CHAPTER 1:Cellular Responses to Stress and Toxic Insults: Adaptation, Injury, and Death Flashcards
the study of the structural, biochemical, and functional changes in cells, tissues, and organs that underlie disease. By the use of molecular, microbiologic, immunologic, and morphologic techniques, pathology attempts to explain the whys and wherefores of the signs and symptoms manifested by patients while providing a rational basis for clinical care and therapy.
Pathology
The four aspects of a disease process that form the core of pathology are
> cause (etiology)
mechanisms of its development (pathogenesis)
the biochemical and structural alterations induced in the cells and organs of the body (molecular and morphologic changes)
functional consequences of these changes (clinical manifestations).
two major classes of etiologic factors:
>
- genetic (e.g., inherited mutations and disease-associated gene variants, or polymorphisms)
>
- acquired (e.g., infectious, nutritional, chemical, physical).
MULTIFACTORIAL arise from the effects of various external triggers on a genetically susceptible individual
refers to the sequence of events in the response of cells or tissues to the etiologic agent, from the initial stimulus to the ultimate expression of the disease
remains one of the main domains of pathology
Pathogenesis
refer to the structural alterations in cells or tissues that are either characteristic of a disease or diagnostic of an etiologic process
molecular and morphologic changes
The end results of genetic, biochemical, and structural changes in cells and tissues are functional abnormalities, which lead to the ?
clinical manifestations (symptoms and signs) of disease.
father of modern pathology?
Rudolf Virchow
What Cellular Response?
Increased demand, increased stimulation (e.g., by growth factors, hormones)
• Hyperplasia, hypertrophy
What Cellular Response?
ALTERED PHYSIOLOGICAL STIMULI; SOME NONLETHAL INJURIOUS STIMULI
CELLULAR ADAPTATIONS
What Cellular Response?
Decreased nutrients, decreased stimulation
• Atrophy
What Cellular Response? Chronic irritation (physical or chemical)
• Metaplasia
What Cellular Response?
REDUCED OXYGEN SUPPLY; CHEMICAL INJURY; MICROBIAL INFECTION
CELL INJURY
What Cellular Response?
Acute and transient
• Acute reversible injury Cellular swelling fatty change
What Cellular Response?
Progressive and severe (including DNA damage)
• Irreversible injury ➙ cell death Necrosis
Apoptosis
What Cellular Response?
METABOLIC ALTERATIONS, GENETIC OR ACQUIRED; CHRONIC INJURY
INTRACELLULAR ACCUMULATIONS; CALCIFICATION
What Cellular Response?
CUMULATIVE SUBLETHAL INJURY OVER LONG LIFE SPAN
CELLULAR AGING
If the limits of adaptive responses are exceeded or if cells are exposed to injurious agents or stress, deprived of essential nutrients, or become compromised by mutations that affect essential cellular constituents, a sequence of events follows that is termed?
cell injury
what is the end result of progressive cell injury from ischemia (reduced blood flow), infection, and toxins?
Cell death
what are the two principal pathways of cell death?
necrosis and apoptosis
Nutrient deprivation triggers an adaptive cellular response, what is this response which later culminate in cell death?
Cell death is also sometimes the end result
autophagy
_____________ are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment
Adaptations
_____________ refers to an increase in the size of cells, resulting in an increase in the size of the organ
> has no new cells, just larger cells
increased size of the cells is due to the synthesis of more structural components of the cells
HYPERTROPHY
what is the most common stimulus for hypertrophy of muscle?
increased workload
For example, the bulging muscles of bodybuilders engaged in “pumping iron” result from an increase in size of the individual muscle fibers in response to increased demand. In the heart, the stimulus for hypertrophy is usually chronic hemodynamic overload, resulting from either hypertension or faulty valves
Hypertrophy can be induced by what factors?
- MECHANICAL SENSORS (that are triggered by increased work load)
- GROWTH FACTORS (including TGF-β, insulin-like growth factor-1 [IGF-1], fibroblast growth factor)
- VASOACTIVE AGENTS (AGONIST) (such as α-adrenergic agonists, endothelin-1, and angiotensin II)
what are the two main biochemical pathways involved in muscle hypertrophy ?
- phosphoinositide 3-kinase/Akt pathway
2. signaling downstream of G protein-coupled receptors
appear to be the major triggers for physiologic hypertrophy
Mechanical sensors
factors in hypertrophy that causes more important in pathologic states?
agonists and growth factors
___________ is an increase in the number of cells in an organ or tissue, usually resulting in increased mass of the organ or tissue.
result of growth factor–driven proliferation of mature cells and, in some cases, by increased output of new cells from tissue stem cells.
Hyperplasia
what specific cellular adaptations that frequently occur together, and they may be triggered by the same external stimulus?
Hypertrophy and Hyperplasia
what type of hyperplasia increases the functional capacity of a tissue when needed?
is well illustrated by the proliferation of the glandular epithelium of the female breast at puberty and during pregnancy, usually accompanied by enlargement (hypertrophy) of the glandular epithelial cells
hormonal hyperplasia (PHYSIOLOGIC HYPERPLASIA)
what type of hyperplasia increases tissue mass after damage or partial resection?
In individuals who donate one lobe of the liver for transplantation, the remaining cells proliferate so that the organ soon grows back to its original size
compensatory hyperplasia
PHYSIOLOGIC HYPERPLASIA
are caused by excesses of hormones or growth factors acting on target cells
Endometrial hyperplasia is an example
Benign prostatic hyperplasia is another common example
pathologic hyperplasia
___________ is reduced size of an organ or tissue resulting from a decrease in cell size and number.
results from decreased protein synthesis and increased protein degradation in cells .
also accompanied by increased autophagy
ATROPHY
what is the atrophy that is common during normal development?
Some embryonic structures, such as the notochord and thyroglossal duct, undergo atrophy during fetal development. The uterus decreases in size shortly after parturition what kind of atrophy?
Physiologic atrophy
what kind of atrophy?
When a fractured bone is immobilized in a plaster cast or when a patient is restricted to complete bedrest, skeletal muscle atrophy rapidly ensues.
