Pathology Irreversible Cell Injury And Cell Death (Test 1, Lecture 3)

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cell death in a living body

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necrosis

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cell death following swelling

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oncosis or oncotic necrosis

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prefex for swelling

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onco-

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cell death with shrinkage because cells are breaking up

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apoptosis

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not necrosis because happens after organism death

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postmortem autolysis

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appear inside mitochondria in irreversible cell injury prior to cell death

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amorphous densities

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inflammation is associated with necorosis or apoptosis

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necrosis

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occurs in hypoxic, toxic or metabolic injury

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fatty change

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first manifestation of almost all forms of injury to cells

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cell swelling (hydropic degeneration)

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________ apperance of necrosis is the result of denaturation of I/C proteins and enzymatic digestion of the lethally injured cell

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morphologic

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on LM, can see eosinophilia due to loss of RNA and denatured proteins with this

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necrosis

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nuclear shrinkage, increased basophilia (condensaiton of chromatin)

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pyknosis

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fragmentation of pyknotic nucleus

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karyorrhexis

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fading basophilia of chromatin reflecting enzymatic degradation of DNA by endonuclease

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karyolysis

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how long does it take for the nucleus in a necrotic cell to completely disappear

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a day or two

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3 primary types of necrosis that can be recognized grossly

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1. coagulative necrosis
2. caseous necrosis
3. liquefactive necrosis

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2 special types of necrosis that are not recognized grossly

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1. gangrenous necrosis
2. fat necrosis

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architecture of dead tissue is preserved (maintain outline and no nucleus); result of denaturized structural proteins and enzymes, so blocking the prteolysis of the dead cells so no lysis at the time but will have lysis eventually

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coagulative necrosis

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friable white 'cheeselike' appearance; a collection of framented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border; characteristic of a granuloma

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caseous necrosis

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(more to do with specific organs/tissues) enzymatic digestion of the dead cells; grossly liquid viscous to creamy white b/c of presence of dead leukocytes (called pus) in focal pyogenic bacterial infections; also call ischemic necrosis within CNS (best example is abcess)

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liquefactive necrosis

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common in caseous necrosis

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mineralization

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3 types of gangrenous necrosis

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1. dry
2. moist
3. gas

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this special type of necrosis starts out as coagulation necrosis

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gangrenous necrosis

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coagulation necrosis secondary to infarction, followed by mummification; involves extremity, tail, ear and udder; caused by ingested toxins (ergot, fescue) or frost bite; no bacterial proliferation

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dry gangrene

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an area of necrotic tissue futher degraded by the liquefactive action of saprophytic bacteria which cause putrefaction; arterial infarction of extremity or intestine, aspiration pneumonia; grossly soft, moist, reddish-brown to black and sometimes gas produciton by saprophytes

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moist gangrene

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necrotic tissue with proliferating anaerobes introduced by penetrating wounds (C. perfringens, C. speticum); grossly dark-red to black with gass bubbles and a fluid exudate containing blood (C=clostridium)

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gas gangrene

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3 types of fat necrosis

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1. enzymatic necrosis or saponification
2. traumatic necrosis
3. necrosis of abdominal fat of cattle

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saponification by the action of pancreatic lipases

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enzymatic necrosis

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resulting from crushed adipose tissue-SQ fat over the sternum b/c that's where they lay, fat adjacent to the pelvic canal of heifers following dystocia

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traumatic necrosis

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cause of this type of fat necrosis is unknown

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necrosis of adominal fat of cattle

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a microscopic descriptive term; not a type of true necrosis of cells; bright pink and amorphous 'hyaline' or fibrin deposits of immune complexes (Ags +Abs), complements with leaked out fibrin in the walls of arteries; immune-mediated vasculitis

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fibrinoid necrosis aka fibrinoid change and fibrinoid degeneration (NOT A TRUE TYPE OF NECROSIS)

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9 sequelae to necrosis or outcomes to tissue necrosis

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1. enzymatic lysis, complete liquefaction, resorption my lymphatics and veins or removed by mOs (usually in small or localized areas of necrosis)
2. complete liquefaction, walled off-cyst or cavitation
3. material not liquefied-phagocytosed by mOs and removed by lymphatics and veins
4. desquamation/slough off-ulcer
5. mineralization
6. atrophy of tissue/organ
7. regeneration
8. fibrosis
9. sequestrum formation (bone)

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3 types of postmortem changes of body condition

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1. rigor mortis
2. algor mortis
3. livor mortis

