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134 terms

Pathology E2

Definitions and concepts covered on the 2nd exam
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Post mortem autolysis
Refers to the autolysis of cells occurring after somatic death; total diffuse hypoxia; varies greatly in onset and rate; PM change includes: autolysis and putrefaction
Somatic death
death of the entire body---essentially heart stoppage
Rigor mortis
contraction of muscles after death; average onset is 2-4 hrs; ATP is depleted; irreversible except by autolysis; may not occur efficiently if animal is wasted
Algor mortis
gradual cooling of the body after death; dependent on the temperature of the body at death (wool, insulation, ambient temp, ruminal gas, outside temps, hyperthermia, other factors)
Livor mortis
hypostatic congestion; gravitational pooling of blood to the side that is down after death; separation of serum from cells begins within one hour after death; blood clots within minutes
Post mortem clotting
within 1 hr after death; separation of cells from clot may give a chicken fat appearance; unattached to the BV walls distinguishing them from thrombi
Clots vs. Thrombus
Clots: coagulation after death
Thrombus: coagulation prior to death
Hemoglobin imbibition
red staining of tissue due to leaching of Hg from autolyzed RBCs and BV after death
Bile imbibition
staining of tissues with bile due to leaching from the bile ducts and GB after death
Pseudomelanosis
blue-green discoloration of tissue caused by the formation of FeS by bacteria (formed by the Fe released by Hg and H2S) *black to dark brown
Softening
results from autolysis of cells and CT; aided by putrefactive bacteria (proteolytic breakdown by anaerobic bacteria)
Bloating
post mortem bacterial gas formation in the lumen of the GIT; can be difficult to distinguish between post-and-antemortem bloat; feed in rumen at time of death = postmortem bloating
Diagnose: displacing of blood, and shoving it towards the shoulders leaving the Superficial cervical LN full of blood due gaseous distention of GIT
Pale foci
in different organs (kidney, liver) can be due to pressure from the distended viscera expressing blood from the vessels; also by bacterial putrefaction of tissue
Mucosal sloughing
occurs in many tissues, but usually rapidly in the GIT; sloughing of enterocytes from the tips of villi within minutes after death
Lens opacity
frozen or cold carcasses; reverse to normal transparency on warming; often confused with cataracts; change in aqueous humor
PM of Intestinal Mucosa
Sloughing of enterocytes into lumen, dense chromatin (part of necrosis), pyknotic nuclei (very condensed); variability of bowl features possible and likely--may be portions of severe necrosis, and some where cells are still intact
Autolysis
self digestion or degradation of cells and tissues by the hydrolytic enzymes normally present within those tissues; occurs in all cells/tissues that die (and even before they die); can occur before or after death
Causes of Cell Injury
Extrinsic: trauma, thermal, electrical energy, ionizing radiation, infx agents, toxins

Intrinsic: spontaneous genetic mutations, by-products of metabolism (ROI), and hypoxia