(PATHOLOGIC ATROPHY)
Decreased workload (atrophy of disuse)
Damage to the nerves leads to atrophy of the muscle fibers supplied by those nerves is what kind of atrophy?
Loss of innervation (denervation atrophy).
(ischemia) to a tissue as a result of slowly developing arterial occlusive disease results in atrophy of the tissue what kind of atrophy?
senile atrophy
(marasmus) is associated with the use of skeletal muscle as a source of energy after other reserves such as adipose stores have been depleted (cachexia)
Inadequate nutrition (atrophy)
loss of estrogen stimulation after menopause results in physiologic atrophy of the endometrium, vaginal epithelium, and breast
Loss of endocrine stimulation (atrophy)
Tissue compression for any length of time can cause atrophy. An enlarging benign tumor can cause atrophy in the surrounding uninvolved tissues
Pressure (atrophy)
what pathway occurs in protein degradation linking to atrophy with this following event: Nutrient deficiency and disuse may activate ubiquitin ligases, which attach the small peptide ubiquitin to cellular proteins and target these proteins for degradation in proteasome.
ubiquitin-proteasome pathway
are membrane-bound vacuoles that contain fragments of cell components
autophagic vacuoles
what is lipofuscin granules linked to atrophy?
brown atrophy
____________ is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type.
represent an adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment.
does not result from a change in the phenotype of an already differentiated cell type; instead it is the result of a reprogramming of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue
METAPLASIA
What is the most common epithelial metaplasia?
COLUMNAR TO SQUAMOUS
EXAMPLE: In the habitual cigarette smoker, the normal ciliated columnar epithelial cells of the trachea and bronchi are often replaced by stratified squamous epithelial cells.
Ω Stones in the excretory ducts of the salivary glands, pancreas, or bile ducts may also cause replacement of the normal secretory columnar epithelium by stratified squamous epithelium
Barrett esophagus is an example of what kind of metaplasia?
Metaplasia from SQUAMOUS TO COLUMNAR
Ω Barrett esophagus, in which the esophageal squamous epithelium is replaced by intestinal-like columnar cells under the influence of refluxed gastric acid
the formation of cartilage, bone, or adipose tissue (mesenchymal tissues) in tissues that normally do not contain these elements is what kind of metaplasia?
Connective tissue metaplasia
Ω myositis ossificans bone formation in muscle)
Metaplasia does not result from a change in the phenotype of an already differentiated cell type; instead it is the result of a REPROGRAMMING of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue. The differentiation of stem cells to a particular lineage is brought about by signals generated by the following?
Ωcytokines
Ωgrowth factors
Ωextracellular matrix components in the cells’ environment
When damage to membranes is severe, lysosomal enzymes enter the cytoplasm and digest the cell, and cellular contents leak out, resulting in what kind of cell death?
always a pathologic process
Necrosis
when the cell’s DNA or proteins are damaged beyond repair, the cell kills itself by what kind of cell death?
serves many normal functions and is not necessarily associated with cell injury.
Apoptosis
It is a form of cell death that is characterized by nuclear dissolution, fragmentation of the cell without complete loss of membrane integrity, and rapid removal of the cellular debris.
serves many normal functions and is not necessarily associated with cell injury.
Apoptosis
Causes of Cell Injury
Ω deficiency of oxygen by reducing aerobic oxidative respiration.
Ω extremely important and common cause of cell injury and cell death
Oxygen Deprivation (hypoxia)
Causes of Cell Injury that capable of causing cell injury include mechanical trauma, extremes of temperature (burns and deep cold), sudden changes in atmospheric pressure, radiation, and electric shock
Physical Agents.
Causes of Cell Injury follows : such as glucose or salt in hypertonic concentrations may cause cell injury directly or by deranging electrolyte balance in cells. Even oxygen at high concentrations is toxic. Trace amounts of poisons, such as arsenic, cyanide, or mercuric salts, may destroy sufficient numbers of cells within minutes or hours to cause death
air pollutants, insecticides, and herbicides; industrial and occupational hazards, such as carbon monoxide and asbestos; recreational drugs such as alcohol; and the ever-increasing variety of therapeutic drugs
Chemical Agents and Drugs.
Causes of Cell Injury that are agents range from the submicroscopic viruses to the large tapeworms. In between are the rickettsiae, bacteria, fungi, and higher forms of parasites. The ways by which these biologic agents cause injury
Infectious Agents.
Causes of Cell Injury that is Injurious reactions to endogenous self-antigens are responsible for several autoimmune diseases
Immunologic Reactions.
Causes of Cell Injury that may result in a defect as severe as the congenital malformations associated with Down syndrome, caused by a chromosomal anomaly, or as subtle as the decreased life span of red blood cells caused by a single amino acid substitution in hemoglobin in sickle cell anemia
cause cell injury because of deficiency of functional proteins, such as enzyme defects in inborn errors of metabolism, or accumulation of damaged DNA or misfiled proteins.
Genetic Derangements.
Causes of Cell Injury that continue to be MAJOR CAUSES OF CELL INJURY. Protein-calorie deficiencies cause an appalling number of deaths, chiefly among underprivileged populations. Deficiencies of specific vitamins
as in anorexia nervosa (self-induced starvation). Ironically, nutritional excesses have also become important causes of cell injury. Excess of cholesterol predisposes to atherosclerosis; obesity is associated with increased incidence of several important diseases, such as diabetes and cancer
Nutritional Imbalances.
what kind of INJURY is characterized by generalized swelling of the cell and its organelles; blebbing of the plasma membrane; detachment of ribosomes from the ER; and clumping of nuclear chromatin.
These morphologic changes are associated with decreased generation of ATP, loss of cell membrane integrity, defects in protein synthesis, cytoskeletal damage, and DNA damage.
Reversible injury
What kind of Cell death?
Cell size: Enlarged (swelling)
Necrosis
What kind of Cell death?
Cell size:Reduced (shrinkage)
Apoptosis
What kind of Cell death?
Nucleus: Pyknosis ➙ karyorrhexis ➙ karyolysis
Necrosis
What kind of Cell death?
