1, PAF, No & other cytokines lead to neutrophil infiltration & further damage
• some IgM response

Question 15

Reperfusion Injury 2

Answer 15

Cytokines promote vasoconstriction, stim cell adherence for platelets & neutrophils

Short ischemia, reperfusion restores everything to nomr

Longer ischemia- reperfusion destructive

*sudden ox blood flow to ischemic A= produce ROS

Question 16

Hepatotoxins

Answer 16

CCl4+ e- P450 metabolized to CCl3 radical= highly reactive

Acetaminophon non toxic in recommended dose but highly toxic in high doses! Form N actyel p benzoquinon imine

Large does overwhelm glucuronate pahtway producing moer of quinone–> toxicity

Question 17

Chemicals leading to Cell injury

Answer 17

Heavy metals in mitoch

Phalloidin & paclitaxel- cytoskeleton

Chemotherapeutic alkylating agens- DNA

Alkylating agents & glutathione- weaken cell’s antiox defenses

CN- inactivat cyt oxidase

Question 18

Viral Infection

Answer 18

Direct- virus depletes nutrients or cell enz

Down reg anti apoptotic proteins

Immuno mediated cytotoxicity

Question 19

Physiological Apoptosis

Answer 19

1. Embryonic morphogenesis
2. Hormone induction- endometrial cell breakdown during menstruation
3. involution of adult tissue- in thymus
4. renewal of cells in GI

Question 20

Pathological Apoptosis

Answer 20

1. DNA damage due to radiation, cytotoxic chemotherapy agents & hypoxia
2. accumulate misfolded proteins
3. cell death in viral infections direct or via T cells
4. TNF Fas R
5. path atrophy due to obstruction

Question 21

Apoptosis mech

Answer 21

Intrinsic

• hormone withdraw, p53, DNA injury, prot misfolding

Extrinsic

• death R
• Fas R- cytotoxic T cell binding
• TNF R
• cytotoxic T cells secrete perforin

Question 22

Intrinsic pathway

Answer 22

Bcl 2 family–> Effectors Bax & Bak–> mitoch–> cyt c & pre apoptotic protiens–> caspases

Question 23

Extrinsic Pathway

Answer 23

Death R

Fas/TNF R–> adaptar proteins–> caspases–> executioner capsases

Question 24

Apoptosis in health & disease

Answer 24

• GF deprivation
• DNA damage
• misfolding of proteins
• apoptosis induced by TNF R family
• cytotoxic T lymp mediated- perforin & Fas

Question 25

Misfolded Proteins

Answer 25

Loss of f

• in CF, can’t fold correctly due to mut
• form toxic protein aggregates- like in Ad w/ amyloid B protein or a synuclein in PD!