Extrinsic and Intrinsic: workload imbalance, nutritional abnormalities, immunologic dysfunction
Cell and Biochemical Sites of Damage in Cell Injury
Decreased ATP: multiple downstream effects
Mitochondrial damage: leakage of proapoptotic proteins
Entry of Ca2+: increased mitochondrial permeability, activation of multiple cellular enzymes
Increased ROS: damage to lipids, proteins, DNA
Membrane damage: PM = loss of cellular components and Lysosomal mem = enzymatic digestion of cellular components
Protein misfolding/DNA damage: activation of proapoptotic proteins
Type of Responses to Injury
dependent on many factors: type of agent, extent of injury, duration of injury, and cell type affected
Maintaining homeostasis
cells respond to stressors in a variety of ways to maintain homeostasis; injury takes place when a cell can no longer maintain a steady state; can be reversible until it reaches limits to which irreversible change and death occur
Respond: 1)adaptation 2)degeneration 3)death
Ischemia
loss of 02 due to inadequate blood flow; most common cause of cell death
Degeneration
NOT necrosis! It is present in reversible situations of cell injury, but at some point may become irreversible
Reversible cell injury
injury from which the cell can adapt or recover and thus return to a normal or almost normal function
Irreversible cell injury
dead cell; the cut between reversible and irreversible is not always clear cut but some cytomorphologic changes include:
-PM damage
-Ca entry into cell
-Mitochondrial swelling/vacuolization
-Amorphous densities (likely Ca) in the mitochondria (impending doom for cell)
-lysosomal swelling
Acute cell swelling
Sequence of events:
1. hypoxia
2. decrease in ox. phos and ATP
3. increased glycolysis, increased IC lactate, and depletion of glycogen stores
4. failure of Na/K pump (no ATP)
5. Net influx of Na, Ca, and H20 (loss of IC K and Mg)
6. swelling of mitochondria and cytocavitary network (RER, SER, etc)
7. detachment of ribosomes, clumping of nuclear chromatin, loss of microvilli, vesiculation of ER, formation of membrane whorls (myelin figures)
8. severe disruption of CM, influx of Ca into mitochondria and cytosol, overall cell enlargement, and clearing of cytosol
9. Irreversible cell injury, necrosis
Hypoxia
partial reduction in the 02 concentration supplied to cells or tissue; common cause of cell death
Anoxia
complete loss of 02 supplied to cells or tissue
Causes of 02 deficiency
-heart failure
-respiratory failure
-ischemia
-anemia
-CO toxicity (reduced transport of 02)
-HCN toxicosis (blockage of cell resp. enzymes)
*Cells of increased susceptibility due to high energy demands: neurons, cardiac monocytes, hepatocytes, renal tubules
Physical agents: extrinsic factors of cell death
trauma-direct cell rupture and death of large numbers of cells, or damage to BV

thermal-ice crystalization(impairs blood flow and ruptures CM), CM damage, denaturation of enzymes and structural proteins, increased rate of enzymatic rxns with accum. of metabolic end products and pH changes

electrical-heat generation, ionic changes, altered conduction of nerves and muscles