Nucleus: Fragmentation into nucleosome-size fragments
Apoptosis
What kind of Cell death?
Plasma membrane: Disrupted.
Necrosis
What kind of Cell death?
Plasma membrane: Intact; altered structure, especially orientation of lipids
Apoptosis
What kind of Cell death?
Cellular contents: Enzymatic digestion; may leak out of cell
Necrosis
What kind of Cell death?
Cellular contents: Intact; may be released in apoptotic bodies
Apoptosis
What kind of Cell death?Adjacent inflammation: Frequent
Necrosis
What kind of Cell death?
Adjacent inflammation: No
Apoptosis
What kind of Cell death?Physiologic or pathologic role: Invariably pathologic (culmination of irreversible cell injury)
Necrosis
What kind of Cell death?
Physiologic or pathologic role: Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage
Apoptosis
What are the Two features of reversible cell injury can be recognized under the light microscope?
Ω cellular swelling
(appears whenever cells are incapable of maintaining ionic and fluid homeostasis and is the result of failure of energy-dependent ion pumps in the plasma membrane)
Ω fatty change
(occurs in hypoxic injury and various forms of toxic or metabolic injury. It is manifested by the appearance of lipid vacuoles in the cytoplasm)
What is the first manifestation of almost all forms of injury to cells ?
Cellular Swelling
Ω Swelling of cells is reversible
Ω may also show increased eosinophilic staining, which becomes much more pronounced with progression to necrosis
On microscopic examination, small clear vacuoles may be seen within the cytoplasm; these represent distended and pinched-off segments of the ER what structure?
hydropic change or vacuolar degeneration
what kind of ultrastructural changes of reversible cell injury?
blebbing, blunting, and loss of microvilli
Plasma membrane alterations
what kind of ultrastructural changes of reversible cell injury?
including swelling and the appearance of small amorphous densities
Mitochondrial changes
what kind of ultrastructural changes of reversible cell injury?
with detachment of polysomes; intracytoplasmic myelin figures may be present
Dilation of the ER
what kind of ultrastructural changes of reversible cell injury?
with disaggregation of granular and fibrillar elements
Nuclear alterations
___________ is the result of denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell
necrosis
MORPHOLOGY
Ω show increased eosinophilia in hematoxylin and eosin (H & E) stains, attributable in part to the loss of cytoplasmic RNA
Ω more glassy homogeneous appearance than do normal cells, mainly as a result of the loss of glycogen particles
Ω whorled phospholipid masses called MYELIN FIGURES that are derived from damaged cell membranes
Ω calcification of such fatty acid residues results in the generation of calcium soaps
Ω characterized by discontinuities in plasma and organelle membranes, marked dilation of mitochondria with the appearance of large amorphous densities, intracytoplasmic myelin figures, amorphous debris, and aggregates of fluffy material probably representing denatured protein
necrotic cells
NUCLEAR CHANGES
The basophilia of the chromatin may fade a change that presumably reflects loss of DNA because of enzymatic degradation by endonucleases
karyolysis
NUCLEAR CHANGES
which is also seen in apoptotic cell death) characterized by nuclear shrinkage and increased basophilia. Here the chromatin condenses into a solid, shrunken basophilic mass
pyknosis
NUCLEAR CHANGES
the pyknotic nucleus undergoes fragmentation
karyorrhexis
is a form of necrosis in which the architecture of dead tissues is preserved for a span of at least some days. The affected tissues exhibit a firm texture. Presumably, the injury denatures not only structural proteins but also enzymes and so blocks the proteolysis of the dead cells; as a result, eosinophilic, anucleate cells may persist for days or weeks
Coagulative necrosis
A localized area of coagulative necrosis is called what?
Infarct
characterized by digestion of the dead cells, resulting in transformation of the tissue into a liquid viscous mass. It is seen in focal bacterial or, occasionally, fungal infections, because microbes stimulate the accumulation of leukocytes and the liberation of enzymes from these cells.
Liquefactive necrosis
material is frequently creamy yellow because of the presence of dead leukocytes and is called
pus
not a specific pattern of cell death, but the term is commonly used in clinical practice. It is usually applied to a limb, generally the lower leg, that has lost its blood supply and has undergone necrosis (typically coagulative necrosis) involving multiple tissue planes
Gangrenous necrosis
Ω encountered most often in foci of tuberculous infection
Ω is derived from the friable white appearance of the area of necrosis
Ω necrotic area appears as a collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border
Caseous necrosis
Ω necrotic area appears as a collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border
granuloma
Ω refers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity
Ω occurs in the calamitous abdominal emergency known as acute pancreatitis
Ω histologic examination the necrosis takes the form of foci of shadowy outlines of necrotic fat cells, with basophilic calcium deposits, surrounded by an inflammatory reaction.
Fat necrosis
The fatty acids, so derived, combine with calcium to produce grossly visible chalky-white areas , which enable the surgeon and the pathologist to identify the lesions
(fat saponification)
special form of necrosis usually seen in immune reactions involving blood vessels. This pattern of necrosis typically occurs when complexes of antigens and antibodies are deposited in the walls of arteries
Fibrinoid necrosis
Deposits of “immune complexes,” together with fibrin that has leaked out of vessels, result in a bright pink and amorphous appearance in H&E stains, called?
fibrinoid
If necrotic cells and cellular debris are not promptly destroyed and reabsorbed, they tend to attract calcium salts and other minerals and to become calcified. This phenomenon, called?
dystrophic calcification
forms of cell injury
Ω The cellular response to injurious stimuli depends on the nature of the injury, its duration
Ω The consequences of cell injury depend on the type, state, and adaptability of the injured cell
Ω Cell injury results from different biochemical mechanisms acting on several essential cellular components
associated with both hypoxic and chemical (toxic) injury
causing
Ω activity of the plasma membrane energy-dependent sodium pump (ouabain- sensitive Na + , K + -ATPase) is reduced
Ω leading to an increased rate of anaerobic glycolysis
Ω Failure of the Ca 2+ pump leads to influx of Ca 2+ ,
Ω reduction in protein synthesis
Ω unfolded protein response
ATP Depletion cause of Mitochondrial damage
what do you call the consequence of mitochondria damage that the opening of this conductance channel leads to the loss of mitochondrial membrane potential, resulting in failure of oxidative phosphorylation and progressive depletion of ATP, culminating in necrosis of the cell.
mitochondrial permeability transition pore
what immunosuppresive drug reduces injury by preventing opening of the mitochondrial permeability transition pore—an interesting example of molecularly targeted therapy for cell injury.
