Term
|
Definition
- any condition of the body or mind that decreases the chances of survival of the individual or of the species
- disorder with a specific cause and recognizable signs and symptoms
- any bodily abnormality or failure to function properly
- condition in which the normal function of some part or organ of the body is disturbed
*some disease can increase survival (ex: Sickel Cell-Malaria) |
|
|
Term
| International Classification of Diseases in 1980 |
|
Definition
(8294 total)
Infectious and parasitic 691
Muscle, skeleton, connective tissue 858
Pregnancy, childbirth and puerperium 917
Nervous system 1167
Injury and poisons 1516 |
|
|
Term
| Disease - can be studied at many levels |
|
Definition
| Populations; Individuals; Isolated organ; Tissues; Cells; Cell organelles; Molecules; Genes |
|
|
Term
|
Definition
] Regeneration - multiplication to replace losses
] Hyperplasia - increase in number above normal
] Hypertrophy - increase in size of a cell
] Atrophy - decrease in size
] Modulation - reversible modification of phenotype
] Metaplasia - replacement by different types of cells
] Subcellular adaptations - adaptations of organelles |
|
|
Term
|
Definition
Replacement of lost cells by cells of the same kind
Mammals can replace lost cells and tissues but not organs or limbs
Regeneration is essential in healing of tissues and organs
Different cells and tissues have different regenerating potential
Regenerating potential of tissues (low* - high*****) |
|
|
Term
| Connective tissue-Regeneration |
|
Definition
*****fibroblasts and endothelial cells - principal role in wound healing
*****bone - osteoblasts and osteoclasts - wovenÞlamellar
* tendons - heal very slowly (have few cells and few blood vessels)
* articular cartilage - can regenerate but not well enough to ensure the spontaneous repair of a joint
- adult adipocytes - cannot duplicate themself |
|
|
Term
|
Definition
***** hepatocytes - (can regenerate 70% of the lobe)
controlled by: TGF-a (+), TGF-b (-), HGF, EGF
trigger - metabolic overload, hepatectomy
transplanted livers adjust their size to the body size of the recipient
***** surface epithelia - programmed to regenerate over denuded area of CT;
differentiate after covering the gap
***** mesothelia - mechanism not well understood; 3-5 d in mouse; (monocyte? free
mesothelial cells? subperitoneal precursors? ) |
|
|
Term
|
Definition
***** smooth muscle - wound healing, new arteries acquire a coat of sm
* striated muscle - crushed or frozen with remaining basal lamina regenerate
successfully;
- surgically amputated muscle do not grow back |
|
|
Term
| Nervous tissue-Regeneration |
|
Definition
** peripheral nerves - axonal sprouts grow 1-3mm/day (cut not too wide, Schwann
cells and their basement membrane play important role)
**** remyelination of peripheral nerves - Schwann cells
* remyelination in central nervous system - oligodendrocytes
-/*?? neurons - canaries during singing season produce new neurons, mouse astrocytes
in culture + EGF (dormant undifferentiated stem cells) |
|
|
Term
|
Definition
CNS has the ability to establish alternative pathways (axonal sprouting Þ formation of new circuits)
-Return to normal function after replacement of lost cells– requires time (new cells have to fully mature and differentiate) |
|
|
Term
| Regeneration can be induced and stimulated by: |
|
Definition
- growth factors
- cell-to-cell communication
- nervous stimuli
- mechanical stimuli (bone, cartilage and fibrous tissue)
- electric currents (bone healing)
*Basement membrane plays role in regeneration – cells normally supported by basement membranes (epithelial, endothelial) regenerate faster if the membrane remains intact (cells crawl along it) |
|
|
Term
|
Definition
Increase in the number of cells in an organ or tissue Þ increased volume
] Takes place if the cellular population is capable of synthesizing DNA
] Biologically similar to regeneration but it leads to increase in size of the organ
] Increased risk for developing cancer |
|
|
Term
|
Definition
*hormonal hyperplasia
-glandular epithelium of the breast during puberty and pregnancy
-endometrium in the menstrual cycle |
|
|
Term
|
Definition
*Mostly effect of excessive hormonal stimulation or growth factors effect
-abnormal menstrual bleeding - hyperplasia of endometrial glands (disturbed balance between estrogen and progesterone) Þ increased risk for endometrial cancer |
|
|
Term
|
Definition
Increase in the size of cells due to the synthesis of more structural
components Þ increase in the size of organ
] Does not involve cell division
] Caused by increased functional demand or by specific stimulation
] When stimuli disappear - cells usually return to their standard size |
|
|
Term
|
Definition
*hormonal hypertrophy
-growth of uterus during pregnancy (increased synthesis of smooth muscle proteins Þ increase in cell size)
-hypertrophy of breast during lactation - prolactin and estrogen |
|
|
Term
|
Definition
*heart - exercise, hypertension, valvular defect Þ increased mass of the heart, cells are adding new sarcomers
*excessive nutrition Þ increase of fat tissue and 50% increase in protein synthesis
(prolonged overnutrition Þ increase in fat cell number - hyperplasia; obesity - combination of hypertrophy and hyperplasia) |
|
|
Term
| Hyperplasia and Hypertrophy: |
|
Definition
Frequently can occur together
Two distinct processes
May be triggered by the same mechanism
In non dividing cells only hypertrophy occurs |
|
|
Term
| Pathways to Hyperplasia and Hypertrophy: |
|
Definition
* Increased functional demand
< Removal of one of two paired organs - other enlarges Þ compensatory hypertrophy
(combination of hypertrophy and hyperplasia)
< Enlargement of the uterus in pregnancy (70-fold increase)
< Increased exercise, hypertension, valve defects Þ increased mass of the heart (by
sarcomere addition, and connective tissue increase)
* Endocrine stimulation
< Enlargement of the uterus and breast in pregnancy
* Excessive nutrition
< Obesity
* Mechanical factors
< Long bones - mechanical load Þ increased bone density
< Skin growth for grafts (stimulated by stretching) |
|
|
Term
|
Definition
Acquired decrease in size of cells, tissues, or organs
often linked to disease and senescence
Is reversible (to some extend) - longer persistence of cause - lower chances of recovery
Treatment - early removal of its cause
Moderate degree of food restriction (undernutrition but without malnutrition) can increase the life span - proven experimentally in mammals to delay many conditions associated with aging (skin problems, senile cataracts, many chronic diseases, cancers, reduction of T lymphocyte function) |
|
|
Term
| Mechanisms of organ atrophy: |
|
Definition
| *Cell deletion - by apoptosis; the most specialized cells disappear first *Cell shrinkage - by self-digestion (autophagic vacuoles and digestion of macromolecules by free nonlysosomal hydrolases) -limited - most cellular organelles are essential for survival |
|
|
Term
|
Definition
*Decreased function - fractured limb in castÞmuscles shrink in days (inactivity accelerates protein catabolism) electrical stimulation and stretching ß atrophy
*Starvation - cells are used as a source of energy: adipocytes shrink first, skeletal muscles next, brain is the least susceptible of all organs
*Reduced blood flow - prolonged inadequacy of blood flow (ischemia) Þ atrophy of the blood-starved areas. Examples:
-sclerosis (hardening of renal arterioles) Þ gradual shrinkage of nephrons supplied by these arterioles
-progressive cell loss (brain atrophy in elderly could be an effect of atherosclerosis)
*Occlusion of secretory ducts Þ glandular cells stop secreting, and slowly disappear;
e.g. exocrine portion of pancreas after ligation of main duct. Islets, large ducts and CT remain intact; (exception - testis after vas deferens ligation)
*Hormonal effects:
-supply of the hormone - eg. small doses of L-thyroxine reduce proliferative activity of irradiated thyroid)
-absence of a trophic hormone, eg.: hypophysectomy leads to adrenal atrophy, can be partially reversed by ACTH); loss of estrogen stimulation after the menopause Þ physiologic atrophy of the endometrium, vaginal and breast epithelium
*Old age - after age 45-55:
- decrease in body mass, in weight of the brain, kidneys, liver and spleen
- increase of body fat
- immune system less responsive
Mechanism not well understood -several hypotheses (could be a process of terminal differentiation):
*Local pressure - caused by growing tumors or swelling (in part also due to reduced blood flow) e.g. meningeal tumorÞatrophy of a large mass of brain tissue
*Denervation - damage to the nerves Þ rapid atrophy of the muscle fibers supplied by
these nerves.