ionizing radiation-ionization of cellular water with prod. of highly ROI injuring cell comp, DNA damage
Viral effects on cell changes
viruses are obligate IC parasites that redirect host cell enzymes toward synthesis of viral proteins and genetic materials to the detriment of host cells; vary from little effect to cell death or neoplastic transformation
Bacterial effects on cell changes
Bacteria are EC, facultative, or obligate IC who can be either opportunistic or the primary pathogen. Cell changes/injury also vary but can be the result of potent toxins or overwhelming/ineffective inflammatory response to bacteria
Fungal effects on cell changes
EC or IC, eukaryotic but not protists that resist destruction by the body that can lead to progressive, chronic inflammatory disease with the loss of normal host tissues; protozoal agents replicate in specific host cells resulting in destruction of infected cells; metazoal parasites cause inflammation, distort tissue, and use host nutrients
Protozoa
single-cell, eukaryotes w/o cell walls; protists non-fungi pathogens; Ic or EC; similar to other infx agents: cause host cell inflammation, death; coccidia are one example
Algae
protists, uni/multicellular, phototropic and contain cell walls; some may infect animals and cause disease
Helminthic parasites
nematodes (roundworms), cestodes (tapeworms), and trematodes (flukes); diverse life cycles; metazoans; cause nutritional deficiencies, tissue destruction, inflammation, create opportunities for secondary infection with other agents
Protein-Calorie Deficiencies
known as kwashiorkor in humans; caloric deficiency forces glycogenolysis, lipolysis, and proteolysis to meet energy demands; sporadically seen ; require metabolic adaptation by a large population of cells
Caloric and other nutrient excesses
result of obesity; excess fat soluble vit = toxicity; mineral imbalances (Ca and P); implicative of cardio disease and others
Genetic Derangment diseases
-Enzyme deficiencies(clotting factor, lysosomal storage disease, maldigestion)
-Neoplasia
-immunodeficiencies
-anatomical defects (poor collagen synthesis)
-physiological (hormone def/excess)
-many others
Hormone imbalance or workload
overworked cells may adapt or become exhausted and die; cells that are no longer stimulated atrophy and ultimately disappear
Chemicals, Drugs, and Toxins
can influence cells by a multitude of mechanisms
-modify function and morphology of specific cells
-most drugs cause cells to adapt within a tolerable range of homeostasis
-block or stimulate CM receptors
-alter specific enzymes
-produce toxic free radicals
-alter cell permeability
-damage chromosomes
-modify metabolic pathways
-damage structural components of cells
Immunocompromised
having the immune system attenuated; from immunisuppressive drugs, irradiation, malnutrition, or disease process
Immunodeficiency
deficiency of immune response or a disorder characterized by a deficient immune response; classified as inherited or acquired disorders in which some aspect of the host defense are absent or functionally defective
Immunosuppression
prevention or dimunition of the immune response, by irradiation or by administration of anti-metabolites, anti-lymphocyte serum, or specifc Ab (immunosuppressive drugs-treatment of graft rejection and autoimmune disease)
Autoimmune disease
body directs its adaptive immune response against its own tissues
Hypersensitivities
immune responses to innocuous Ags that lead to symptomatic reactions upon re-exposure
Aging
involves a collection of different processes and events; altered control of cell growth; many processes lead back to the accum. of damage to DNA; slowed metabolic processes; lifetime damage to DNA or accumulation of cellular debris interfering with normal cell functions
Hydropic degeneration
cell swelling; increased cell size and volume due to overload of water in the cell; occurs due to loss of cell homeostasis
Mechanisms:
-damage to CM
-failure of cellular energy production
-injury to enzymes regulating ion channels of membranes
Process of Cell Swelling
1. Injury
2. hypoxia-induced failure of ATP formation or CM damage
3. decreased ATP
4. Na and water into cell, K out of cell
5. Increased osmotic pressure
6. Moves water into cell
7. Cisternae of ER rupture forming vacuoles
8. Extensive vacuolization
9.Hydropic degeneration
CCL4 Toxicity
can induce fatty change and cell necrosis by lipid peroxidation; direct damage to membranes by radicals; disrupts double bonds in FA and inserts 02 (peroxidation); radicals have unpaired electros that are highly reactive and pull H2 off of other compounds creating more radicals