Ω One of the structural components of the mitochondrial permeability transition pore is the protein cyclophilin D,
cyclosporine
include cytochrome c and proteins that indirectly activate
apoptosisi nducing enzymes
called
caspases
that leads the Mitochondria to apoptosis rather than necrosis
TRUE OR FALSE
Cytosolic free calcium is normally maintained at very low concentrations making extracellular levels higher
most intracellular calcium is sequestered in mitochondria and the ER
TRUE
TRUE OR FALSE
The accumulation of Ca 2+ in mitochondria results in opening of the mitochondrial permeability transition pore and, as described above, failure of ATP generation.
TRUE
TRUE OR FALSE
Increased cytosolic Ca 2+ activates a number of enzymes, with potentially deleterious cellular effects. These enzymes include phospholipases (which cause membrane damage), proteases (which break down both membrane and cytoskeletal proteins), endonucleases (which are responsible for DNA and chromatin fragmentation), and ATPases (thereby hastening ATP depletion).
TRUE
TRUE OR FALSE
Increased intracellular Ca 2+ levels also result in the induction of apoptosis, by direct activation of caspases and by increasing mitochondrial permeability
TRUE
cellular injury induced by restoration of blood flow in ischemic tissue
ischemia-reperfusion injury
chemical species that have a single unpaired electron in an outer orbit
initiate autocatalytic reactions, whereby molecules with which they react are themselves converted into free radicals
Free radicals
Ω are a type of oxygen-derived free radical whose role in cell injury is well established
Ω are produced normally in cells during mitochondrial respiration and energy generation, but they are degraded and removed by cellular defines systems
Ω are also produced in large amounts by leukocytes, particularly neutrophils and macrophages, as mediators for destroying microbes, dead tissue, and other unwanted substances
Reactive oxygen species (ROS)
When the production of ROS increases or the scavenging systems are ineffective, the result is an excess of these free radicals, leading to a condition called?
oxidative stress
MECHANISMS OF PRODUCTION of this free radical is incomplete reduction of O2 during oxidative phosphorylation; by
phagocyte oxidase in leukocytes
superoxide anion O2-
MECHANISMS OF PRODUCTION
Generated by SOD from O2- and by oxidases in peroxisomes
H2O2 ( hydrogen peroxide)
MECHANISMS OF PRODUCTION
Generated from H2O by hydrolysis, e.g., by radiation; from H2O2 by
Fenton reaction; from O2-

OH (hydroxyl radical)
MECHANISMS OF PRODUCTION
Produced by interaction of O2-
and NO generated by NO synthase in many cell types (endothelial cells, leukocytes, neurons, others)
ONOO - peroxynitrite
MECHANISMS OF INACTIVATION
Conversion to H2O2 and O2 by SOD
superoxide anion O2-
MECHANISMS OF INACTIVATION
Conversion to H2O and O2 by
catalase (peroxisomes), glutathione peroxidase (cytosol,mitochondria)
H2O2 ( hydrogen peroxide)
MECHANISMS OF INACTIVATION
Conversion to H2O
by glutathione peroxidase
OH (hydroxyl radical)
MECHANISMS OF INACTIVATION
Conversion to HNO2 by peroxiredoxins
cytosol, mitochondria
ONOO - peroxynitrite
PATHOLOGIC EFFECTS
Stimulates production of degradative enzymes in leukocytes and other cells; may directly damage lipids, proteins, DNA; acts close to site of production
superoxide anion O2-
PATHOLOGIC EFFECTS
Can be converted to O2-
H and OCl - , which destroy microbes and cells; can act distant from site of production
H2O2 ( hydrogen peroxide)
PATHOLOGIC EFFECTS
Most reactive oxygen-derived free radical; principal ROS responsible for damaging lipids, proteins, and DNA
OH (hydroxyl radical)
PATHOLOGIC EFFECTS
Damages lipids, proteins, DNA
ONOO - peroxynitrite
ONOO -
peroxynitrite
OH
(hydroxyl radical)
H2O2
( hydrogen peroxide)
O2-
superoxide anion
OCl -
hypochlorite
SOD
superoxide dismutase
Generation of Free Radicals
reduction-oxidation reactions that occur during normal metabolic processes
During normal respiration, molecular O2 is reduced by the transfer of four electrons to H2 to generate two water molecules. This conversion is catalyzed by oxidative enzymes in the ER, cytosol, mitochondria, peroxisomes, and lysosomes. During this process small amounts of partially reduced intermediates are produced in which different numbers of electrons have been transferred from O2, these include superoxide anion,hydrogen peroxide and
hydroxyl ions
Generation of Free Radicals
Absorption of radiant energy (e.g., ultraviolet light, x-rays).
ionizing radiation can hydrolyze water into O2- and hydrogen (H) free radicals
Generation of Free Radicals
Generation of Free Radicals
Rapid bursts of ROS are produced in activated leukocytes during inflammation
This occurs by a precisely controlled reaction in a plasma membrane multiprotein complex that uses NADPH oxidase for the redox reaction ( Chapter 2 ). In addition, some intracellular oxidases (such as xanthine oxidase) generate O2-
Generation of Free Radicals
Enzymatic metabolism of exogenous chemicals or drugs
can generate free radicals that are not ROS but have similar effects (e.g., CCl4 can generate CCl3)
Generation of Free Radicals
Transition metals such as iron and copper
donate or accept free electrons during intracellular reactions and catalyze free radical formation, as in the Fenton reaction (H2O2 + Fe 2+ ➙ Fe 3+ + OH + OH-). Because most of the intracellular free iron is in the ferric (Fe 3+ ) state, it must be reduced to the ferrous (Fe 2+ ) form to participate in
the Fenton reaction. This reduction can be enhanced by O2- , and thus sources of iron and O2- may cooperate in oxidative cell damage
Generation of Free Radicals
Nitric oxide (NO)
an important chemical mediator generated by endothelial cells, macrophages, neurons, and other cell types ( Chapter 2 ), can act as a free radical and can also be converted to highly reactive peroxynitrite anion (ONOO - ) as well as NO2 and NO3 - .