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the contraction of muscles after death due to ATP and glycogen depletion (required for muscle relaxation); it commences 1-6 hours after death and persists 1-2 days; it is irreversible except by autolysis

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rigor mortis

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gradual cooling of the cadaver

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algor mortis

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hypostatic congestion; the gravitational pooling of all body fluid especially blood to the down side of the animal

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livor mortis

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other postmortem changes

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1. bloating
2. organ displacement
3. pale foci on the liver
4. mucosal sloughing
5. lens opacity occurs when the carcass is cold or frozen-may be confused with cataract

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fermentation of ingesta, tissue breakdown, and saprophytic proliferation; if severe, rupture diaphragm; must be distinguished from antemortem ______

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bloating

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______ of all cells after somatic death (a total diffuse hypoxia) by own cellular enzymes

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postmortem autolysis

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postmortem bacterial proliferation and dissolution of host tissues

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postmortem decomposition

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produciton of color and texture changes, gas production, and odors

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putrefaction

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red staining of tissues by Hb released from lysed RBCs, particularly onthe intima of major vessels; if the integrity of the intima is lost, Hb penetrates the vascular wall and extends into the adjacent tissue

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hemoglobin imbibition

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can be antemortem, but becomes more sever in postmortem

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bile imbibition

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not going to happen in live animal; blue green discoloration of the tissue by FeS formed by the reaction of H2S generated by anaerobic Clostridium sp on Fe from Hb

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psuedomelanosis

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in this type of _____, the RBCs settle to the bottom of a large vessel, resulting in the _____ having 2 portions with distinct line of demarcation; currant jelly

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postmortem clost

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cell injury results from many different _________ _________ acting on several essential cellular components

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biochemical mechanisms

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6 types of biochemical mechanisms of cell injury

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1. depletion of ATP
2. mitochondrial damage
3. influx of Ca and loss of Ca homeostasis
4. accumulation of oxygen-derived free readical (oxidative stress)
5. defects in membrane permeability
6. damage to DNA and proteins

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3 major causes of ATP depletion

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1. reduced supply of oxygen and nutrition
2. mitochondrial damage
3. toxins (i.e. cyanide)

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5 consequences of ATP depletion

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1. reduction of Na pump causing Na and water influx which leads to cell swelling
2. altered cellular energy metabolism
3. failure of Ca pump leading to Ca influx
4. reduction in protein synthesis
5. damage to mitochondrial and lysosomal membranes which leads to necrosis

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5 causes of mitochondrial damage

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1. increased cytosolic Ca
2. ROS (radical oxygen species)
3. hypoxia
4. toxins
5. mutations in mitochondrial genes

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2 consequences of mitochondrial damage

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1. necrosis-formation and opening of MPTP (mitochondrial permeability transition pore)>loss of mitochondrial membrane potential>failure of oxidative phosphorylation and ATP depletion>necrosis
2. apoptosis-sequestered between the inner and outer mitochondrial membranes are some apoptosis-activating proteins, including cytochrome c and proteins that indirectly activate caspases so increased permeability of the outer membrane>leakage of the porteins into the cytosol>death by apoptosis

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3 consequence of influx of Ca and loss of Ca homeostasis

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1. increased Ca in mitochondria >opening of MPTP and failure of ATP generation
2. increased cytosolic Ca activates a number of enzymatic phospholipases, proteases, endocucleases and ATPases
3. increased IC Ca results in the induction of apoptosis by direct activation of capsases and by increasing mitochondrial permeability

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what is MPTP

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mitochondrial permeability transition pore

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chemical species that have a single unpaired electron in an outer orbit

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free radical

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____ _____ initiate autocatalytic reactions, whereby molecules with which they react are themselves are converted into _____ _____, thus propagating the chain of damage

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free radicals

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energy created by this unstable configuration is released thru reactions with adjacent organic/inorganic molecules, such as proteins, lipids, carbs, nucleic acids

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accumulation of ROS or FR

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what is ROS

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reactive oxygen species

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6 ways free radicals are generated within cells

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1. red-ox reactions in normal metabolic processes
2. absorption of radiant energy (UV, x-rays)
3. rapid bursts of ROSs in activated leukocytes during inflammation
4. enzymatic metabolism of exogenous chemicals (CCl4) or drugs
5. transition metals (Fe, Cu) donate or accept free electrons druing I/C reactions and catalyze FR formation
6. NO generated by ECs, MOs, neurons and other cells can act as a FR and can aslo be converted to ONOO-, NO2, NO3-