-OH radical
Most toxic radical
CCL4 toxicity leading to fatty liver
CCL4->SER->CCL3- =>lipid radicals-> 02->lipid peroxidation-> membrane damage to RER->polysome detachment-> decreased apoprotein synthesis->fatty liver
CCL4 toxicity leading to Inactivation of Mitochondria, Cell Enzymes, and Denaturation of Proteins
CCL4->SER->CCL3-=>lipid radicals-> 02-> Lipid peroxidation->release of products of lipid peroxidation->damage to PM->decreased permeability to Na+, H20, Ca2+->Cell swelling->massive influx of Ca2+-> inactivation of mitochindria, cell enzymes, and denaturation of proteins
Hydropic degeneration
microscopic appearance of acute cell swelling; it occurs in endothelium, epithelium, alveolar pneumocytes, hepatocytes, renal tubular epithelial cells, neurons, and glial cells of the brain
Ballooning degeneration
severe hydropic degeneration; cells become very large due to swelling, and may rupture. Some may even include viral inclusion bodies; cytoplasm = clear space; typically seen in epidermal cells infected by epitheliotropic viruses (poxviruses) progressing to blisters
Significance and Fate of Acute Cell Swelling
- loss of function
- necrosis
- secondary lesions may develop from swollen cells casuing obstructions or thrombosis/ischemic necrosis of tissue
- reversion of the cell back to a normal state may occur if the injurious state is corrected before the damage becomes irreversible
Reversible cell injury
characterized by: generalized swelling of the cell and its organelles, blebbing of the PM, detachment of ribosomes from the ER, and clumping of nuclear chromatin
Irreversible cell injury
characterized by: increasing swelling of the cell, swelling and disruption of lysosomes, presence of large amorphous densities in swollen mitochondria, disruption of cellular membranes, and profound nuclear changes
Pyknosis
nuclear condensation; shrunken, dark, homogenous, and round due to chromatin clumping
karyorrhexis
fragmentation of nucleus; NE ruptures, dark nuclear fragments are released into cytoplasm
Karyolysis
dissolution of the nucleus; nucleus is extremely pale or absent due to the dissolution of chromatin by RNAses and DNAses
Laminated (myelin) figures
derived from damaged membranes of organelles and the PM; first appear during the reversible stage and become more pronounced in irreversibly damaged cells
Necrosis or Oncotic necrosis or oncosis
death of cells in the LIVING animal following irreversible cell injury that initially results in cellular swelling; lack or loss of ATP; causes inflammation
Apoptosis
death of cells in the LIVING animal that occurs following cellular shrinkage; may be PCD or type 1 cell death; it may also be physiologic or pathologic; energy dependent; does not elicit inflammation; PCD is often used to describe physiologic and apoptosis to pathologic
Postmortem autolysis
death and degradation of cells that occurs after somatic death; no ATP; tissues and cells dying; cell swelling can be difficult to differentiate from necrosis
Sources and Consequences of Increased Cytosolic Calcium in Cell Injury
activates many different enzymatic processes and essentially starts chewing everything up; induces the release of mitochondrial contents; some enzymes activated are: phospholipases, proteases, endonucleases, and ATPases
ROS in Cell Injury
This is a normal process that can cause problems for the cell; 02 free radicals are always forming as a normal phys process; cellular components at risk: proteins, membrane lipids, and nucleic acids
Major antioxidant enzymes
superoxide dismutase, catalase, and glutathione peroxidase (Vit E is a precursor for glutathione peroxidase)
Fenton (Haber-Weiss) Reaction
normal reaction where Fe2+ is oxidized by H202 to Fe3+ => OH radical and OH anion; it is then reduced back to Fe2+, a OOH radical, and a proton by the same H202
Cytochrome P450 enzymes
primarily located in the SER of hepatocytes, but may be found in other cells also.
-main role: metabolize lipid-soluble chemicals into water soluble compounds for excretion from their body in bile or urine; occurs in 3 phases; require a wavelength of 450 and have red pigmentation => why they are called P450 enzymes
3 phases of lipid metabolism by Cyt P450
Phase 1: biotransformation: chemicals are bioactivated to a high energy reactive intermediate molecule (involve oxidation, reduction, and hydrolysis); enzymes: centrolobular region of liver; require 02 and NADPH (how liver detoxifies drugs)