Removal of Free Radicals
block the initiation of free radical formation or inactivate (e.g., scavenge) free radicals. Examples are the lipid-soluble vitamins E and A as well as ascorbic acid and glutathione in the cytosol
Antioxidants
Removal of Free Radicals
iron and copper can catalyze the formation of ROS. The levels of these reactive metals are minimized by binding of the ions to storage and transport proteins thereby minimizing the formation of ROS.
transferrin, ferritin, lactoferrin, and ceruloplasmin
Removal of Free Radicals
present in peroxisomes, decomposes H2O2 (2H2O2 ➙ O2 + 2H2O).
enzyme
Catalase
Removal of Free Radicals
are found in many cell types and convert O2- to H2O2 (2 O2- + 2H➙ H2O2 + O2). This group includes both manganese–SOD, which is localized in mitochondria, and copper-zinc–SOD, which is found in the cytosol.
enzyme
Superoxide dismutases
Removal of Free Radicals
protects against injury by catalyzing free radical breakdown (H2O2 + 2GSH ➙ GSSG [glutathione homodimer] + 2H2O, or 2OH + 2GSH ➙ GSSG + 2H2O). The intracellular ratio of oxidized glutathione (GSSG) to reduced glutathione (GSH) is a reflection of the oxidative state of the cell and is an important indicator of the cell’s ability to detoxify ROS.
Glutathione peroxidase
In the presence of O2, free radicals may cause
peroxidation of lipids within plasma and organellar membranes. Oxidative damage is initiated when the double bonds in unsaturated fatty acids of membrane lipids are attacked by O2-derived free radicals, particularly by OH-
Lipid peroxidation in membranes
Free radicals promote oxidation of amino acid side chains, formation of protein-protein cross-linkages (e.g., disulfide bonds), and oxidation of the protein backbone
• Oxidative modification of proteins.
• Lesions in DNA. Free radicals are capable of causing single- and double-strand breaks in DNA, cross-linking of DNA strands, and formation of adducts. Oxidative DNA damage has been implicated in cell ageing and in malignant transformation of cells
Lesions in DNA
Mechanisms of Membrane Damage
cause injury to cell membranes by lipid peroxidation
Reactive oxygen species
Mechanisms of Membrane Damage
reduced as a consequence of defective mitochondrial function or hypoxia, both of which decrease the production of ATP and thus affect energy-dependent enzymatic activities
Decreased phospholipid synthesis .
Mechanisms of Membrane Damage
probably due to activation of endogenous phospholipases by increased levels of cytosolic and mitochondrial Ca 2+ .
leads to the accumulation of lipid breakdown products, including unesterified free fatty acids, acyl carnitine, and lysophospholipids, which have a detergent effect on membranes
Increased phospholipid breakdown
Mechanisms of Membrane Damage
serve as anchors connecting the plasma membrane to the cell interior. Activation of proteases by increased cytosolic calcium may cause damage to elements of the cytoskeleton. In the presence of cell swelling, this damage results, particularly in myocardial cells, in detachment of the cell membrane from the cytoskeleton, rendering it susceptible to stretching and rupture.
Cytoskeletal abnormalities
opening of the mitochondrial permeability transition pore leading to decreased ATP, and release of proteins that trigger apoptotic death.
Mitochondrial membrane damage
results in loss of osmotic balance and influx of fluids and ions, as well as loss of cellular contents. The cells may also leak metabolites that are vital for the reconstitution of ATP, thus further depleting energy stores.
Plasma membrane damage
results in leakage of their enzymes into the cytoplasm and activation of the acid hydrolases in the acidic intracellular pH of the injured (e.g., ischemic) cell
Ω contain RNases, DNases, proteases, phosphatases, glucosidases, and cathepsins. Activation of these enzymes leads to enzymatic digestion of proteins, RNA, DNA, and glycogen, and the cells die by necrosis
Injury to lysosomal membranes
most common type of cell injury in clinical medicine and has been studied extensively in humans, in experimental animals, and in culture systems
ISCHEMIC AND HYPOXIC INJURY
referring to reduced oxygen availability
Hypoxia
the supply of oxygen and nutrients is decreased most often because of reduced blood flow as a consequence of a mechanical obstruction in the arterial system. It can also be caused by reduced venous drainage
tends to cause more rapid and severe cell and tissue injury
ischemia
particularly if the ischemic zone is reperfused
Massive influx of calcium into the cell then occurs
promotes new blood vessel formation, stimulates cell survival pathways, and enhances anaerobic
glycolysis
hypoxia-inducible factor-1,
when blood flow is restored to cells that have been ischemic but have not died, injury is paradoxically exacerbated and proceeds at an accelerated pace. As a consequence, reperfused tissues may sustain loss of cells in addition to the cells that are irreversibly damaged at the end of schema
by increased generation of reactive oxygen and nitrogen species from parenchymal and endothelial cells and from infiltrating
such as calcium, may also enter reperfused cells, damaging various organelles, including mitochondria, and increasing the production of free radicals.
nflammation as a result of the production of cytokines and increased expression of adhesion molecules by hypoxic parenchymal and endothelial cells, which recruit circulating neutrophils to reperfused tissue
ISCHEMIA-REPERFUSION INJURY
involved in host defense and is an important mechanism of immune injury ( Chapter 6 ). Some IgM antibodies have a propensity to deposit in ischemic tissues, for unknown reasons, and when blood flow is resumed, complement proteins bind to the deposited antibodies, are activated, and cause more cell injury and
complement system
what kind of injury
in mercuric chloride poisoning, mercury binds to the sulfhydryl groups of cell membrane proteins, causing increased membrane permeability and inhibition of ion transport. In such instances, the greatest damage is usually to the cells that use, absorb, excrete, or concentrate the chemicals—in the case of mercuric chloride, the cells of the gastrointestinal tract and kidney
conversion by cytochrome P-450 to the highly reactive free radical.