*Toxic agents, drugs - some drugs induce atrophy by causing selected cells to undergo
apoptosis
*X-rays - induce atrophy of many tissues;
on the cellular level Þ direct cellular damage (including death) and indirect effect due to microcirculatory damage
*Immunologic mechanisms
-an autoimmune attack (eg. loss of parietal cells in atrophic gastritis)
-over activation of suppressor T lymphocytes Þ aplastic anemia |
|
|
Term
|
Definition
Mild, reversible modification of phenotype
Can occur in any kind of cell in hours and does not require cell division |
|
|
Term
|
Definition
*not pathologic cells
*temporarily adapted to different needs or stimuli
*remain recognizable as members of their cell type |
|
|
Term
| Examples of Modulated Cells |
|
Definition
*Fibroblasts (synthetic functions) - possess contractile apparatus - modulation Þ myofibroblasts - wound contraction
*Smooth muscle cells (specialized for contraction) - also synthesize collagen, elastin and glycosaminoglycans - depending on stimuli
*Endothelial cells - can modulate from the continuous to fenestrated in many pathologic conditions
Concern of tissue culture experts - the best documented modulations (slight alteration of growing condition can cause modulation) |
|
|
Term
|
Definition
Differentiated tissue of one kind is replaced by a differentiated tissue of
another kind
In adults:
*Occurs within epithelia and within mesenchyme (not across germ layers e.g. from epithelia to mesenchyme; from bone to nerve)
*In cells that can replicate (not known to occur in striated
muscle cells and in neurons)
Embryonal cells - have greater possibilities |
|
|
Term
|
Definition
Induced by chemical or mechanical irritants, hormones or vitamins
Mechanisms
-type A Þ type B; rare in mammalian cells
-type A is eliminated and its progenitors produce type B (undifferentiated cells exist in epithelia and CT) |
|
|
Term
|
Definition
*epithelial metaplasia - common on surface linings
-smoker’s bronchi: columnar ciliated Þstratified squamous;
-pancreatic ducts in chronic inflamation or Vit A deficiency
-tongue leukoplakia Þ keratinized
*connective tissue (CT) metaplasia - Ct Þ bone
-metaplastic bone often develops in muscle CT - result of trauma in young athletes
-bone forms around the joints of some paraplegics
-metaplastic bone sometimes found in scars
Mechanism unknown |
|
|
Term
|
Definition
-sometimes is clearly adaptive and useful (stratified squamous eg. around kidney stone)
-several types of epithelial metaplasia predispose to malignant epithelial tumor (leukoplakia, Barrett’s epithelium) - not understood why
-CT metaplasia does not predispose to malignant evolution
-metaplasia is always reversible |
|
|
Term
|
Definition
Adaptations of organelles
Cells may have their organelles to adopt in response to different stimuli and current need to perform their functions |
|
|
Term
| Intracellular accumulations |
|
Definition
| abnormal amount of various substances in the cell |
|
|
Term
| Intracellular Accumulations May be derived from |
|
Definition
* cell’s own metabolism
* extracellular space
* outer environment
Substances may accumulate either transiently or permanently
may be harmless to the cells, sometimes may be toxic |
|
|
Term
| Accumulated substances can be: |
|
Definition
] a normal cellular constituents accumulated in excess
(water, lipids, proteins, carbohydrates)
] an abnormal substances:
exogenous (mineral, product of infectious agent) or endogenous (product of abnormal synthesis or metabolism) |
|
|
Term
| General mechanisms Intracellular Accumulation |
|
Definition
*Normal endogenous substance produced at a normal or increased rate, but the rate of
metabolism is inadequate to remove it (e.g. accumulation of triglycerides in the liver Þ fatty change)
*Genetic or acquired defects in the metabolism, packaging, transport or secretion Þ
normal or abnormal endogenous substance accumulates (e.g. mutation Þ nonfunctional enzymes Þ intracellular deposition - storage diseases; protein folding Þ a1-antitrypsin deficiency)
*Deficiency of critical enzymes Þ no or limited breakdown of substrates that accumulate in lysosomes Þ lysosomal storage diseases(e.g. Tay -Sachs disease)
*An abnormal exogenous substance is deposited and accumulates because cell is unable to degrade phagocytosed particles (e.g. accumulation of carbon particles and silica)
*Cell may be producing the abnormal substance or storing products of pathologic
processes occurring elsewhere in the body |
|
|
Term
| Main groups of accumulated substances: |
|
Definition
| Lipids, carbohydrates, proteins, water and electrolytes, “pigments” |
|
|
Term
|
Definition
| Triglycerides (main lipids of fat cells), cholesterol/cholesterol esters and phospholipids can accumulate in cells. |
|
|
Term
| *Steatosis or fatty change |
|
Definition
Abnormal accumulation of triglycerides in cells
often seen in:
liver - major organ involved in fat metabolism;
also in:
heart, muscle, kidney
Causes:
-toxins (alcohol, CCl4) alcohol abuse-major cause of steatosis
-protein malnutrition, cause: decreased apoproteins synthesis
-diabetes mellitus and obesity
-anoxia (inhibits fatty acid oxidation) |
|
|
Term
|
Definition
| Mature adipose tissue in the stroma (between parenchymal cells) |
|
|
Term
| *Cholesterol and cholesterol esters |
|
Definition
Cells use cholesterol for the synthesis of cell membranes without intracellular accumulation of cholesterol or cholesterol esters
Cholesterol accumulation - pathologic condition seen in:
Atherosclerosis, xanthomas, inflammation and necrosis, cholesterolosis |
|
|
Term
|
Definition
Atherosclerotic plaques - smooth muscle cells & macrophages in tunica intima filled with lipid vacuoles (made of cholesterol & cholesterol esters mostly Þ foamy appearance of cells).
Some foamy cells rupture Þ release contents into the extracellular space Þ cholesterol esters crystallizeÞ needles |
|
|
Term
|
Definition
Intracellular accumulation of cholesterol in macrophages of skin and tendon connective tissue. Clusters of cholesterol filled macrophages (foamy cells) produce tumorous mass called xanthoma
Hereditary and acquired hyperlipidemic conditions |
|
|
Term
| Inflammation and necrosis |
|
Definition
Foamy macrophages frequently present at the sites of injury and inflammation
Phagocytose cholesterol and phospholipids from membranes of injured cells
Myelin can be present in phagocytic cells at the sites of injury and inflammation |
|
|
Term
|
Definition
| Focal accumulation of cholesterol-filled macrophages in the lamina propria of gall bladder |
|
|
Term
| Accumulation of Carbohydrates |
|
Definition
Glycogen
Water-soluble, readily available store of energy present in the cytoplasm
Excessive intracellular deposits - in patients with abnormal glucose or glycogen metabolism |
|
|
Term
| Examples of Carbohydrate Accumulation |
|
Definition
Diabetes mellitus
Glycogen storage diseases (glycogenoses)
Diabetes mellitus - disorder of glucose metabolism - glycogen found in:
Epithelial cells of proximal tubules in the kidney, liver cells, b cells of the islets of Langerhans, heart muscle cells
Glycogen storage diseases (glycogenoses) - caused by enzymatic defect in the synthesis or breakdown of glycogen Þ massive accumulation of glycogen Þ cell injury and death |
|
|
Term
|
Definition
| Abnormal accumulation of proteins in cell |
|
|
Term
| Causes of Accumulation of Proteins |
|
Definition
*excess of protein in the cell environment - beyond cell capacity to metabolize it
(e.g. reabsorption droplets in renal proximal tubules - seen in renal diseases associated with proteinuria - protein loss in urine)
*defects in protein folding may cause protein depositions (misfolded and partially folded
intermediates aggregate inside cells, in the extracellular environment or in both;
caused by: genetic mutations, aging, environmental factors
present in: several neurodegenerative “proteinopathies”: Alzheimer, Huntington, Parkinson diseases (aggregates may either directly or indirectly cause the pathologic changes) |
|
|
Term
| Intracellular accumulations |
|
Definition
fluids (water and electrolytes)
Excess fluid - as vacuoles or diffuse waterlogging |
|
|
Term
| * Vacuoles - common in cells due to: |
|
Definition
-pinocytosis - cell drinking
-organelle swelling - pathologic - ER, mitochondria, lysosomes.
mechanism not understood; not known why other organelles do not swell |
|
|
Term
|
Definition
result of osmotic disturbance
-acute - ionic pumps in cell membrane fail (failure of blood supply or poison Þ energy supplies cut off; especially critical in the brain)
-chronic - in complications of diabetes - glucose can penetrate membrane of some cells (insulin independent mechanism) Þ cells overloaded with glucose Þ glucose converted to osmotically active sorbitol and fructose Þcell swelling Þleaky plasma membrane Þ cell death |
|
|
Term
| Intracellular accumulations - pigments |
|
Definition
*exogenous - from outside - e.g. carbon (most common )
*endogenous - normal constituents of cells - e.g. melanin |
|
|
Term
|
Definition
Anthracosis - inhalation of soot Þ blackening of the lungs
*Some dust cells crawl to the connective tissue of the lung (free carbon particles can possibly cross the alveolar barrier and are phagocytized in CT).
* Carbon filled macrophages can move into lymph nodes, liver and spleen.
