02/16b Cell Injury II - Mechanisms of Cell Injury Flashcards
What factors determine the cellular response to injury, and the consequences of that injury?
Cellular response depends on nature, duration, and severity of injury
Consequences depends on type, state, and adaptability of the injured cell
What are the six mechanisms of cell injury?
Depletion of ATP Mitochondrial damage Entry of calcium into the cell Increase in reactive oxygen species Membrane damage DNA damage and protein misfolding
What are the three broad consequences of loss of ATP?
Decreased action of ion pumps (Na/K, Na/Ca)
Increased anaerobic glycolysis
Detachment of ribosomes from the ER
What happens to the cell when the Na/K pump stops working due to a lack of ATP?
There is an influx of Ca2+, Na+, and water, and an efflux of K+
This results in ER swelling, cellular swelling, loss of microvilli, and membrane blebs
What is the result of increased anaerobic glycolysis in the injured cell?
Increase in lactic acid, causing a decrease in pH
This causes clumping of nuclear chromatin and disruption of enzyme function
What happens after ribosomes detach from the ER in the injured cell?
Decrease in protein synthesis
Lipid deposition in inappropriate places due to a lack of protein transporters
A decrease in ATP is common after what sorts of injury to the cell? Why?
Hypoxic and toxic (chemical) injury - interferes with oxidative phosphorylation
What are the consequences of mitochondrial damage?
Loss of membrane potential via the membrane permeability transition
Failed oxidative phosphorylation and loss of ATP
Leakage of cytochrome c and other proteins which activate apoptosis
What are the consequences of calcium entry into the cell? Why?
Activation of lots of enzymes - ATPases, phospholipases, proteases, endonucleases
These enzymes break down cellular components, including membranes, proteins, and nucleic acids
This happens because Ca2+ is a co-factor for many enzymes
What are the major biologically important ROS?
Superoxide anion radical (O2-*) Hydrogen peroxide (H2O2) Hydroxyl radical (*OH)
How is superoxide produced? What does it react with?
Produced by phagocyte oxidase (in neutrophils and macrophages)
Oxidizes lipids, proteins, and DNA
How is hydrogen peroxide produced? What does it do?
Produced by superoxide dismutase and other oxidases like P450 and NADPH oxidase
Destroys microbes and can act at distant sites
How is the hydroxyl radical produced? What does it react with?
Produced from water by hydrolysis
Oxidizes lipids, proteins, and DNA
What types of processes produce reactive oxygen species, particularly superoxide?
Inflammation
Radiation
Chemicals
Reperfusion injury
What are the five normal, physiologic functions of ROS?
Act in normal metabolism and respiration Absorption of radiant energy Inflammation and combat of infection Enzymatic metabolism of chemicals or drugs Nitric oxide synthesis
How are free radicals removed from the body or prevented from forming?
Antioxidants like glutathione and vitamins A, E, and C
Transport proteins like transferrin, ferritin, and ceruloplasmin bind iron and copper to prevent them from catalyzing the formation of ROS
Enzymes like catalase, superoxide dismutase, and glutathione peroxidase scavenge free radicals
What are the pathologic effects of ROS?
Lipid peroxidation of plasma membrane and organelles
Oxidation of proteins with loss of enzyme activity, protein misfolding, and abnormal cross-linking
Oxidation of DNA which causes mutations and strand breaks
How do ROS cause lipid damage?
O2- free radicals attack the double bonds present in unsaturated fatty acids
This yields unstable peroxides and propagates the injury and ultimately causes membrane injury
How do ROS cause protein damage?
Oxidize cysteine residues, resulting in formation of disulfide bonds
This causes conformational changes, loss of enzyme activity, and protein misfolding and cross-linking
What is contraction band necrosis?
An area of abnormally cross-linked proteins
How do ROS damage DNA?
Cause single- and double-stranded breaks
Cause DNA cross-linking and adducts
If cells cannot repair the injury, it can lead to cellular aging and malignant transformation
How are membranes damaged during cellular injury?
By reactive oxygen species
Decrease in phospholipid synthesis and increase in phospholipid breakdown, causing net phospholipid loss
Increase in cytosolic calcium causes activation of lipase and protease enzymes, resulting in lipid breakdown products and cytoskeletal damage, which in turn damage the membrane
What are the consequences of membrane damage?
Mitochondrial damage and the concomitant problems involved
Plasma membrane damage results in loss of osmotic balance and loss of membrane proteins, enzymes, and nucleic acids
Lysosome membrane damage results in leakage of enzymes which can destroy cellular components
These consequences can all lead to cell death
What are the consequences of DNA damage and protein misfolding in the cell?
They can both initiate apoptosis
What are four clinical examples of cell injury
Ischemic and hypoxic injury
Ischemia-reperfusion injury
Chemical injury
Radiation injury
What is the difference between ischemia and hypoxia?
Ischemia is reduced blood flow, caused by atherosclerosis or reduced venous return, which results in less oxygen and nutrient delivery to tissues
Hypoxia is reduced oxygen availability
What is ischemia-reperfusion injury?
When blood flow is restored to ischemic cells which are injured by have not died, some of the injured cells may die after reperfusion
May be caused by release of cellular contents into the restored blood supply by dead cells, resulting in creating of ROS, complement activation, and inflammation
Common in coronary bypass grafts and stints
What are the two types of chemical injury? Give examples of each
Direct - combination with a critical molecule or organelle (mercuric chloride binds -SH groups in proteins)
Indirect - conversion to toxic metabolites by P450 mixed function oxidase (carbon tetrachloride poisoning causes creation of free radicals and lipid peroxidation)
What are the consequences of radiation injury?
Low dose - suppression of hematopoiesis
Moderate dose - epithelial necrosis and ulceration
High dose - cerebral edema and coma