CHEMICAL (TOXIC) INJURY
pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins
Apoptosis
fragments contain portions of the cytoplasm and nucleus
apoptotic bodies
normal phenomenon that serves to eliminate cells that are no longer needed, and to maintain a steady number of various cell populations in tissues
Involution of hormone-dependent tissues upon hormone withdrawal
programmed destruction of cells during embryogenesis
Cell loss in proliferating cell populations
Elimination of potentially harmful self-reactive lymphocytes
neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response
Death by apoptosis
eliminates cells that are injured beyond repair without eliciting a host reaction, thus limiting collateral tissue damage
DNA
Accumulation of misfiled proteins
basis of several degenerative diseases of the central nervous system and other organs
Cell death in certain infections
Pathologic atrophy in parenchymal organs after duct obstruction
Apoptosis
Excessive accumulation of these proteins in the ER leads to a condition called
ER stress
The cell is smaller in size; the cytoplasm is dense ( Fig. 1-22A ); and the organelles, though relatively normal, are more tightly packed. (Recall that in other forms of cell injury, an early feature is cell swelling, not shrinkage.)
Cell shrinkage (Apoptosis)
This is the most characteristic feature of apoptosis. The chromatin aggregates peripherally, under the nuclear membrane, into dense masses of various shapes and sizes ( Fig. 1-22B ). The nucleus itself may break up, producing two or more fragments.
Chromatin condensation of apoptosis
The apoptotic cell first shows extensive surface blebbing, then undergoes fragmentation into membrane-bound apoptotic bodies composed of cytoplasm and tightly packed organelles, with or without nuclear fragments ( Fig. 1-22C ).
Formation of cytoplasmic blebs and apoptotic bodies of apoptosis
The apoptotic bodies are rapidly ingested by phagocytes and degraded by the phagocyte’s lysosomal enzymes.
Phagocytosis of apoptotic cells or cell bodies, usually by macrophages
One of these changes is the movement of some phospholipids from the inner leaflet to the outer leaflet of the membrane, where they are recognized by a number of receptors on phagocytes
These lipids are also detectable by binding of a protein called annexin V
phosphatidylserine
express THROMBOSPONDIN, an adhesive glycoprotein that is recognized by phagocytes, and macrophages themselves may produce proteins that bind to apoptotic cells (but not to live cells) and thus target the dead cells for engulfment
bodies may also become coated with natural antibodies and proteins of the complement system, notably C1Q
Initiation of apoptosis occurs principally by signals from two distinct pathways:
the intrinsic, or mitochondrial, pathway
the extrinsic, or death receptor–initiated, pathway
Both pathways converge to activate caspases, which are the actual mediators of cell death.
involves the action of sensors and effectors of the Bcl-2 family, which induce leakage of mitochondrial proteins.
is the major mechanism of apoptosis in all mammalian cells
result of increased mitochondrial permeability and release of pro-apoptotic molecules (death inducers) into the cytoplasm
the intrinsic, or mitochondrial, pathway
engagement of death receptors leads directly to caspase activation
initiated by engagement of plasma membrane death receptors on a variety of cells. Death receptors
the extrinsic, or death receptor–initiated, pathway
Bcl-2, Bcl-x, and Mcl-1.
Intrinsic (Mitochondrial) Pathway of Apoptosis
Growth factors and other survival signals stimulate production of anti-apoptotic proteins
These proteins normally reside in the cytoplasm and in mitochondrial membranes, where they control mitochondrial permeability and prevent leakage of mitochondrial proteins that have the ability to trigger cell death
normal function of the IAPs is to block the activation of caspases
net result of Bax-Bak activation coupled with loss of the protective functions of the anti-apoptotic Bcl family members is the release into the cytoplasm of several mitochondrial proteins that can activate the?
One of these proteins is cytochrome c
Intrinsic (Mitochondrial) Pathway of Apoptosis
caspase cascade
cytochrome c binds to a protein called Apaf-1 (apoptosis- activating factor-1, homologous to Ced-4 in C. elegans), which forms a wheel-like hexamer that has been called the apoptosome.
are members of the TNF receptor family that contain a cytoplasmic domain involved in protein-protein interactions that is called the death domain because it is essential for delivering apoptotic signals
Death receptors
the extrinsic, or death receptor–initiated, pathway
type 1 TNF receptor (TNFR1) and a related protein called Fas (CD95),
death receptors
FLIP, which binds to pro-caspase-8 but cannot cleave and activate the caspase because it lacks a protease domain
The ligand for Fas is called Fas ligand (FasL).
FasL is expressed on T cells that recognize self antigens (and functions to eliminate self-reactive lymphocytes
This pathway of apoptosis can be inhibited by a protein called?
the extrinsic, or death receptor–initiated, pathway
FLIP, which binds to pro-caspase-8 but cannot cleave and activate the caspase because it lacks a protease domain
the mitochondrial pathway leads to activation of the initiator of what caspase?
caspase-9
the death receptor pathway to the initiators what caspases?
caspase-8 and -10
what are the Executioner caspases?
caspase-3 and -6, act on many cellular components. For instance, these caspases, once activated, cleave an inhibitor of a cytoplasmic DNase and thus make the DNase enzymatically active; this enzyme induces the characteristic cleavage of DNA into nucleosome- sized pieces
Caspases also degrade structural components of the nuclear matrix, and thus promote fragmentation of nuclei. Some of the steps in apoptosis are not fully defined. For instance, we do not know how the structure of the plasma membrane is changed in apoptotic cells, or how membrane blebs and apoptotic bodies are formed.
cause to attributable to decreased synthesis of Bcl-2 and Bcl-x and activation of Bim and other pro- apoptotic members of the Bcl family.