Carbon particles remain inside the local macrophages for a life time (generation after generation of macrophages) |
|
|
Term
| Endogenous - normal constituents of cells - melanin |
|
Definition
eumelanin - insoluble polymer of tyrosine, and
phaeomelanin - polymer of tyrosine and cysteine)
Present in:
skin, hair, pigmented epithelium of the eye, meninges
Melanocytes produce a mixture of eumelanin and phaeomelanin packed in granules, and actively implant them into the body of the cells close to them |
|
|
Term
| Neuromelanin - melanin of the nervous system |
|
Definition
*chemically - like a brown eumelanin of the skin
*not produced by specific pigment cells such as melanocytes
*resides in neurons (in residual bodies together with lipofuscin)
Present in:
Neurons, especially in substantia nigra and locus coeruleus (brain stem)
Melanin functions: absorption of light (converts light to heatÞ becomes oxidized - darker) |
|
|
Term
|
Definition
largely a matter of increased or decreased pigmentation
¨albinism -congenital, partial or total absence of melanin (due to the lack of tyrosinase)
¨Addison’s disease - patches of increased pigmentation (damaged or destroyed adrenals Þ drop in adrenal cortical hormones levels Þ pituitary increases ACTH and MSH levels Þ stimulation of melanocytes
Melanins are biologically very important but little understood |
|
|
Term
| Endogenous - normal constituents of cells – lipofuscin (Latin Fuscus = brown) |
|
Definition
Insoluble pigment also called lipochrome, wear-and-tear or aging pigment
Found in: all animals, amount increases with age
Composed of:
polymers of lipids and phospholipids complexed with protein (membrane lipids become peroxidized due to free radicals action, crosslinked Þ nonfunctional lipofuscin)
* does not cause cell injury
* appears as yellow-brown, granular, often perinuclear pigment
Prominent in:
heart, neurons and liver of aging patients, severe malnutrition |
|
|
Term
| Endogenous - normal constituents of cells - hemosiderin |
|
Definition
| hemoglobin-derived; form of iron storage in cells (iron + protein apoferritin Þ ferritin micelles, a normal constituent of most cell types; local or systemic excess of iron Þ ferritin forms hemosiderin granules (hemosiderin = aggregates of ferritin micelles) |
|
|
Term
|
Definition
-golden yellow-to-brown, granular or crystalline
-under normal conditions small amounts of hemosiderin present in mononuclear
phagocytes of bone marrow, spleen and liver (all actively involved in red cell breakdown) |
|
|
Term
| local excess of iron - e.g. bruises |
|
Definition
local hemorrhage Þ red -blue bruise Þ lysis of erythrocytes Þ phagocytosis by macrophages Þ lysosomal enzymes convert hemoglobin through 1. biliveridin - green bile - 2. bilirubin - red bile- to 3. hemosiderin - golden yellow
Systemic overload of iron Þ hemosiderin deposited in many organs and tissues Þ hemosiderosis, seen in:
increased absorption of dietary iron; impaired use of iron; hemolytic anemia; transfusions |
|
|
Term
| Endogenous - normal constituents of cells - bilirubin |
|
Definition
-normal major pigment found in bile
-derived from hemoglobin but contains no iron (a stack of porphyrin rings that broke open and lost their iron)
-normal formation and excretion are vital to health
-can be formed anywhere in the body - all cells contain heme proteins as cytochromes Þ any cell type can form bilirubin during the catabolism of cytochromes) |
|
|
Term
Macrophages - produce bilirubin on much larger scale than other cells when digest damaged and worn out erythrocytes
Very toxic |
|
Definition
*as fat soluble can cross cell membranes and kill cells, probably by a toxic effect on
mitochondria (bilirubin precursor biliverdin is harmless)
*poorly soluble in water - can not diffuse efficiently in tissue fluid to reach cells
*bound by albumin Þ delivered to the liver Þ conjugated with glucuronic acid Þ
excreted in the bile |
|
|
Term
| lipofuscin, melanin - are harmless |
|
Definition
*melanin may be a detoxifiyng polymer
*there is no example of disease due to their effect on cells
hemosiderin, bilirubin - all part of normal life but can be very toxic. |
|
|
Term
| Intracellular accumulations - Pathologic calcification |
|
Definition
| Abnormal deposition of calcium salts together with smaller amounts of iron, magnesium and other mineral salts |
|
|
Term
| 2 Mechanisms: Pathologic Calcification |
|
Definition
Metastatic calcification - may occur in normal tissues when plasma concentration of calcium rises above a critical level (hypercalcemia) - deposits of apatite crystals develop throughout the body
- is generalized
- can be lethal if the underlying metabolic defect is not removed
Dystrophic calcification - far more common mechanism
- is localized
- Ca serum levels are normal
- in areas of necrosis (atheromas of advanced atherosclerosis,
in aging or damaged heart valves) |
|
|
Term
| Plasma membrane - Functions |
|
Definition
- Skin of the cel
physical boundary, organ of contact, recognition, adhesion, communication, exchange, and respiration
Involved in a tremendous variety of pathologic conditions
Most defects of cell membrane are caused by trauma, enzymes, toxins etc.
Congenital diseases of the cell membrane are rare |
|
|
Term
| Acquired disorders: Plasma Membranes |
|
Definition
¨ Blebbing
¨ Failure of the membrane pumps
¨ Increased permeability of the plasma membrane
¨ Toxic injury of the cell membrane
¨ Disorders of membrane receptors
¨ Defects in ion channels
¨ Lack of a receptor
¨ Inadequate number of the receptors |
|
|
Term
| Dangers of cellular swelling: |
|
Definition
*Distended membrane may become leaky
*Swollen cells occupy more space Þ compress capillaries and inhibit blood flow Þ catastrophic results for the brain
Only extreme swelling is easy to recognize in histologic sections - doubling of volume = only 26% increase in diameter |
|
|
Term
|
Definition
The most common symptom of acute cellular disease
Blebs - protrusions, shaped like blisters, contain fluid, no organelles, some pinch off, small can retract, some may explode. Occur in seconds or minutes after cell damage.
Very sensitive indicator of cell suffering. Some blebs are reversible.
Mechanism: cell membrane lifted away from the cytoplasm as it had become disconnected from the cytoskeleton
Erythrocytes rarely form blebs - their membranes are firmly anchored to the cytoskeleton |
|
|
Term
| Failure of the membrane pumps |
|
Definition
Cells use ~30% of their energy to keep sodium pumps working
Sudden drop in energy supplies Þ membrane pumps failure Þ acute cellular swelling (internal organelles may or may not participate)
Cellular swelling is common and can develop very rapidly |
|
|
Term
| Increased permeability of the plasma membrane |
|
Definition
Cells can tolerate small wounds - extensive leaks in the plasma membrane Þ lethal
Many toxic agents kill target cells by perforating plasma membranes
All cell membranes are fluid - if perforated Þ self-seal very fast (to be lethal holes have to be kept open, numerous or very large)
Many poisons produced by plants, snakes, insects, fish and amphibians act on cell membranes
Human killer lymphocytes and complement proteins kill their targets by perforating plasma membranes |
|
|
Term
| Membrane perforating agents: |
|
Definition
Phospholipases - enzymes, in almost all snake poisons (digest the cell membrane directly and turn the phospholipid molecule into a detergent: lecithin + phospholipase Þlysolecithin
Saponins - plant and echinoderm poisons, disrupt the cell membrane by combining with cholesterol |
|
|
Term
| Chemical factors that lead to changes in membrane fluidity: |
|
Definition
*Alcohol - in acute alcoholic intoxication has “disordering” or “fluidyfying” effect on cell membranes (increased sensitivity to drugs in severely intoxicated individuals)
In chronic alcoholic intoxication - opposite effect - cell membranes adapt and become more rigid and less sensitive to drugs
*Excess of cholesterol - cholesterol molecules stabilize membranes, can move in and out exchanging with cholesterol in the environment
In normal erythrocytes number of cholesterol molecules is equal to phospholipid molecules.
Too much cholesterol Þ excess equilibrates with erythrocytes membranes Þ RBC membranes 25-65% overloaded and stiffened Þ prickly shape Þ removed by spleen
(e.g. in alcoholics with liver cirrhosis) |
|
|
Term
| Some toxins target proteins in the cell membrane: |
|
Definition
Tetrodoxin - poison of the puffer fish - kills cells by blocking sodium channels
Batrachotoxin - in the secretion of frog - kills cells by keeping sodium channels open (people of the Colombian forest poison their weapons with this toxin) |
|
|
Term
| Disorders of membrane receptors |
|
Definition
| Cell membrane receptors can malfunction in many ways - Diseases of cell communication |
|
|
Term
| Examples: Disorders of membrane receptors |
|
Definition
Overstimulation of a receptor by a toxin. E.g. Vibrio cholerae toxin - attaches to a specific glycolipid in the cell membrane (acts as a receptor) Þ modification of G protein Þ irreversible stimulation of adenylate cyclase Þ continuous secretion of sodium and water (20-30 liters/day; so-called rice water diarrhea)
Other toxins such as E. coli toxin work in a similar way
Stimulation of a receptor by an antireceptor antibody - in some cases receptor responds to antibody binding in the same way as to its normal ligand (Hyperthyroidism of Grave’s disease - thyroid driven by normal regulatory hormone and by antibody)
Blocking of a receptor by an antireceptor antibody - antibodies develop against the acetylcholine receptor at the neuromuscular junction Þ lack of muscle stimulation
(mechanism of muscular weakness in myasthenia gravis - autoimmune) |
|
|
Term
| Defects in ion channels: inherited diseases |
|
Definition
| Cystic fibrosis - Cl-; Familial hemiplegic migraine - Ca2+; Benign familial neonatal convulsions - K+; Liddle syndrome (hypertension) - Na+; Myasthenia gravis - Na+ |
|
|
Term
|
Definition
in familial hypercholesterolemia lack of low-density lipoprotein (LDL) receptors Þ LDL accumulates in the blood
Lack of testosterone receptors |
|
|
Term
| Inadequate number of the receptors |
|
Definition
| reduced number of insulin receptors in type II diabetes |
|
|
Term
| Plasma membrane - Congenital disorders |
|
Definition
Muscular dystrophy - widespread membrane defect
* absence of dystrophin that may strengthen plasma
membrane by anchoring it to the cytoskeleton
* membrane defects in blood cells and other tissues
* about 5% of muscle fibers show missing patches of plasma membrane Þ high blood levels of muscular enzyme creatine phosphokinase
*membrane damage and muscle cell necrosis |
|
|
Term
| Plasma membrane - Other disorders |
|
Definition
*Free radical damage - lipid peroxidation
* Increased or decreased adhesiveness
* Abnormalities in cell-to-cell communication
* Expression of unusual proteins
* Enzymatic removal of coating molecules
And more . . .