Phase 2: involves formation of covalent bonds with polar molecules (glucuronic acid); forms water soluble metabolite that can be excreted

Phase 3: transport of molecules across the cell membrane into the lumen of the canniculus by molecular pumps

*These functions in the centrolobular area make it more susceptible to toxic damage b/c it contains the most P450, and it also has less 02
Malondialdehyde
reactive aldehyde and forms covalent protein adducts; referred to as advanced lipoxidation end products; also reacts with deoxyadenosine and deoxyguanosine forming mutagenic DNA adducts
Cytoplasmic changes in cellular necrosis
- increased acidophilia due to loss of rRNA
- increased paleness, due to preceding water loading, and loss of proteins
- detachment of cells from the BM and neighboring cells
- shrinkage of cells after they have ruptured and lose their contents (may give a darker staining intensity)
- fragmentation and loss of structure once the cell has ruptured
Coagulative necrosis
1st type of oncotic necrosis: preservation of the basic cell outlines of necrotic cells, cytoplasm homogenous and eosinophilic due to coagulation of proteins, nuclei are pyknotic, karyorrhetic, karyolytic or absent; due to reduced blood flow usually infection in cattle (thrombi from g- bacterial infection)
Infarct vs. Infarction
Infarct: necrotic lesion caused by ischemia
Infarction: process by which an infarct occurs
*Infarcts are typically manifested by coagulative necrosis of affected tissues (kidney, liver, heart, skeletal muscle)
*Those in the brain and SC = liquefactive necrosis
Caseous necrosis
2 type of oncotic necrosis: continual breakdown of necrotic cells into granular fragments (grossly resembles cottage cheese); occur in any tissue and most of the debris is dead leukocytes; older lesion; found within sites of granulomas or chronic inflammation---(Mycobacterium TB); frequently calcified (dystrophic calcification) called tubercles because macrophages cannot breakdown/kill bacteria
Liquefactive necrosis
3rd type of oncotic necrosis: conversion of the necrotic tissue into liquid that varies from clear to cloudy to opaque; occurs in brain due to small % of CT and high lipid content (dissolution of neutropil); other tissues seen as purulent (suppurative) inflammation with neutrophiles having infiltrated the causing formation of pus (necrotic tissue + neutrophils); contain macrophages called "gitter cells"
Gangrenous necrosis
initially characterized by coagulative necrosis then complication by saprophytic bacterial infection(bacteria that live in dead, organic matter) and subsequently suppuration and putrefaction (decomposition of organic matter by these microbes); clinically referred to as gangrene
Gangrene
clinical condition characterized by lesions of gangrenous necrosis; 3 types: moist, dry, and gas gangrene
Moist gangrene
an area of necrotic tissue (usually coagulation necrosis) which is further degraded by the liquefactive action of saprophytic bacteria that usually cause putrefaction; grossly tissues become soft, moist, and reddish-brown to black; if saprophytic produce gas with putrid odor (Moist and nutrient rich environment = happy bacteria)
Dry gangrene
is coagulative necrosis secondary to infarction followed by mummification (lower portions of extremities--terminal blood supply); usually due to ingested toxins--ergot and fescue cause vasoconstriction leading to thrombosis and infarction or cold---direct freezing and disruption of cells by IC and EC ice crystal formation and vascular damage; mummification due tot loss of water from dead tissue b/c of lack of blood supply
Gas Gangrene
coagulative necrosis with other changes, particularly by gas build up from bacterial fermentation in the necrotic tissue; caused by toxigenic promary pathogen (Clostridium spp.); usually induced by wound; thoroughbred mare case
Fat necrosis
3 types:
enzymatic: pancreatic necrosis of fat; most important (dogs primarily); activation of pancreatic lipases that have escaped the duct system of the pancreas

traumatic: trauma involved; thermal injury (heating pad case); adipose tissue is crushed (subcutaneous tissues and fat adjacent to pelvic canal in dystoic heifers)

necrosis of abdominal fat in cattle: cause unknown

*All appear grossly as white, chalky lesions; histologically see basophilic fluid representing saponification (Na, Ca, and K salts of FA)
Sequestrum
any fragment of necrotic material, especially bone, that resists degradation; may cause irritation and delay repair
Healing of an abcess
occurs after sequestered pus is phagocytosed and/or carried off by lymphatics; greatly hastened by drainage (rupture to outside or surgical drainage)
Purpose of inflammation of necrotic tissue
to allow digestion by heterolytic enzymes of WBCs and liquefaction of necrotic tissue so that it can be removed by macrophages to promote regeneration of normal tissue
Hyperemia
dilated blood vessels engorged with blood
Autophagy
degradation of cytoplasmic proteins and organelles by their enclosure in double membrane bound cytoplasmic vesicles that fuse with lysosomes (in living animal); considered alternative form of PCD or type 2 cell death that does not require caspases and characterized by lysosome accumulation
Toroids
chromatin in nuclei of cells undergoing apoptosis often is condensed into a pattern that resembles a torus (ring-shape); chromatin condensation in apoptotic cells may also be crescent-shaped (crescentic caps)
Histopathologic characteristics of apopotosis
-individual cells are shrunken
-chromatin is condensed
-cytoplasm is fragmented
-cytoplasmic buds often contain a fragment of nucleus from on the surface, separate, and are phagocytosed by adjacent cells as apoptotic bodies
-inflammation is absent
Some Cell Uses for Apoptosis
- normal embryonic/fetal development
- normal tissue makeover
- metamorphosis
-atrophy: pancreatic duct obstruction
- Hormone-independent atrophy: endometrium cyclic proliferation and deletion in females
- GF-dependent survival
Mechanisms of Apoptosis
Major inducers of apoptosis: withdrawal of GFs/hormones, receptor-ligand interactions (Fas, TNF), CTLs, Injury (radiation, toxins, free radicals)