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4 ways to remove free radicals

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1. spontaneous dismutation
2. antioxidants (Vit A, E, C, glutathione)-block the initiation of FR fomation or inactivate (scavenge) FRs
3. binding of Fe/Cu to storage and transport proteins (transferrin, ferritin, lactoferrin, ceruloplasmin) minimizes the formation of ROS
4. FR-scavenging enzymes

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3 examples of FR=scavenging enzymes

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1. catalase in peroxisomes-decomposes hydrogen peroxide
2. superoxide dismutase-convert oxygen to hydrogen peroxide
3. glutathione perioxidase in cytosol-catalyzes FR breakdown

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The I/C ratio of oxidized _____ to reduced _____ is a reflection of the oxidative state of the cell and is an important indicator of the cell's ability to detoxify ROS

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glutathione

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what are the three pathologic effects of free radicals

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1. lipid peroxidaiton in membranes
2. oxidative modification of proteins
3. lesions in DNA

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what is ONOO-

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peroxynitrite

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radical damage to lipids

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peroxidation

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where do FR or ROS reactions take place

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mitochondria

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what is SOD

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superoxide dismutase

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what is GSH

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reduced glutathione

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what is GSSG

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oxidized glutathione

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what is NADPH

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reduced form of nicotinamide adenine dinucleotide phosphate

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early loss of selevtive ________ __________ leading ultimately to overt ________ damage is consistent feature of most forms of cell injury except apoptosis

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membrane permeability; membrane

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The I/C ratio of oxidized _____ to reduced _____ is a reflection of the oxidative state of the cell and is an important indicator of the cell's ability to detoxify ROS

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glutathione

Front 72

what are the three pathologic effects of free radicals

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1. lipid peroxidaiton in membranes
2. oxidative modification of proteins
3. lesions in DNA

Front 73

what is ONOO-

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peroxynitrite

Front 74

radical damage to lipids

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peroxidation

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where do FR or ROS reactions take place

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mitochondria

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4 mechanisms of membrane damage

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1. results form ATP depletion and Ca-mediated activation of p-lipases
2. bacterial toxins (endotoxins), viral proteins, lytic C components
3. physical and chemical agents
4. biochemical mechanisms suchs as ROS>lipd peroxidation, decreased phospholipid synthesis, increased phospholipid breakdown, and cytoskeletal abnormalities

Front 77

3 consequences of membrane damage

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1. mitochondrial membrane damage
2. plasma membrane damage
3. injury to lysosomal membranes

Front 78

opening of the MPTP leading to decreased ATP, and release of proteins that trigger apoptotic death

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mitochondrial membrane damage

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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

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plasma membrane damage

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lysosomes 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

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injury to lysosome membranes

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common causes of DNA damage

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drugs, radiation, oxidative stress, mutations, misfolded proteins, etc.

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DNA damage too severe to be repaired >_______

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apoptosis

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characteristics of irreversibility

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1. inability to reverse mitochondrial dysfunction (lack of oxidative p and ATP generation) even after resolution of the original injury
2. profound disturbances in membrane function

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a transcription factor and a protective respone to hypoxic stress; promomtes new blood vessel formation; stimulates cell survival pathways; enhances anaerobic glycolysis

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hypoxia-inducible factor-1 (HIF)

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3 clinical examples of cell injury and necrosis

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1. ischemic and hypoxic injury
2. ischemia-reperfusion injury
3. chemical /toxic injury

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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

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ischemia-reperfusion injury

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3 possible causes of ischemia-reperfusion injury

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1. increased generation of RO and N species during reoxygenation
2. ischemic injury is associated with inflammation as a result of the produciton of cytokines and increased expression of adhesion molecules by hypoxic parenchymal and endothelial cells
3. activaiton of the complement system may contribute to ischemia-reperfusion injury (IgM has a promenisty to deposit in ischemic tissues)

Front 88

direct injury by combining with critical molecular components; conversion to reactive toxic metabolites, usually by P-450 MFO

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chemical/toxic injury

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a 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

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apoptosis

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membrane-bound fragments which contain portions of the cytoplasm and nucleus

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apoptotic bodies

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common causes of DNA damage

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drugs, radiation, oxidative stress, mutations, misfolded proteins, etc.