Practically all diseases involve the cell membrane
Inflammation - leukocyte adhesion to the endothelium, leukocyte aggregation, cell fusion
Immunology - centered on cell membrane -cell surface of each species defines what is ‘self’
Infection by bacteria and viruses - depends on specific surface interactions (how bacteria and viruses select their targets)
Tumor biology - largely a matter of altered cell surface
Pathology of intercellular communication
Demyelinating diseases of the nervous system - diseases of the cell membrane |
|
|
Term
| And more . . . Plasma Cell Diseases |
|
Definition
Practically all diseases involve the cell membrane
Inflammation - leukocyte adhesion to the endothelium, leukocyte aggregation, cell fusion
Immunology - centered on cell membrane -cell surface of each species defines what is ‘self’
Infection by bacteria and viruses - depends on specific surface interactions (how bacteria and viruses select their targets)
Tumor biology - largely a matter of altered cell surface
Pathology of intercellular communication
Demyelinating diseases of the nervous system - diseases of the cell membrane |
|
|
Term
|
Definition
the cell’s power plant
¨ Correlation between structural and functional abnormalities not well understood
¨ Mitochondrial diseases have a wide variety of systemic effects (mainly neurologic and muscular). Some diseases inherited by mitochondrial inheritance (have own DNA), most mitochondria contributed by the mother) |
|
|
Term
| Mitochondria - functional anomalies |
|
Definition
Biochemical defect can be in:
* utilization of substrate
* coupling of oxidation and phosphorylation
* respiratory chain |
|
|
Term
|
Definition
| diverse and rare. Clinically affect muscle and brain (alternative name - mitochondrial encephalomyopathies), e.g.myoclonic epilepsy, mitochondrial encephalopathy |
|
|
Term
“Mitochondrial fever” - Luft’s disease
(mitochondrial myopathy) |
|
Definition
*First recognized disease of the mitochondria (R. Luft 1962)
*Uncoupling of oxidation and phosphorylation in the mitochondria
*Mitochondria produce heat instead of energy
*Symptoms: fatigue, fever, intolerance of heat, sweating, low weight, twice normal metabolic rate
Not to be confused with malignant hyperthermia - a disorder of muscle metabolism
Since Luft’s discovery - variety of mitochondrial disorders described
Tissues with the highest demand for ATP - nerves and muscle - most seriously impacted in these disorders
Depending on the affected proteins - mitochondrial disorders range in severity: from causing death in infancy, seizures, blindness - to intolerance to exercise or nonmotile sperm |
|
|
Term
| Mitochondria - structural anomalies |
|
Definition
*Mitochondriomas - mitochondria replicate in excess Þ fill up the cell Þ cytoplasm largely replaced by a compact mass of mitochondria
In: Warthin’s tumor, (tumors of salivary glands), occasionally in other cells (liver)
*Calcium deposits - Mitochondria normally serve as intracellular calcium store. Part of pumped calcium precipitates as phosphate in mitochondrial matrix. Normal in osteoblasts, pathologic in other cells (amorphous or crystalline masses of calcium salts). May represent calcium overload.
Other changes of mitochondria
*Many different changes seen at EM level: mitochondrial swelling, bizarre shapes
* Giant mitochondria - induced by many agents (hypophysectomy, jaundice, viral hepatitis, alcohol, nutritional deficiencies) - mechanism unknown (found in many organs especially heart and muscles)
* Toxic mitochondrial damage |
|
|
Term
|
Definition
the cell’s synthetic machinery
SER- smooth: steroid hormone synthesis, detoxification
RER - rough: proteins for export
Free ribosomes: produce proteins for internal purposes |
|
|
Term
| Pathology of the ribosomes |
|
Definition
*Aggregation into crystals (cooling, programmed cell death)
*Detachment from cisternae, dispersion of polysomes (some toxic agents)
¨ Retention of fluid or proteins
*ER can retain fluid and swell into vacuoles - unclear why
*Perinuclear cisterna in dying cells swells - Perinuclear halo |
|
|
Term
| Retention of proteins - ER storage diseases |
|
Definition
*ER - quality control over protein secretion - misfolded or unassembled molecules destroyed
*Congenitally defective proteins tend to form aggregates and retain in ER
*Alpha-1-Antitrypsin Deficiency - Best known example of ER storage diseases
alpha-1-Antitrypsin:
*potent elastase inhibitor, *synthesized by liver, *secreted into blood
Many granulocytes die every day in the lung capillaries Þ spill enzymes that must be neutralized immediately. Elastase - especially dangerous - destroys the elastic framework of the lung. Low level of plasma a -1-Antitrypsin Þ emphysema
Liver of affected individuals produces alpha-1-antitripsin defective by single AA substitution Þ not secreted Þ retain in the ER. Common, many variants of different severity (homozygots - 1:1750 individuals; the heterozygots - 1:20).
a -1-Chymotrypsin Deficiency - a-1-Chymotrypsin - stored in ER
Fibrinogen - stored in ER |
|
|
Term
| Disorders related to detoxification |
|
Definition
SER and RER contains cytochrome P-450 - oxidase
Cytochrome P-450:
*metabolizes and inactivates certain toxic substances
*most (if not all) cells contain P-450 in SER and RER
Liver - principal site of detoxification - contains a lot of P-450 - specializes in inactivation of exogenous, lipid-soluble substrates (a number of drugs and pollutants)
Toxic agents are absorbed and transported to the liver. P-450 is inducible - synthesized in response to toxic substrates. Sometimes instead of converting toxic substrates into inactive molecules P-450 produces free radicals.
ER responds to fat-soluble drugs and exogenous toxic agents by:
*production of large amounts of cytochrome P-450 Þ high production of free radicals Þ destruction of ER
*hyperplasia -heavy smokers need higher doses of certain drugs (constant nicotine detoxification Þ hyperplastic ER Þ destruction of drugs - caffeine, beta blockers - at a faster rate), insomniacs become tolerant to barbiturates |
|
|
Term
|
Definition
Two major roles:
*Protein synthesis - pathologic storage
*Detoxification - ER can create dangerous free radicals, poisons or carcinogens |
|
|
Term
|
Definition
protein modification, sorting and shipment
Compared with other organelles contributes little to pathology |
|
|
Term
|
Definition
*Chemically modifies produced in ER proteins and lipids
*Attaches “address labels” to proteins and lipids Þ directs them to correct destinations
*Lack of “address label” Þ shipment to the extracellular space, e.g. I-cell disease
All lysosomal enzymes get M-6-P label in Golgi Þ directs them to lysosomes.
No label attached Þ lysosomal hydrolases secreted and present in the extracellular fluid
Undigested substrates accumulate in large cell inclusions (I-cell disease, rare & fatal)
Not all cell types affected
Deficiency in an enzyme required for mannose phosphorylation |
|
|
Term
|
Definition
the cell’s principal digestive organs
Some catabolic functions take place in the cytosol; most of the intracellular digestion is performed in the lysosomes, 60 lysosomal enzymes identified so far, not all present in all cells. Acid phosphatase always present - lysosomal marker
Primary lysosomes + phagocytic vesicles Þ secondary lysosomes Þ digestion (what can not be digested - retained) Þ residual bodies (tertiary lysosomes)
Involved in most cellular diseases and have > 50 of their own |
|
|
Term
| Contribute to cellular pathology by (Lysosomes) |
|
Definition
* Massive release of enzymes into the cell
* Massive release of enzymes to the extracellular spaces
* Failure of the lysosomes to fuse with phagosomes
* Failure of the lysosomes to digest |
|
|
Term
| Massive release of enzymes into the cell itself |
|
Definition
Crystal-induced diseases:
* Gout - accumulation of sodium urate crystals
* Silicosis - in lungs, silica fibers cause lysosomal leakage
* Asbestosis - similar mechanism
* Pseudogout (form of arthritis caused by microscopic calcium pyrophosphate crystals) |
|
|
Term
| Massive release of enzymes to the extracellular spaces |
|
Definition
Occurs in two different circumstances:
* Inflammation Þ leukocytes spill enzymes while they phagocytize and die)
* Shock (virtually all tissues of the body poorly perfused by blood Þ generalized cell damage Þ lysosomal enzyme spilled out of the cells) |
|
|
Term
| Failure of the lysosomes to fuse with phagosomes |
|
Definition
Not a disease - rather survival strategy of some parasites
Mycobacterium tuberculosis
when ingested by macrophage Þ enclosed in phagosome - prevents fusion of phagosome with lysosomes Þ bacillus survives and is safe inside the macrophage that supposed to destroy it. (Virulence and infectivity of M. tuberculosis correlates with its production of sulfatides - acidic glycolipids)
Toxoplasma - while being phagocytized Þ manages to “choose” the patch of macrophage membrane to be enclosed that lacks signals needed for fusion with lysosomes Þ survives and lives in the infected tissues |
|
|
Term
| Failure of the lysosomes to digest |
|
Definition
| Lysosomes are normal but presented with indigestible object - indigestible material remains stored in residual bodies |
|
|
Term
| Lysosomal storage diseases |
|
Definition
Lysosomes are congenitally abnormal (lack or malfunction of enzyme)
~ 40 diseases - inherited in a Mendelian autosomal recessive pattern, often fatal (can be diagnosed prenatally)
Lysosomes stuffed with the substrate of the affected enzyme Þ cells loaded with huge lysosomes Þ eventually may die
Some cell types are affected more than others - depends on the disease |
|
|
Term
| The same disease may be produced by several mechanisms: (lysosomal storage diseases) |
|
Definition
*Lysosomal enzyme is missing
*Enzyme may be present but inactive
*Enzyme may be synthesized but fail to reach the lysosomes
*Enzyme may be unstable at the acid lysosomal pH
*Activator protein can be missing
*Enzyme may be blocked by an inhibitor - such a drug (acquired) |
|
|
Term
Classified on the basis of the substrate that accumulates
Main substrates: Lysosomal Storage Disease |
|
Definition
*Glycogen and glycoproteins
*Mucopolysaccharides
*Sphingolipids
*Lipids (triglycerides and cholesterol esters)
*Mucolipids |
|
|
Term
| Symptoms: lysosomal storage diseases |
|
Definition
*Child normal at birth but fails to thrive
*Large liver and spleen may be present
*Neurological symptoms
*Mental retardation
*Blindness
*Deafness
*Heart and muscle dysfunction
*Clouded cornea (due to large, light-diffracting lysosomes in corneal cells) |
|
|
Term
| Affected tissues and organs: lysosomal Storage disease |
|
Definition
*Extreme overloading with substrate where the metabolism of that substrate is most active
*At the microscopic level some pathologic storage occurs everywhere
E.g. Hurler’s disease – gargoylism, Gangliosidosis -Tay-Sachs disease, Glycogen storage - Pompe disease - a-glucosidase deficiency, Gaucher’s disease, Glucocerebrosidase deficiency - cerebroside accumulation in phagocytic cells |
|
|
Term
| Drug-induced lysosomal diseases |
|
Definition
| Lysosomes become abnormal by taking up a drug or other molecule that makes digestion impossible |
|
|
Term
| Drugs that cause lysosomal storage disorders: |
|
Definition
*Antidepressants
*Inhibitors of cholesterol biosynthesis
*Vasodilators
*Antihistamines
*Anticancer agents
*Antibiotics |
|
|
Term
|
Definition
oxidize organic molecules ~ 1000 per liver cell
¨ Specialize in beta-oxidation of long chain fatty acids (C24-26). Mitochondria use shorter chains.