Control and Regulation: Bcl-2 family

Executioner caspases-> endonuclease activation, breakdown of cytoskeleton

Apoptotic body formation
Phosphatidlyserine
one of the signals recognized by phagocytes (normally it is expressed on the inner leaflet of the PM, but for apoptosis it is flipped and expressed on the outer leaflet)---an "Eat Me" signal for the cell to be phagocytosed
Ced-3
an important executioner caspase leading to PCD
Caspases
member of a family of proteases that can bring about PCD; enzymes that have cysteine residues and cleave after aspartate ; nuclear lamins are one target of caspases

Other targets: ICAD (inhibitor of DNAse), cytoskeletal proteins, golgi matrix proteins
Caspase activation
Caspase-9 is activated as a complex with Apaf-1 and cyt C in the apoptosome -> activated Caspase-9 cleaves caspase-3 causing its activation->effector caspase->apoptosis
Bcl-2 family
a member of a family of proteins that regulate PCD; closely related to Ced-9 in C. elegans that activates Ced-3 for PCD
Antiapoptotic: Bcl-2
Pro-apoptotic: Bax and Bak
Pro-apoptotic BH3-only: Bid, Bad, Noxa, Puma, Bim
Mitochondrial pathway of apoptosis
Death signal->Bak, Bax form oligomers in the outer membrane of the mitochondria->cyt c from intermembrane space->formation of apoptosome containing Apaf-1 and caspase-9->caspase-9 activated further activating other caspases (caspase-3) by proteolytic cleavage->apoptosis
Regulation of caspases by IAPs in Drosophilia
IAPs inhibit both effector and iniator caspases; inhibits apoptosis by interacting with caspases
p53 Role in DNA Damage-Induced Apoptosis
DNA damage leads to activation of ATM and CHK2 protein kinases->CHK2 and activated ATM phosphorylate and stabilize p53->results in increased IC levels of p53->p53 induces cell cycle arrest and allows for an attempt to repair damaged DNA

*Important for preventing the formation of mutations and cancer
*Inhibits p21 halting Cdk1/cyclin and CDK2/cyclin in the cell cycle (arrests in G1)
*targets PUMA and NOXA for PCD
PI 3-Kinase Pathway and Cell Survival
promotes cell survival by keeping apoptosis from occurring; AKT-kinase activated also by mTOR can trigger cell survival; requires growth factors that signal cell survival and activate tyrosine kinases leading to the activation of PI-3->PIP3->protein kinase AKT->phosphorylates a number of proteins that lead to cell survival
mTOR pathway
central regulator of cell growth that couples the control of protein synthesis to the availability of GFs, nutrients, and energy
Cell death receptors
Extrinsic death cell receptors: TNF and other receptors consist of 3 polypeptide chains so their binding to cell death receptors induces receptor trimerization; recruiting caspase 8 by adaptor molecules; activation of caspase 8 cleaves/activates effector caspases->BID->caspase 9->effector capases->apoptosis
(Fas ligand is another example)
Intrinsic mitochrondrial pathway of apoptosis
survival signal->production of antiapoptotic proteins (Bcl2)->no leakage of Cyt C from mitochondria->no cell death
*if there is a lack of survival signals or DNA damage due to irradiation (etc) sensors activate BH3 only proteins->antagonism of Bcl2->Bak/Bax->cyt c leakage->activation of caspases
PARP
Poly-ADP ribose polymerase found in the cells nucleus whose main role is to detect any single stranded DNA breaks to the enzymatic machinery in SSB repair; if SSB is detected PARP synthesizes PAR which signals DNA repairing enzymes