Growth Factor Deprivation
genotoxic stress
DNA damage
p53 protein accumulates in cells when DNA is damaged
p53 triggers apoptosis
by pro-apoptotic members of the Bcl family, notably Bax, Bak, and some BH3-only proteins
response activates signaling pathways that increase the production of chaperones, enhance proteasomal degradation of abnormal proteins, and slow protein translation, thus reducing the load of misfolded proteins in the cell ( Fig. 1-27 ). However, if this cytoprotective response is unable to cope with the accumulation of misfolded proteins, the cell activates caspases and induces apoptosis (This process is called ER stress.)
unfolded protein response
control the proper folding of newly synthesized proteins
Chaperones
Cytotoxic T lymphocytes (CTLs) recognize foreign antigens presented on the surface of infected host cells ( Chapter 6 ). Upon activation, CTLs secrete?
PERFORIN, a transmembrane pore-forming molecule, which promotes entry of the CTL granule serine proteases called granzymes. Granzymes have the ability to cleave proteins at aspartate residues and thus activate a variety of cellular caspases
defective apoptosis may be the basis of autoimmune disorders
For instance, if cells that carry mutations in p53 are subjected to DNA damage, the cells not only fail to die but are susceptible to the accumulation of mutations because of defective DNA repair, and these abnormalities can give rise to cancer
is a process in which a cell eats its own contents. It is a survival mechanism in times of nutrient deprivation, when the starved cell lives by cannibalizing itself and recycling the digested contents
Autophagy
autophagy genes” (called Atgs
such as nutrient deprivation, activate autophagy genes that create vacuoles in which cellular organelles are sequestered and then degraded following fusion of the vesicles with lysosomes
autophagic vacuole, which subsequently fuses with lysosomes to form an?
autophagolysosome
the cellular components are digested by lysosomal enzymes
most accumulations are attributable to four types of abnormalities: Intracellular Accumulations
Ω A normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it
Ω abnormal endogenous substance product of a mutated gene, accumulates because of defects in protein folding and transport and an inability to degrade the abnormal protein efficiently. Examples include the accumulation of mutated α1-antitrypsin in liver cells
Ω normal endogenous substance accumulates because of defects, usually inherited, in enzymes that are required for the metabolism of the substance. Examples include diseases caused by genetic defects in enzymes involved in the metabolism of lipid and carbohydrates, resulting in intracellular deposition of these substances, largely in lysosomes
Ω abnormal exogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulations of carbon particles
are components of the myelin figures found in necrotic cells.
Phospholipids
often seen in the liver because it is the major organ involved in fat metabolism, but it also occurs in heart, muscle, and kidney
causes
include toxins, protein malnutrition, diabetes mellitus, obesity, and anoxia. In developed nations the most common causes of significant fatty change in the liver (fatty liver) are alcohol abuse and nonalcoholic fatty liver disease, which is often associated with diabetes and obesity
Steatosis (Fatty Change)
most often seen in the liver and heart. In all organs fatty change appears as clear vacuoles within parenchymal cells. Intracellular accumulations of water or polysaccharides (e.g., glycogen) may also produce clear vacuoles. The identification of lipids requires the avoidance of fat solvents commonly used in paraffin embedding for routine hematoxylin and eosin stains
stained with Sudan IV or Oil Red-O, both of which impart an orange-red color to the contained lipids
begins with the development of minute, membrane-bound inclusions (liposomes) closely applied to the ER. Accumulation of fat is first seen by light microscopy as small vacuoles in the cytoplasm around the nucleus. As the process progresses the vacuoles coalesce, creating cleared spaces that displace the nucleus to the periphery of the cell (
Steatosis (Fatty Change)
contiguous cells rupture and the enclosed fat globules coalesce, producing so-called
fatty cysts.
Lipid is found in cardiac muscle in the form of small droplets, occurring in two patterns. In one, prolonged moderate hypoxia, such as that produced by profound anemia, causes intracellular deposits of fat
which create grossly apparent bands of yellowed myocardium alternating with bands of darker, red-brown, uninvolved myocardium (tigered effect).
(tigered effect). in heart
Steatosis (Fatty Change)
smooth muscle cells and macrophages within the intimal layer of the aorta and large arteries are filled with lipid vacuoles, most of which are made up of cholesterol and cholesterol esters
foam cells), and aggregates of them in the intima produce the yellow cholesterol-laden atheromas characteristic of this serious disorder
Atherosclerosis.
Intracellular accumulation of cholesterol within macrophages is also characteristic of acquired and hereditary hyperlipidemic states. Clusters of foamy cells are found in the subepithelial connective tissue of the skin and in tendons, producing tumorous masses known as
xanthomas.
refers to the focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder
Cholesterolosis
lysosomal storage disease is caused by mutations affecting an enzyme involved in cholesterol trafficking, resulting in cholesterol accumulation in multiple organs (
Niemann-Pick disease, type C
Intracellular accumulations of proteins usually appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm. By electron microscopy they can be amorphous, fibrillar, or crystalline in appearance. In some disorders, such as certain forms of amyloidosis, abnormal proteins deposit primarily in extracellular spaces
PROTEINS
Excesses of proteins within the cells sufficient to cause morphologically visible accumulation have diverse causes.
Ω Reabsorption droplets in proximal renal tubules are seen in renal diseases associated with protein loss in the urine (proteinuria) the protein appears as pink hyaline droplets within the cytoplasm of the tubular cell
proteins that accumulate may be normal secreted proteins that are produced in excessive amounts, as occurs in certain plasma cells engaged in active synthesis of immunoglobulins
certain plasma cells engaged in active synthesis of immunoglobulins That ( ER becomes hugely distended producing large, homogeneous eosinophilic inclusions called
Russell bodies.
types of cytoskeletal proteins
microtubules
thin actin filaments
thick myosin filaments
Intermediate filaments
Intermediate filaments are divided into five classes
;
Ω keratin filaments (characteristic of epithelial cells),
Ω neurofilaments (neurons), Ω desmin filaments (muscle cells), Ω vimentin filaments (connective tissue cells),
Ωglial filaments (astrocytes).