¨ Contain ~ 15 enzymes including oxidase (produces H2O2) and catalase (destroys H2O2)
¨ Protect cells against H2O2 buildup
¨ Synthesize plasmalogens (phospholipids present in myelin
¨ Degrade bacterial walls |
|
|
Term
| Rare congenital diseases: Peroxisomes |
|
Definition
Peroxisomes are almost absent, diminished, or lacking an enzyme. Diagnosis - based on elevated level of very long fatty acids
-Zellweger syndrome - probably lack of plasmalogens in the myelin Þ severe demyelination (defect in the protein translocating enzyme to peroxisomes - “translocation pathology”), mechanism unclear |
|
|
Term
| Drug-induced diseases (mechanism unclear): Peroxisomes |
|
Definition
-Various hypolipidemic drugs Þ increased number of peroxisomes in the liver
-Aspirin Þ increased number of peroxisomes in the liver (mechanism unclear) |
|
|
Term
|
Definition
the cell’s "skeleton" and "musculature"
Cytoskeleton = 3 kinds of filaments + their associated regulatory proteins:
* Actin filaments (cell motility, contraction, adhesion)
* Intermediate filaments (polarity, structural support)
* Microtubules (cytokinesis, transport, structural support)
Cytoskeleton - integrated system. Components interact and are interconnected via binding proteins. Pathology of the cytoskeleton is very complex |
|
|
Term
| Pathology of Actin filaments - Drug-induced diseases |
|
Definition
Actin filaments - target of several drugs and potent toxins
Phalloidin - (from deadly mushroom Amantia phylloides) binds selectively to the sides of actin filaments and prevents depolymerization
Cytochalasin B - (from Kodo millet) prevents polymerization of actin filaments. Very potent poison (in ancient India was used to kill tigers) |
|
|
Term
Pathology of Intermediate filaments
5 classes of intermediate filaments: |
|
Definition
¨ Cytokeratin filaments (epithelial cells)
¨ Desmin filaments (muscle cells)
¨ Vimentin filaments (connective tissue cells)
¨ Neurofilaments (neurons)
¨ GAFP - glial filaments (astrocytes)
Only the cytokeratins and neurofilaments are involved in significant pathological conditions |
|
|
Term
| Cytokeratin filaments (over 20 known human cytokeratins) |
|
Definition
Eg. hyaline masses of cytokeratin filaments (Mallory bodies or alcoholic hyaline) in liver cells of alcoholics. Unclear etiology
Inclusions similar to Mallory bodies but not related to alcohol abuse present in:
*liver cells (in obesity, jaundice)
*pulmonary epithelium (in asbestosis)
*some liver and lung tumors
Crooke’s hyalin - in the basophiles of pituitary gland - formed in response to high blood levels of glucocorticoids (adrenal tumor or adrenal hyperplasia - Cushing’s syndrome)
Congenital disorders - (mutation in IF genes - multiple human disorders)
Epidermolysis bullosa simplex - alteration in one of the keratine genes |
|
|
Term
|
Definition
* Several drugs and toxic agents cause abnormal accumulations of neurofilaments in the neurons or in the axons
* Swelling of axons overfilled with neurofilaments - typical for neuropathies
In Alzheimer disease - the neurofibrillary tangle found in brain - contains neurofilaments and microtubule-associated proteins (MAPs) |
|
|
Term
| Microtubules are targets of many drugs that bind to tubulin: |
|
Definition
Colchicine (from meadow saffron) - very toxic
Vinca alkaloids (from the Madagascar periwinkle) - anticancer drug
Taxol (from the bark of Taxus brevifolia) - anticancer drug
Podophyllotoxin (from the root of May apple - Podophyllum)
Griseofulvin (from Penicillium griseofulvum) - antifungal
Immotile cilia syndrome - congenital (1 per 15,000 births). Immotile spermatozoa and cilia in other organs (respiratory tract, Fallopian tubes) – missing dynein arms in cilia |
|
|
Term
|
Definition
| Very complex structure: DNA, RNA, associated proteins, regulatory proteins etc. Nuclear size, shape and structure - tells a lot about condition of the nucleus and cell |
|
|
Term
|
Definition
*nuclear size - reflects nuclear ploidy
*large, pale nucleus, enlarged nucleolus - active transcriptional state
*large and very basophilic nucleus - excessive DNA content
*small and very basophilic nucleus - low level of activity (transcription off)
*grotesque nuclear shapes - typical for malignant tumors
*increases greatly when cells are activated to a high level of protein synthesis, nucleoli
enlarge too |
|
|
Term
| Nucleus can break down by: |
|
Definition
*Karyolysis-slowly looses affinity for basic dyes Þ fades away - typical in ischemic cell death
*Pyknosis - changes into a dense, highly basophilic mass
*Karyorrhexis - becomes pyknotic and breaks up into small pieces
Pyknosis and karyorrhexis – seen in apoptosis |
|
|
Term
| Nuclear inclusions - many different types, most unexplained, seen in EM |
|
Definition
* Cellular organelles - perhaps trapped during mitosis
* Droplets of lipid, glycogen or protein
* Membrane infoldings
* Viruses
* Fibrils
*Crystals
*Tubules |
|
|
Term
|
Definition
| A great deal can be learned from the direct microscopic study of chromosomes (can be visualized only in dividing cells |
|
|
Term
| How to study: Chromosomes |
|
Definition
*Grow cells in culture (e.g. WBC); Treat with colchicine (arrests mitoses in metaphase)
*Stain chromosomes with nuclear stain
*Obtain “spreads” of the metaphase chromosomes
*Photograph the best mitoses
*Cut individual chromosomes
*Identify by size and shape, pair
*Paste in a standard order Þ KARYOTYPE, now computer programs used to identify and arrange chromosomes
Clinical features of selected Trisomies (Associated with increased maternal age)
*Trisomies 13 and 18 Þ much more severe malformations than in 21
*Down syndrome (21) - most common, a major cause of mental retardation (1 in 700 newborns in USA) |
|
|
Term
| Cell injury - structural and/or functional damage |
|
Definition
Pathologic stimuli → cellular adaptations (new, altered steady state - preservation of cell viability and modulated function as a response to stimuli)
Limits of adoptive response to a stimulus exceeded or adaptation is not possible → Cell injury
Is reversible up to a certain point - if the stimulus persists (or is severe enough from the beginning) → irreversible cell injury → cell death (ultimate result of cell injury) |
|
|
Term
|
Definition
* Oxygen deprivation (hypoxia)
* Physical agents
*Chemical agents and drugs
*Infectious agents
* Immunologic reactions
*Genetic defects
*Nutritional imbalances |
|
|
Term
| Oxygen deprivation (hypoxia) |
|
Definition
Common cause of cell injury and cell death
Hypoxia should be distinguished from Ischemia (loss of blood supply). Ischemia - injures cells faster than hypoxia |
|
|
Term
|
Definition
• inadequate blood oxygenation (cardiorespiratory failure)
•loss of oxygen-carrying capacity of the blood (anemia, CO poisoning)
Depending on the severity of the hypoxic state cells may adapt, undergo injury or die
Critical role of oxygen in cell injury: Many injurious agents - chemical, physical, biological - cause damage by generating free radicals
Free radicals - involved in many pathologic and physiologic events |
|
|
Term
|
Definition
*mechanical trauma
*extremes of temperature (burns and deep cold)
*sudden changes in atmospheric pressure
*radiation
*electric shock |
|
|
Term
| Chemical agents and drugs |
|
Definition
* free radicals
* poisons (arsenic, cyanide, mercuric salts)
* environmental and air pollutants
* insecticides and herbicides
* industrial and occupational hazards (CO, asbestos)
* social stimuli (alcohol, drugs)
* therapeutic drugs |
|
|
Term
|
Definition
*prions
*viruses
*bacteria
*chlamydiae, rickettsiae, mycoplasma
*fungi
*protozoa
*helminthes (parasitic worms) |
|
|
Term
|
Definition
Immune system - body defense against biologic agents
Immune reactions may cause cell injury
Examples:
*Anaphylactic reaction to a foreign protein or drug;
*Reactions to endogenous self-antigens (responsible for autoimmune diseases) |
|
|
Term
|
Definition
Important causes of cell injury
May cause defects as gross as congenital malformations (Dawn syndrome) and very subtle defects (single amino acid substitution in sickle cell anemia)
Many inborn errors of metabolism are examples of cell damage due to alterations at the level of DNA |
|
|
Term
|
Definition
One of the major causes of cell injury
protein - calorie deficiencies
vitamins deficiencies
nutritional excesses (excess of lipids → atherosclerosis; overloading of cells with fat → obesity)
Composition of the diet makes significant contribution to a number of diseases
E.g. vitamins deficiencies
A - night blindness, vulnerability to infection
D - rickets
E - spinocerebellar degeneration
C - scurvy
B2 - dermatitis, stomatitis
mineral deficiencies
Fe - anemia
Zn - growth retardation
I - hypothyroidism |
|
|
Term
| Biochemical mechanisms responsible for reversible cell injury and cell death are complex |
|
Definition
| Multiple causes of cell injury → multiple pathways to cell death that interact with one another |
|
|
Term
| Cellular response to injurious stimuli depends on: |
|
Definition
* Type of injury
* Duration
* Severity
small doses of toxin or brief ischemia → reversible injury
large doses of the same toxin or prolonged ischemia → instantaneous death or irreversible injury leading to cell death |
|
|
Term
| Consequences of cell injury depend on: |
|
Definition
* cell type
* cell state
* cell adaptability
e.g. loss of blood and hypoxia - striated muscle cell in the leg can be placed at rest and survive; striated muscle cell in heart may die
Exposure of two individuals to identical concentrations of toxin - may be without effect in one and may produce cell death in another |
|
|
Term
| General biochemical mechanisms of cell injury |
|
Definition
* ATP depletion - common consequence of ischemic and toxic injury (O2↓ → oxidative phosphorylation ↓ → ATP↓)
* Mitochondrial damage - all types of injurious stimuli
* Oxygen and oxygen derived free radicals - imbalance between free radical generating and scavenging systems → oxidative stress
* Defects in membrane permeability - consistent feature of all forms of cell injury (may affect mitochondria, plasma membrane and other cellular membranes)
* Irreversible mitochondrial damage - will ultimately kill cells (formation of high conductance channel - mitochondrial permeability transition in the inner mitochondrial membrane; leakage of cytochrome c into the cytosol)
Maintenance of membrane potential is critical for mitochondrial oxidative phosphorylation. Cytochrome c - can trigger apoptotic death pathways in the cytosol
* Intracellular calcium and loss of calcium homeostasis
Ischemia and toxins → increase in Ca++ - influx across plasma membrane, from ER and mitochondria → activation of cellular enzymes (phospholipases - membranes; proteases - membrane and cytoskeletal proteins; ATPases - ATP depletion; endonucleases - chromatin)
* Free radicals - atoms or molecules with an single unpaired electron in the outermost orbit → unstable and highly reactive
Energy of this unstable configuration - released through reactions with adjacent molecules (proteins, lipids, carbohydrates, nucleic acids)
Free radicals also initiate autocatalytic reactions (molecules with which free radicals react are themselves converted into free radicals - propagate the chain of damage)
Involved in many pathological processes |
|
|
Term
| Sources of free radicals: |
|
Definition
-absorption of radiant energy (UV, x-rays) e.g. ionizing radiation can hydrolyze water → hydroxyl (OH·) and hydrogen (H·) free radicals
-enzymatic metabolism of exogenous chemicals or drugs, e.g. CCl4 can generate CCl3·
-reduction-oxidation reactions that occur during normal metabolic processes
-transition metals (Fe, Cu) donate or accept free electrons during intracellular reactions and catalyze free radical formation (Fenton reaction: H2O2 + Fe2+Ü Fe3+ + OH· + OH-)
-nitric oxide (NO) can act as free radical |
|
|
Term
| Effects of free radicals relevant to cell i |
|
Definition
-lipid peroxidation of cell and organelles membranes (free radicals in the presence of oxygen)
-oxidative modification of proteins:
1.oxidation of amino acid side chains.
