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Pathology Summary Chapter 2
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Summary Chapter 2 Cell Injury, Cell Death, and Adaptations Robbins Basic Pathology 10th edition.
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Test Bank for Robbins Basic Pathology 10th Edition by Vinay Kumar, Abul K. Abba & Jon C. Aster 9780323353175 Chapter 1-24 | Complete Guide A+
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Chapter 2- Causes of cell injury:
1) Hypoxia and ischemia: Hypoxia refers to oxygen deficiency and ischemia to reduced
blood supply (eg. arterial obstruction)
Deficiency of oxygen leads to failure of many energy-dependent metabolic pathways,
and ultimately to death of cells by necrosis
Cells subjected to the stress of hypoxia activate transcription factors of the
hypoxiainducible factor 1 (HIF-1) family → stimulates the synthesis of proteins that help
the cell to survive in the face of low oxygen / cause adaptive changes in cellular
metabolism
Persistent or severe hypoxia and ischemia ultimately lead to failure of ATP generation
and depletion of ATP in cells. This leads to:
Reduced activity of plasma membrane ATP-dependent sodium pumps:
intracellular accumulation of sodium and efflux of potassium: causing cell
swelling and dilation of the ER
Increase in anaerobic glycolysis
Structural disruption of the protein synthetic apparatus
Increase in accumulation of ROS
Irreversible damage to mitochondrial and lysosomal membranes
After ischemic injury, the inflammation may increase with reperfusion because it
enhances the influx of leukocytes and plasma proteins
2) Toxins: Air pollutants, insectides, CO, asbestos, cigarette smoke, ethanol and drugs.
Direct-acting toxins: some toxins act directly by combining with a critical molecular
component or cellular organelle
Latent toxins: must first be converted to reactive metabolites, which then act on
target cells
3) Infectious agents: All types of disease-causing pathogens, including viruses, bacteria,
fungi and protozoans.
4) Immunologic reactions: Eg. autoimmune reactions against one’s own tissues, allergic
reactions against environmental substances, and excessive or chronic immune
responses to microbes (causes all inflammatory reactions)
5) Genetic abnormalities: Genetic defects may cause cell injury as a consequence of
deficiency of functional proteins, such as enzymes in inborn errors of metabolism, or
accumulation of damaged DNA or misfolded proteins, both of which trigger cell death
when they are beyond repair
6) Nutritional imbalances: Protein–calorie insufficiency among impoverished
populations remains a major cause of cell injury, and specific vitamin deficiencies
7) Physical agents: Trauma, extremes of temperature, radiation, electric shock, and
sudden changes in atmospheric pressure all have wide-ranging effects on cells.
8) Aging: Cellular senescence results in a diminished ability of cells to respond to stress
and, eventually, the death of cells and of the organism.
Generation and removal of ROS
Free radical-mediated cell injury (oxidative stress) is seen in many circumstances,
including chemical and radiation injury, hypoxia, cellular aging, tissue injury caused by
inflammatory cells, and ischemia-reperfusion injury. Accumulation of free radicals in
, cells, may damage lipids (lipid peroxidation of membranes), proteins (crosslinking and
other changes in proteins) and DNA (singlestrand breaks)
ROS are produced normally in small amounts in all cells during the redox reactions
(oxygen is partially reduced)
ROS are produced in phagocytic leukocytes, mainly neutrophils and macrophages
Superoxide is converted to hydrogen peroxide (H2O2) spontaneously and by the
action of the enzyme SOD. In the presence of metals, H2O2 is converted to reactive hydroxyl
radical OH
NO is another reactive free radical produced in macrophages and other
leukocytes. It can react with O2- to form a highly reactive compound, which also participates
in cell injury.
- Cells have developed mechanisms to remove free radicals and thereby minimize their
injurious effects: SOD (rate of decay of superoxide), GSH peroxidases (catalyzes the
breakdown of H2O2), catalase (catalyzes the decomposition of H2O2) and, endogenous or
exogenous anti-oxidants
Endoplasmic Reticulum Stress
- Intracellular accumulation of misfolded proteins may be caused by abnormalities that
increase the production of misfolded proteins or reduce the ability to eliminate them →
gene mutations, aging, infections, increased demand for secretory proteins and
changes in intracellular pH and redox state
- Protein misfolding within cells may cause disease by creating a deficiency of an essential
protein or by inducing apoptosis (Alzheimer disease, Huntington disease etc.)
DNA damage
- Damage to DNA is sensed by intracellular sentinel proteins, which transmit signals that
lead to the accumulation of p53 protein. p53 first arrests the cell cycle (at the G1 phase)
to allow the DNA to be repaired before it is replicated. However, if the damage is too
great to be repaired successfully, p53 triggers apoptosis, mainly by stimulating BH3-only
sensor proteins that ultimately activate Bax and Bak, (Bcl-2 family)
When p53 is mutated or absent, cells with damaged DNA that would otherwise undergo
apoptosis survive
Mitochondrial Dysfunction
- Mitochondrial changes occur in necrosis and apoptosis and may result in several
biochemical abnormalities:
Failure of oxidative phosphorylation leads to progressive depletion (uitputting) of ATP,
culminating in necrosis of the cell
Abnormal oxidative phosphorylation also leads to the formation of ROS, which have
many deleterious effects, as already described.
Damage to mitochondria is often associated with the formation of a high-conductance
channel in the mitochondrial membrane, called the mitochondrial permeability
transition pore loss of mitochondrial membrane potential and pH changes, further
compromising oxidative phosphorylation.
Mitochondria also contain proteins such as cytochrome c that, when released into the
cytoplasm, tell the cell there is internal injury and activate a pathway of apoptosis
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