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DNA damage too severe to be repaired >_______

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apoptosis

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characteristics of irreversibility

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1. inability to reverse mitochondrial dysfunction (lack of oxidative p and ATP generation) even after resolution of the original injury
2. profound disturbances in membrane function

Front 94

a transcription factor and a protective respone to hypoxic stress; promomtes new blood vessel formation; stimulates cell survival pathways; enhances anaerobic glycolysis

Back 94

hypoxia-inducible factor-1 (HIF)

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3 clinical examples of cell injury and necrosis

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1. ischemic and hypoxic injury
2. ischemia-reperfusion injury
3. chemical /toxic injury

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the dead cell and its fragments are rapidly ________, before the contents have leaked out, and therefore no _________ reaction in the host

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phagocytosed; inflammatory

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______ induced by some pathologic stimuli may progress to _______

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apoptosis; necrosis

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does not promote cell proliferation, but inhibits cell death; apoptosis participant

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B-cell lymphoma 2 gene(BCL-2)

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the amino acid sequence LXXGD, in which X represents any amino acid; conserved between most core BCL-2 family members and among ____ proteins; apoptosis participant

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BH3 motif

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a protein-interaction module that consists of 6 alpha-helices and that is involved in apoptosis and other signaling pathways; apopotosis participant

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death domain

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the process by which the outer membrane of mitochondria leaks certain soluble intermembrane space proteins, such as cytochrome c, into cytoplasm; apoptosis participant

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mitochonidrial outer membrane permeabilization (MOMP)

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the caspase-9 activation complex that is composed of APAF1 (apoptotic protease activating factor 1) heptamers and that is assembled on binding APAF1 monomers to cytochrome c; apoptoisis participants

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apoptosome

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one of a family of proteins that inhibits apoptosis by binding or degrading caspases; apoptosis participant

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inhibitor of apoptosis protein (IAP)

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5 causes of apoptosis in physiologic situations

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1. programmed destruction of cells during embryogenesis
2. involution of hormone-dependent tissues upon hormone withdrawal
3. cell loss in proliferating cell populations
4. elimination of potentially harmful self-reactive lymphocytes
5. death of host cells that have served their useful purpose

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4 causes of apoptosis in pathologic situations

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1. DNA damage
2. accumulation of misfolded proteins
3. cell death in certain infections
4. pathologic atrophy in parenchymal organs after duct obstruction

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4 morphologic changes in apoptosis

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1. cell shrinkage
2. chromatin condensation
3. formation of cytoplasmic blebs and apoptotic bodies
4. phagocytosis of apoptotic cells or bodies, usually mOs

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3 biochemical features of apoptosis

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1. activation of caspases (cysteine proteases)
2. DNA and protein breakdown
3. membrane alterations and recognition by phagoctyes

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3 mechanisms or phases of apoptosis

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1. initiation phase (intrinsic and extrinsic pathways)
2. execution phase
3. removal of dead cells

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major mechanism of apoptosis in all mammalian cells; mitochondrial cytochrome c and other pro-apoptotic proteins released into the cytoplasm initiates the suicidal program of apoptosis; the release of these mitochondrial proteins is contolled by a balance between pro- and anti-apoptotic members of the Bcl family of proteins; GFs and other survival signals stimulate produciton of anti-apoptotic proteins

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intrinsic (mitochondrial) pathway of apoptosis

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BCL-2 family proteins

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apoptosis inhibitors

Front 111

pathway is initiated by engagement of plasma membrane death receptors (DRs) on a variety of cells; DRs are TNFR family that contain a cytoplasmic domain involved in protein-protein interactions that is called death domain because it is essential for delivering apoptotic signals; best known DRs are the TNFR1 and a related protein called Fas

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extrinsic pathway of apoptosis

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following activatoin of the intitiator caspase-9 by the mitochondrial pathway and the initiators caspase-8 and -10 by the DR pathway, the enzymatic death program is set in motion by rapid and sequential activation of the executioner caspases

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execution phase of apoptosis

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______ is flipped out on the outer layer of the plasma membrane in apoptotic cells, where it is recognized by mOs

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phosphatidylserine

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the _______ of apoptotic cells is so efficient that dead cells disappear within minutes without a trace and inflammation

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phagocytosis

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process by which a cell eats its own contents;

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autophagy

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a survival mechanism in time of nutrient deprivation-the starved cell lives by cannibalizing itself and recycling the digested contents

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autophagy

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I/C organelles and portions of cytosol-first subsequently fusses with lysosomes to form an autophagolysosome

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autophagy

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triggers cell death distince from necrosis and apoptosis

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autophagy

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probable mechanism of cell loss in some degerative diseases of nervous system and muscle

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autophagy