2.formation of protein-protein cross-links.
3. oxidation of the protein backbone → protein fragmentation
-lesions in DNA-reactions with thymine in nuclear and mitochondrial DNA → single-stranded breaks in DNA (present in cell aging and in malignant transformation)
Cells have developed multiple mechanisms to remove free radicals and minimize cell injury |
|
|
Term
| Systems that inactivate free radicals: |
|
Definition
* antioxidants
block initiation of free radical formation or inactivate - scavenge- free radicals → terminate radical damage e.g. vitamins E , A, C, glutathione
* binding of ions to storage and transport proteins - Fe and Cu can catalyze reactive oxygen species formation. Binding of these ions to storage and transport proteins lowers their level in the tissues → lowers OH· formation
* enzymes specialized in H2O2 and O2- break down - located near the sites of specific free radical generation; include: Catalase - present in peroxisomes - decomposes H2O2 (2 H2O2 Ü O2 + 2 H2O), Superoxide dismutases - SOD (Zn & Cu)- present in many cell types - convert superoxide to H2O2 (2O2- + 2H Ü H2O2 + O2), Glutathione peroxidase - catalyzes free radical breakdown
In many pathological processes, the final effects induced by free radicals depend on the net balance between free radical formation and termination |
|
|
Term
| How free radical reactions are relevant to pathology? |
|
Definition
*Leukocytes use oxygen-derived free radicals to kill bacteria - the same free radicals can turn against the leukocytes themselves or against any nearby tissue
*Injury spills blood which releases iron - catalyzes free radical reactions → increase in damage (especially in the brain)
*Ischemia - should be relieved by reperfusion - but when oxygen-rich blood returns to the ischemic tissue, production of oxygen-derived free radicals increases. It is a problem in organ preservation for transplants
*Radiotherapy - x-rays kill tumor cells and cause tissue damage in part by producing free radicals
*Tumors - caused by many mechanisms - one is believed to be DNA damage by free radicals
*Toxins, drugs, pollutants - their metabolism produces free radicals (CCl4Ü CCl3· Þ damaged ER; cigarette smoke, ozone, NO, NO2, anticancer drugs initiate free radical reactions)
*Atherosclerosis - involves the peroxidation of low-density lipoprotein (LDL). Antioxidant therapy is being tested
*Aging - free-radical hypothesis of aging
*Arthritis - breakdown of hyaluronic acid (essential component of lubricant in joints) involves free radicals
*Lung damage - exposure to pure oxygen → destruction of alveolar epithelium, capillary endothelium (mitochondria produce more free radicals from the electron transport chain electrons and O2) |
|
|
Term
| Imbalance between free radical generating and radical-scavenging systems result in oxidative stress |
|
Definition
Study of free radicals lead to discovery of mechanisms of diseases and development of new therapies
Hot topics:
*free radical injury to the central nervous system - myelin - made of cell membranes (lipids - good target for free radicals; injury spills erythrocytes that contain Fe)
*inflammation
*ischemia |
|
|
Term
|
Definition
ultimate effect of cell injury
It is very difficult to distinguish between reversible cell injury and recent cell death (diagnosis should rely on functional rather than morphologic criteria - dye exclusion test) |
|
|
Term
|
Definition
* accident (failure of the blood supply, trauma, heat, dehydration, poisons, histologic fixatives)
* suicide (every cell type is ready to undergo programmed cell death if it receives the proper
signal)
* killer cells (specialized for killing other cells)
Well understood and most common form of accidental cell death - ischemic cell death |
|
|
Term
|
Definition
* Necrosis (cell death with swelling - accidental)
* Apoptosis (cell death with shrinkage - programmed cell death) |
|
|
Term
| Necrosis (cell death with swelling - accidental) |
|
Definition
| Wide spectrum of morphologic changes follow cell death in living tissue - largely due to enzymatic action on lethally injured cell |
|
|
Term
| Morphologic appearance of necrosis is the result of: |
|
Definition
*Enzymatic digestion of the cell
- catalytic enzymes derived from the death cell itself (autolysis)
- digestive enzymes from the lysosomes of migrating leukocytes (heterolysis)
*Denaturation of proteins (begins in the live cell and continues in the dead cell, mechanism unknown - may be triggered by initial drop in pH) |
|
|
Term
| Morphology of necrotic cells |
|
Definition
On LM level:
• increased eosinophilia
• more glossy homogenous appearence
• vacuolated cytoplasm (after organelles digestion)
• calcification of death cells may occur
On EM level:
• discontinuities in plasma and organelle membranes
• dilated mitochondria and large amorphous densities
• aggregation of amorphous material (probably denatured proteins)
• intracytoplasmic myelin figures
Nuclear changes - by karyolysis, pyknosis or karyorrhexis |
|
|
Term
| Types of Necrosis (morphologic patterns): |
|
Definition
Coagulative necrosis
Caseous necrosis
Liquefactive necrosis
Fat necrosis |
|
|
Term
|
Definition
Preservation of general tissue architecture (ghostlike eosinophilic remnant), lost nucleus
Necrotic cells removed by fragmentation and phagocytosis e.g. myocardial infract
Characteristic of hypoxic death of cells in all tissues except the brain |
|
|
Term
|
Definition
a distinctive form of coagulative necrosis
Term caseous derived from the gross appearance (white and cheesy)
Lost tissue architecture. Microscopically - amorphous granular debris (fragmented coagulated cells)
surrounded by inflammatory border (granulomatous reaction)
Most often in foci of tuberculosis infection |
|
|
Term
|
Definition
Dominant enzyme digestion
Complete digestion of dead cells by hydrolytic enzymes - transformation of tissue into a liquid viscous mass. Necrotic area infiltrated by neutrophils and converted to an abscess
Characteristic of focal bacterial or fungal infections. Also in hypoxic cell death within central nervous system |
|
|
Term
|
Definition
focal areas of destruction
Typically caused by release of activated pancreatic lipases into the pancreas and the peritoneal
cavity. Characteristic of acute pancreatitis.
Activated lipases liquefy fat cell membranes and break stored triglycerides → release of fatty acids that combine with calcium → grossly visible chalky white areas.
