Chapter 2: Mechanisms of Cellular Injury Flashcards
The cellular response to injurious stimuli depends on what?
Nature of the injury, its duration, and its severity (dose/ischemic time)
The consequences of cell injury depend on what?
The type, state, and adaptability of the injured cell
What are the principal targets of injurious stimuli?
Mitochondria, cell membranes, the machinery of protein synthesis and secretion, and DNA
How can mitochondria be damaged?
Increases of cystolic Ca2+, ROS, and oxygen deprivation
What are the three major consequences of mitochondrial damage?
ATP depletion, formation of ROS, and leakage of mitochondrial proteins
What is decreased ATP synthesis and ATP depletion frequently associated with?
Both hypoxic and chemical injury
What are the major causes of ATP depletion?
Reduced supply of oxygen and nutrients (because of ischemia and hypoxia), mitochondrial damage and the actions of some toxins (cyanide)
What is the high-conductance channel that forms in the mitochondrial membrane as a result of mitochondrial damage?
The mitochondrial permeability transition pore
What is the effect of the mitochondrial permeability transition pore opening?
It leads to the loss of the mitochondrial membrane potential, which leads to a failure of oxidative phosphorylation and progressive ATP depletion that leads to necrosis
What are the cellular systems affected by ATP depletion?
The plasma membrane energy dependent sodium pump, cellular energy metabolism (so there will be increased rates of glycogenolysis and glycolysis), glycogen stores will be depleted, accumulation of lactic acid, and a reduction in protein synthesis
What does incomplete oxidative phosphorylation lead to?
Formation of ROS
What is a consistent feature of most forms of cell injury (except apoptosis)?
Early loss of the selective membrane permeability which leads to overt membrane damage
What are the most important sites of selective membrane damage during cell injury?
Mitochondrial membrane, the plasma membrane, and membranes of lysosomes
What are some mechanisms that contribute to membrane damage?
ROS, decreased phospholipid synthesis, increased phospholipid breakdown, cytoskeletal damage
What is the effect of plasma membrane damage?
It results in the loss of osmotic balance and influx of fluids and ions
What is the effect of injury to the lysosomal membranes?
Leakage of their enzymes into the cytoplasm and activation of acid hydrolases push cells into necrosis
Increased production or decreased scavenging of ROS may lead to an excess of free radicals. This condition is known as what?
Oxidative stress
What 3 things could cause the production of ROS?
Radiation, toxins, or reperfusion
What enzyme converts superoxide into H2O2?
Superoxidase dismutase (SOD)
How is H2O2 decomposed to H2O?
By glutathione peroxidase or catalase
ROS are also produced in large amounts by activated what?
Leukocytes, particularly neutrophils and macrophages, during inflammatory reactions aimed at destroying microbes and cleaning up dead cells
What effect does ROS accumulation have on lipids?
They damage lipids through lipid peroxidation, which damages membranes
What effect does ROS accumulation have on proteins?
ROS accumulation leads to protein modifications, which leads to protein breakdowns or misfolding
What effect does ROS accumulation have on DNA?
It leads to mutations
How can you get increased intracellular Ca2+?
Ischemia and certain toxins
What effect does excessive Ca2+ in the mitochondria have?
Failure of ATP generation
What does increased cytosolic Ca2+ activate?
Phospholipases, proteases, endonucleases, and ATPase
What is the difference between ischemia and hypoxia?
Blood flow is maintained in hypoxia, ischemia is hypoxia induced by reduced blood flow
Why is ischemia more severe than hypoxia?
In ischemia, not only does aerobic metabolism cease, but anerobic energy generation also fails after glycolytic substrates are exhausted
What three things happen when there is a loss of ATP?
Decreased Na+ pump action, increased anaerobic glycolysis, and detachment of ribosomes
What are four possible mechanisms for ischemia-reperfusion injury?
Oxidative stress, intracellular calcium overload, inflammation, and activation of the complement system
What does mild ischemia cause?
Reversible cell injury
What does severe/prolonged ischemia cause?
Death by necrosis and apoptosis
What causes reperfusion injury?
Oxidative stress due to release of free radicals from leukocytes and endothelial cells. Also intracellular calcium overload, inflammation, and activation of complement
Chemicals induce cell injury by one of two general mechanisms. What are they?
Direct toxicity and conversion to toxic metabolites