Alzheimer disease contains neurofilaments and other proteins which causes
?
neurofibrillary tangle
Aggregation of abnormal proteins . Abnormal or misfolded proteins may deposit in tissues and interfere with normal functions
forms of amyloidosis
are sometimes called proteinopathies or protein-aggregation diseases.
usually refers to an alteration within cells or in the extracellular space that gives a homogeneous, glassy, pink appearance in routine histologic sections stained with hematoxylin and eosin
HYALINE CHANGE
readily available energy source stored in the cytoplasm of healthy cells.
appear as clear vacuoles within the cytoplasm
Diabetes mellitus is the prime example of a disorder
glycogen storage diseases, or glycogenoses
are colored substances, some of which are normal constituents of cells (e.g., melanin), whereas others are abnormal and accumulate in cells only under special circumstances. Pigments can be exogenous, coming from outside the body, or endogenous, synthesized within the body itself.
PIGM ENTS
The most common exogenous pigment is?
pigments inoculated are phagocytosed by dermal macrophages, in which they reside for the remainder of the life of the embellished
The pigments do not usually evoke any inflammatory response.
carbon (coal dust
ubiquitous air pollutant of urban life. When inhaled it is picked up by macrophages within the alveoli and is then transported through lymphatic channels to the regional lymph nodes in the tracheobronchial region
Accumulations of this pigment blacken the tissues of the lungs and the involved lymph nodes
anthracosis
coal worker’s pneumoconiosis
is an insoluble pigment, also known as lipochrome or wear-and-tear pigment
composed of polymers of lipids and phospholipids in complex with protein
derived through lipid peroxidation of polyunsaturated lipids of sub cellular membranes
not injurious to the cell or its functions
Lipofuscin
prominent in the liver and heart of aging patients or patients with severe malnutrition and cancer cachexia
is an en-dogenous, non-hemoglobin-derived, brown-black pigment formed when the enzyme tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes
Melanin, Greek (melas, black),
only endogenous brown-black pigment
Melanin, Greek (melas, black),
a black pigment that occurs in patients with alkaptonuria, a rare metabolic disease. Here the pigment is deposited in the skin, connective tissue, and cartilage, and the pigmentation is known as?
homogentisic acid
ochronosis
a hemoglobin-derived, golden yellow-to-brown, granular or crystalline pigment that serves as one of the major storage forms of iron
Hemosiderin
When there is a local or systemic excess of iron, ferritin forms?
which are easily seen with the light microscope
hemosiderin granules
When there is systemic overload of iron hemosiderin may be deposited in many organs and tissues, a condition called
hemosiderosis
main causes of hemosiderosis are (1) increased absorption of dietary iron, (2) hemolytic anemias, in which abnormal quantities of iron are released from erythrocytes, and (3) repeated blood transfusions because the transfused red cells constitute an exogenous load of iron
Iron pigment appears as a coarse, golden, granular pigment lying within the cell’s cytoplasm . It can be visualized in tissues by histochemical reaction of?
Prussian blue
more extreme accumulation of iron, however, in an inherited disease called ___________ is associated with liver, heart, and pancreatic damage, resulting in liver fibrosis, heart failure, and diabetes mellitus
hemochromatosis
the normal major pigment found in bile. It is derived from hemoglobin but contains no iron. Its normal formation and excretion are vital to health, and jaundice is a common clinical disorder caused by excesses of this pigment within cells and tissues
Bilirubin
the abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts
Pathologic Calcification
There are two forms of pathologic calcification?
When the deposition occurs locally in dying tissues it is known as dystrophic calcification
the deposition of calcium salts in otherwise normal tissues is known as metastatic calcification-almost always results from hypercalcemia secondary to some disturbance in calcium metabolism
kind of calcification that is encountered in areas of necrosis, whether they are of coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat
DYSTROPHIC CALCIFICATION
have a basophilic, amorphous granular, sometimes clumped appearance.
calcium salts
progression of calcium salt deposition with lamellated configuration is called?
psammoma bodies
is the result of a progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences
Cellular Aging
concept that most normal cells have a limited capacity for replication was developed from a simple experimental model for aging. Normal human fibroblasts, when placed in tissue culture, have limited division
potential
After a fixed number of divisions all somatic cells become arrested in a terminally nondividing state, known as senescence
Decreased cellular replication
a rare disease characterized by symptoms of premature aging, are defective in DNA replication and have a markedly reduced capacity to divide.
Werner syndrome
show premature aging, and the defective gene product is a DNA helicase—a protein involved in DNA replication and repair and other functions requiring DNA unwinding
A defect in this enzyme causes rapid accumulation of chromosomal damage that may mimic the injury that normally accumulates during cellular aging
the amount of oxidative damage, which increases as an organism ages, may be an important cause of senescence.
• Accumulation of metabolic and genetic damage
are short repeated sequences of DNA (TTAGGG) present at the linear ends of chromosomes that are important for ensuring the complete replication of chromosomal ends and for protecting chromosomal termini from fusion and degradation
Telomeres
When somatic cells replicate, a small section of the telomere is not duplicated and telomeres become progressively shortened. As the telomeres become shorter the ends of chromosomes cannot be protected and are seen as broken DNA, which activates the DNA damage response and signals cell cycle arrest. Telomere length is normally maintained by nucleotide addition mediated by an enzyme called telomerase
a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of
chromosomes
is repressed by regulatory proteins, which provide a mechanism for sensing telomere length and restrict unnecessary elongation
activity is highest in germ cells and present at lower levels in stem cells, but it is usually undetectable in most somatic tissues
Telomerase
which the mutated gene encodes a protein involved in repairing double-strand breaks in DNA ( Chapter 7 ). Thus, the balance between cumulative metabolic damage and the response to that damage could determine the rate at which we age. In this scenario aging can be delayed by decreasing the accumulation of damage or by increasing the response to that damage.
taxia-telangiectasia,
that the most effective way of prolonging life span is?
calorie restriction
the effect of calorie restriction on longevity appears to be mediated by a family of proteins called
sirtuins. [80] Sirtuins have histone deacetylase activity, and are thought to promote the expression of several genes whose products increase longevity. These products include proteins that increase metabolic activity, reduce apoptosis, stimulate protein folding, and inhibit the harmful effects of oxygen free radicals. [81] Sirtuins also increase insulin sensitivity and glucose metabolism, and may be targets for the treatment of diabetes