In the living body most necrotic cells and their debris disappear by a combined process of enzymatic digestion and fragmentation with phagocytosis of debris by leukocytes
If necrotic cells and their debris are not promptly destroyed and reabsorbed, they tend to attract calcium salts and other minerals and become calcified (dystrophic calcification) |
|
|
Term
|
Definition
(cell death with shrinking - programmed)
Form of cell death designed to eliminate unwanted host cells through activation of coordinated, internally programmed series of events |
|
|
Term
|
Definition
- during development
- as a mechanism to maintain cell populations in tissues
- as a defense mechanism such as in immune reactions
- when cells are damaged by disease
- in ageing |
|
|
Term
| Morphologic events in apoptosis: |
|
Definition
*cell shrinkage (smaller cells, dense cytoplasm, more tightly packed organelles)
*chromatin condensation (most characteristic feature of apoptosis)
*formation of cytoplasmic blebs and apoptotic bodies (sequence of events: apoptotic cells ê
extensive surface blebbing ê fragmentation into a membrane-bound apoptotic bodies
containing cytoplasm, tightly packed organelles with or without a nuclear fragment)
*phagocytosis of apoptotic cells or bodies by adjacent healthy cells or macrophages (phagocytosed
apoptotic bodies are rapidly degraded in lysosomes)
plasma membrane is thought to remain intact until the last stages |
|
|
Term
| Apoptosis-Biochemical events characteristic for apoptosis: |
|
Definition
*protein cleavage (activation of hydrolytic enzymes including cysteine proteases - caspases (present in normal cells as inactive proenzymes) → protein hydrolysis (lamins, cytoskeleton) and activation of endonucleases → degradation of nuclear DNA
*protein cross-linking (transglutaminase activation ê protein cross-linking ê cytoplasmic proteins
converted into covalently linked shrunken structures that may break into apoptotic bodies)
*DNA breakdown (DNA fragmentation into 50 -300 kilobase pieces ê subsequent
internucleosomal cleavage into 180 - 200 base pairs by Ca++- and Mg++ - dependent endonucleases ê shown as DNA ladders by gel electrophoresis
*phagocytic recognition - apoptotic cells contain phosphatidylserine in the outer layer of the plasma
membrane -”flipped out” from the inner layer; in some cases of apoptosis adhesive glycoprotein - thrombospondin is expressed on the surfaces of apoptotic bodies; these membrane alterations allow early recognition of dying cells by macrophages and adjacent cells for phagocytosis - without the release of proinflammatory cellular components)
Apoptotic cell disposal with minimal or no effect on the surrounding tissue |
|
|
Term
|
Definition
1. Signaling pathways that initiate apoptosis
2. Control and integration stage
3. Execution phase
4. Removal of dead cells phase |
|
|
Term
| 1. Signaling pathways that initiate apoptosis |
|
Definition
Apoptotic stimuli generate transmembrane or intracellular signals
*Transmembrane signals - positive or negative
-Negative - certain hormones, growth factors generate signal transduction cascades suppressing
preexisting death programs - they are normal survival stimuli - their absence ê failure of
suppression of death programs ê apoptosis
-Positive -receptor-ligand interactions generate signals to activate death programs (tumor necrosis
factor-TNF superfamily)
*Intracellular signals - (e.g. binding of glucocorticoides to nuclear receptors, heat, radiation, hypoxia, viral infection) |
|
|
Term
| 2. Control and integration stage |
|
Definition
Performed by specific proteins that connect death signals to the execution program. 2 pathways:
• Extrinsic - Direct transmission of signals - from cell surface death receptors after binding of ligand (e.g. TNF) by specific adapter proteins to the execution mechanism
• Intrinsic - Regulation of mitochondrial function by Bcl-2 family of anti-apoptotic proteins (~ 20 known, all regulate apoptosis)
Growth factors and other survival signals stimulate production of anti-apoptoticmembers of Bcl-2 family (Bcl-2 and Bcl-x most important)
Bcl-2 reside in mitochondrial membranes and in the cytoplasm
Depravation of survival signals → Bcl-2 / Bcl-x lost and replaced by pro-apoptotic proteins (bak, Bax, Bim) → increased mitochondrial membrane permeability → reduction of membrane potential → mitochondrial swelling or increased permeability of outer membrane → release of apoptotic trigger - cytochrome c into the cytosol → activation of caspases (by binding of cytochrome c to apoptosis activating factor, apaf-1) |
|
|
Term
|
Definition
Common for all types of apoptosis
Proteolytic cascade triggered and mediated by proteases from caspase family - final pathway
Caspases:
highly conserved across species; more than 10 members; can be divided to 2 basic groups - initiator and executor; must be activated by other caspases |
|
|
Term
| 4. Removal of dead cells phase |
|
Definition
Marker molecules present on apoptotic cells and their fragments → recognition by adjacent cells or phagocytes → phagocytic uptake and disposal. Very efficient-no inflammation
Apoptosis is responsible for many physiologic, adaptive and pathologic events:
*programmed destruction of cells during embryogenesis
Involved in implantation, organogenesis, developmental involution and metamorphosis.
*hormone-dependent involution in adults
ovarian follicular atresia in the menopause; prostatic atrophy after castration, regression of the lactating breast
*cell deletion in proliferating cell populations (intestinal epithelia)
*cell death in tumors
*death of neutrophils in an acute inflammatory response
*death of B and T lymphocytes after cytokine depletion
*pathologic atrophy in some organs after duct obstruction (pancreas, parotid gland and kidney)
*cell injury in certain viral diseases (viral hepatitis - Councilman bodies)
Cell death can be produced by a variety of injurious stimuli
(when applied in low doses, heat, radiation, cytotoxic anticancer drugs and hypoxia induce apoptosis; large doses of the same stimuli causes necrotic cell death) |
|
|
Term
|
Definition
changes in quantity and quality of normal components of extracellular matrix (ECM) and the appearance of abnormal materials
Can be congenital (about 150 defects known) or acquired
*Cells grow, move and differentiate in intimate contact with ECM and are physically attached to ECM by variety of receptors for ECM molecules
*Signals transmitted from the cell to the matrix and from the matrix to the cell
*Cells produce molecules of ECM
*ECM forms a substratum for cells to adhere, move, proliferate
*ECM can regulate cell functions and phenotype
Cells relate very closely to their environment. Extracellular spaces are filled with a mixture of molecules. ECM can be arranged in different ways and contains migrating and resident cells. |
|
|
Term
|
Definition
| Collagen fibers, elastic fibers, proteoglycans, fibronectin & laminin, basement membrane |
|
|
Term
|
Definition
over 20 types known
*the most abundant protein in the animal world (accounts for almost 1/3 of the mammalian body’s protein)
*is responsible for holding the body together
*involved in wound healing
*very stable
*secreted by fibroblasts, smooth muscle cells, epithelia |
|
|
Term
|
Definition
Congenital diseases - caused by defects in genes coding for collagen and/or enzymes active in posttranslational events → defective collagen fibers
2 main groups of congenital collagen diseases:
Osteogenesis imperfecta (brittle bone disease or Lobstein's disease)
Ehler-Danlos syndrome |
|
|
Term
| Osteogenesis imperfecta (brittle bone disease or Lobstein's disease) |
|
Definition
*1 in 25,000 people affected
*wide range of severity (depending on the mutation in one of the two procollagen genes - over 70 known mutations)
*"blue" semitransparent sclera and opalescent teeth
*short individuals with weak and brittle bones |
|
|
Term
|
Definition
*11 known varietes - molecular defect known for a few of them (usually defective enzymes required for posttranslational processing of collagen)
*extremely loose joints ("rubber people" ' "floppy babies")
*thin, hyperextensible skin |
|
|
Term
| Acquired defects Collagen |
|
Definition
-Poor nutrition or toxic agents
-Deficient hydroxylation - scurvy (vitamin C - cofactor in hydroxylation reactions - low
hydroxylation of lysine → reduced cross-linking → defective collagen fibers)
-Defective cross-linking - copper deficiency (lysyl oxidase)
-Excessive cross-linking - in ageing and diabetes
-Digestion by enzymes - collagenases - produced by fibroblasts, epithelial cells, inflammatory cells, bacteria (corneal disease - corneal stroma destruction; osteoarthritis breakdown of collagen in hyaline cartilage; gas gangrene)
-Calcification - age related tendency of collagen to calcify
-Heat shrinkage - heated to 65°C collagen fibers shrink to one-third of their original length (contracted fibers turned into gelatin; appl.: skin laser resurfacing, laser surgery of joint capsule)
leather - dermal collagen made almost unshrinkable by tanning - cross-linking)
-Pathologic changes due to glucose
Cross-linking of collagen - nonenzymatic glycation
Pathologic collagen cross-linking → stiff joints (inability to approximate the palmar surfaces)
Some “collagen diseases” in fact are not diseases of collagen e.g. a group of CT autoimmune diseases: systemic lupus erythematosus, rheumatiod arthritis, rheumatic fever, dermatomyositis, scleroderma (connective tissue diseases with normal collagen) |
|
|
Term
|
Definition
*complex polymer - ~ 19 proteins
*product of fibroblasts and smooth muscle cells
*resistant to many chemical agents
*contains cross-links that regulate its elasticity
*elastin + fibrillin → elastic fibers |
|
|
Term
| Pathology of elastin - Genetic defects |
|
Definition
Marfan Syndrome
Cutis laxa |
|
|
Term
|
Definition
*mutations in two fibrillin genes on chromosomes 5 and 15
*glycoprotein fibrillin - component of the microfibrils, associated with elastin; especially abundant in aorta, periosteum and lens ligament; *disease of elastic fibers (elastin molecule itself is not affected)
*wide spectrum of clinical manifestations
*1 i 10,000 people affected
*tall individuals with long, spidery fingers; loose joints; deformed spine; floppy mitral velves; defective walls of aorta |
|
|
Term
|
Definition
*heterogenous group, overlaps in part with Ehler-Danlos syndrome
*too few elastic fibers
*skin lacks recoil (appears too large for the body)
*vocal cords lack tension → baritonal voice; aortic defects; emphysema; dislocation of hips |
|
|
Term
| Pathology of elastin - Acquired defects |
|
Definition
-Ageing - elastin is very sensitive to ageing
-Crosslinking - increases with age Þ stiffer arteries
-Calcium - increased amount of Ca bound to the elastic fibers
-Digestion by elastases - not as specific as collagenases; digest not only elastin; present in pancreatic juice, in neutrophils granules, on the surfaces of macrophages; produced by many bacteria -open up connective tissue spaces
*produced by neutrophils - most relevant to human disease Examples: emphysema - result of imbalance between elastase and alpha-1-chemotrypsin
In smokers more neutrophils attracted to the lungs → release of enzymes → elastin digestion in alveolar walls → emphysema
-Solar elastosis (dermatoheliosis) thickened dermis - increased amount of abnormal elastic fibers produced by damaged by sunlight fibroblasts - e.g. “redneck” |
|
|
Term
|
Definition
Thin mat underlying epithelia and separating other cell types from CT
Consists of:
type IV collagen (arranged in network), laminin, heparan sulfate, entactin, fibronectin |
|
|
Term
| Pathology of basement membranes - genetic defects |
|
Definition
Alport syndrome (hereditary progressive glomerulopathy)
Thin membrane disease - benign familial hematuria
Nephronophtisis syndrome |
|
|
Term
| Alport syndrome (hereditary progressive glomerulopathy) |
|
Definition
*thinned glomerular basement membranes → allow the escape of red blood cells
*nerve deafness and eye disorders (posterior cataracts, corneal dystrophy)
*males affected more frequently than females and are more likely to progress to renal failure
*most patients have an X-linked dominant pattern (mutations in the gene encoding the a5 chain of collagen type IV)
*could be a diffuse abnormality of all basement membranes, symptoms appear at ages 5 to 20 years. Onset of renal failure between ages 20 and 50 years in man |
|
|
Term
|
Definition
benign familial hematuria
*mutations in genes encoding a3 and a4 chains type IV collagen
*diffuse thinning of glomerular BM
*hematuria and mild proteinuria, good prognosis, no hearing or ocular abnormalities |
|
|
Term
|
Definition
| – rare. Cause of renal failure in the young |
|
|
Term
| Pathology of basement membranes -Acquired defects |
|
Definition
Basement membranes as molecular traps
*Heparan sulfate and fibronectin - highly charged, “sticky” molecules; high affinity for calcium and silver ions
Argyria - condition developed from exposure to silver nitrate (used as a cure for gastric ulcers)
Pathologic thickening - In a chronic state of irritation - e.g thickening of BM in the bronchial mucosa of asthmatics
Porphyria - abnormal sensitivity to sunlight - thickening of basement membrane of skin capillaries
thickening of basement membrane of renal and perirenal capillaries in analgesic phenacetin abuse
Diabetes - nonenzymatic glycation
Persistent hyperglycemia → nonenzymatic glycation - protein cross-linking → formation of “advanced glycosylation end-products” (AGE) (partially reversible by control of hyperglycemia - importance of metabolic control in diabetes)
*thickening of pericapillary basement membranes in diabetes
Possible effects of hyperglycemia on capillary basement membrane (BM):
AGE develop on and between BM molecules → disturbed BM self assembly → reduction of BM susceptibility to enzymatic degradation → plasma proteins trapped in BM |
|
|
Term
|
Definition
Proteogycan = hyaluronic acid + core protein + glycosaminoglycans
heparan sulfate, chondroitin sulfate, dermatan sulfate, hyaluronan
In CT proteoglycans:bind fluid - responsible for holding water, bind variety of molecules e.g. growth factors |
|
|
Term
| Myxedema (“mucous edema”) |
|
Definition
Special edema due to an excess of proteoglycans or their building blocks
in advanced hyperthyroidism - hyaluronic acid accumulation in tissue spaces due to reduced degradation → puffy face; thick, cold skin; swollen tongue; stiff joints |
|
|
Term
|
Definition
| leads to hyperthyroidism; excessive glycosaminoglycans deposition; autoimmune disease - autoantibodies to the TSH receptor; increased incidence among family members of affected patients; affects 1.5-2% of women in US |
|
|
Term
| Pathology of proteoglycans - acquired defects |
|
Definition
Joints
Proteoglycans - bulk of the articular cartilage matrix
Extracellular degeneration of cartilage → osteoarthritis (degenerative arthritis) begins with the reduction in the proteoglycan content in the articular cartilage. Unclear mechanism
Next - collagen fibers that form scaffolding for proteoglycans are exposed and separate from the structure. Normally shiny cartilage surface changes to velvety. |
|
|
Term
|
Definition
] pathologic, insoluble, extracellular, fibrous proteins (95%)
] serum P component, proteoglycans, glycoaminoglycans (5%)
] usually derived from precursors present in blood
] deposited between cells in various tissues and organs |
|
|
Term
| Amyloid - chemical nature |
|
Definition
~20 biochemically distinct, insoluble proteins; most common:
*AL - amyloid light chain - contains immunoglobulin light chains derived from plasma cells,
*AA - amyloid associated - nonimmunoglobulin synthesized by the liver
*Aβ amyloid - in the cerebral lesion of Alzheimer disease
*several other biochemically distinct proteins (depending on the clinical settings)
] P component - glycoprotein - present in all forms of amyloidosis
] CT derived proteoglycans and highly sulfated glycosaminoglycans |
|
|
Term
|
Definition
extracellular accumulation of amyloid ranging from local microscopic deposits to extensive infiltration of vital organs
massive form - side-effect of chronic inflammatory diseases (tuberculosis, osteomyelitis)
microscopic forms - associated with rheumatoid arthritis, tumors, ageing, Alzheimer’s disease
also occurs in hereditary forms
immunologic mechanisms are suspected to contribute to development of amyloidosis |
|
|
Term
| Amyloidosis - classification based on: |
|
Definition
*identification of the protein precursor involved
*acquired or inherited
*deposits distribution pattern
] Systemic (generalized) - involving several organ systems
*Acquired
*Hereditary
] Localized - deposits limited to a single organ |
|
|
Term
| Acquired Systemic Amyloidosis |
|
Definition
AL type (of immune origin, also called “primary” or myeloma-related)
AA type (reactive systemic or “secondary”amyloidosis) |
|
|
Term
| AL type (of immune origin, also called “primary” or myeloma-related) |
|
Definition
•protein precursor - immunoglobulin light chain
•systemically distributed
•proliferation of B lymphocytes or plasma cells
•source of amyloid fibrils - single clone of B lymphocyte-derived cells
Clinical features: neuropathy, cardiomyopathy (amyloid between cardiac muscle cells), carpal tunnel syndrome, amyloid deposits in joints and dermis, skin hemorrhages
E.g.: in Myeloma (20% of AL cases), in Waldenström’s macroglobulinemia, in agammaglobulinemia |
|
|
Term
| AA type (reactive systemic or “secondary”amyloidosis) |
|
Definition
•protein precursor - circulating acute-phase reactant (SAA - serum amyloid A), lipoprotein produced by the liver
•systemically distributed; associated with:
-neoplastic diseases (renal adenocarcinoma, Hodgkin’s disease)
-infectious chronic inflammatory diseases (tuberculosis, leprosy)
-noninfectious chronic inflammatory diseases (rheumatoid arthritis - 3% adult, 10% juvenile)
-heroine abuse
-paraplegia
Clinical features: amyloid deposits in the kidneys, liver, spleen and adrenal glands (main cause of death - chronic kidney failure) |
|
|
Term
| Hereditary Systemic Amyloidosis |
|
Definition
-several forms, most of them rare, occur in limited geographic areas
Neuropathic form
Cardiopathic form
Nephropathic forms
Hemodialysis-associated amyloid |
|
|
Term
|
Definition
•progressive systemic polyneuropathy (appears at 25-35y of age)
•systemically distributed
•protein precursor - transthyretin, plasma protein involved in retinol and thyroxine transport
•20 known point mutations in transthyretin coding gene
•3 forms (distribution of neuropathy and location of affected families)
-affected lower limbs - Portugal, Japan, Sweden
-affected upper limbs - Germany, Switzerland
-affected face - Finland |
|
|
Term
|
Definition
| progressive cardiomyopathy, protein precursor - transthyretin |
|
|
Term
|
Definition
•the most common form of hereditary systemic amyloidosis
•protein precursor - SAA (serum amyloid A)
•responsible gene located on the short arm of chromosome 16
2 forms (distribution of nephropathy and location of affected families)
-Familial Mediterranean fever - individuals of Armenian, Jewish, Arabic origins; Clinical features: amyloid deposits in kidneys
-Urticaria-deafness syndrome - Clinical features: nerve deafness (no amyloid found in the inner ear or cochlear nerve) widespread amyloidosis especially in the kidneys |
|
|
Term
| Hemodialysis-associated amyloid |
|
Definition
•protein precursor - β2-microglobulin (persistent high plasma concentrations in renal diseases; can not be filtered through the dialysis membranes; normally catabolized in the kidney)
•systemically distributed
•60 - 80% of patients on long-term dialysis develop amyloid deposits
Clinical features: amyloid deposits in the synovium, joints, and tendons; carpal tunnel syndrome |
|
|
Term
|
Definition
-Amyloid deposits limited to a single organ or tissue
Endocrine-related amyloid
Beta amyloid - Alzheimer’s disease
Spongiform encephalopaties |
|
|
Term
| Endocrine-related amyloid |
|
Definition
Microscopic amyloid deposits found in:
*endocrine tumors (e.g. thyroid medullary carcinoma, pancreatic islet tumors, pheochromocytoma)
*pancreatic islets in adult onset of diabetes and ageing (amyloid derived from an islet-associated polypeptide IAPP, synthesized by normal b cells) |
|
|
Term
| Beta amyloid - Alzheimer’s disease |
|
Definition
The most common form of localized amyloidosis
Protein precursor - beta (or A4) amyloid (unknown function)
Brain changes in Alzheimer’s - qualitatively similar to ageing without dementia - but much more severe.
3 types of deposits:
*neurofibrillary tangles - inside neurons, react histochemically like amyloid, nature still unclear
*senile plaques - spherical lesions (central amyloid core wrapped in a tangle of abnormal axons and glial cells)
*congophilic angiopathy - amyloid in the walls of cerebral arteries and arterioles |
|
|
Term
| Spongiform encephalopaties |
|
Definition
•a group of disorders
•transmission within and between species
•transmissible agent - prion - abnormally folded membrane protein encoded on chromosome 20, makes normal protein also to fold abnormally (prion - proteinacious infective particle)
•modification of host proteins into amyloid
Prion-associated diseases cause dementia in humans
e.g. Creutzfeldt-Jakob disease, Kuru, fatal familial insomnia, Gerstmann-Sträussler syndrome
In animals: scrapie, BSE (bovine spongiform encephalopathy) Creutzfeldt-Jakob disease can be caused by eating beef containing abnormal prion proteins |
|
|
Term
|
Definition
Group of disorders with extracellular deposition of protein arranged in the form of b-pleated sheet fibrils. Can be:
*acquired or inherited
*systemic or local
Brain - the most common and important site for local amyloidosis |
|
|
Term
|
Definition
*Extracellular Matrix - not spared by atrophy (it depends in part on cellular
metabolism)
*in immobilized limb:
- articular cartilage tends to loose proteoglycans
- ligaments loose strength |
|
|