*With DNA cleavage by caspases, PARP can deplete cellular ATP and lead to cell necrosis
*PARP can also induce apoptosis via PAR which stimulates AIF
Tunel assay
detecting DNA strand breaks in the tissue; light microscope level a tunel assay is used to detect apoptosis (allows for quantification of apoptosis in cells)
Autophagy and Integrated Stress Response
autophagy is a response of the cell to stress, and many of the same stressors that trigger apoptosis also trigger autophagy
(Stimulated by multiple forms of cell stress: nutrient or GF factor deprivation, hypoxia, ROS, DNA damage, protein aggregates, damaged organelles, or IC pathogens)
Autophagy & Metabolic Stress
generates free aa and fa that can be recycled in a cell-autonomous fashion or delivered systemically to distant sites within the organism (de novo synthesis of proteins are essential for stress adaptation)
Autophagy as Housekeeper
-eliminates defective proteins and organelles
-prevention of abnormal protein aggregate accumulation
-removal of IC pathogens
-can degrade entire organelles and pathogens: unique function separating it from the ubiquitin-proteosome system
*Critical for autophagy-mediated protection against cancer, aging, neurodegenerative diseases, and infection
Autophagy-Guardian of the Genome
can limit DNA damage and chromosomal instability
*Deficient autophagy: failure of checkpoints, repair proteins, insufficient energy for proper DNA replication and repair, deregulated turnover of centrosomes, excess ROS, etc
Autophagy and Neurodegenerative Disease
clearance of aggregate-prone mutant proteins associated with several different neurodegenerative diseases
*similar roles in muscle disease
Autophagy and Cancer
regulation of autophagy overlaps closely with signaling pathways that regulate tumorigenesis
-AKT and PI3 inhibit autophagy (Tor pathways)
-p53 is the most common tumor suppressor gene positively regulating DNA damaged cells
Autophagy and Aging
dietary restriction (intermittent fasting) is a potent inducer of autophagy and increased lifespan in all species
-IGF-1 pathway: fasting decreases insulin and IGF-1 synthesis which increases autophagy through a reduction in Akt pathway
Heterophagy vs. Autophagy
Heterophagy: source of phagocytosed material is external to the cell (neutrophils, macrophages, and other cells participating in uptake of cell debris)
Autophagy: sources of phagocytosed material is internal to the cell (remove non-functional organelle)
Autophagic vacuoles (autophagosomes)
appearance in the light microscope: eosinophilic inclusions (liver and kidney)
-residual bodies with lipofuscin (golden-brown pigment associated with aging in heart and neurons)
-lamellar debris (myelin figures)
-accumulates: products of ubiquitin-proteosome pathway, misfolded proteins, lipoprotein membranes
Hypertrophy
increase in size of cells or organs (can be due to an increase in number and/or size of organelles)
Hyperplasia
increase in number of cells of a tissue or organ
Atrophy
decrease in size or amount of cell, tissue, or organ AFTER normal growth has been reached
Metaplasia
potentially reversible change in which one adult cell is replaced by another adult cell of the same germ line (ciliated columnar epithelium->stratified squamous epithelium)
Dysplasia
disorderly arrangement of cells within epithelium
Neoplasm
a new growth composed of cells, originally derived from normal tissues, that have undergone heritable genetic changes allowing them to become relatively unresponsive to normal growth controls and to expand beyond their normal anatomic boundaries
*Hyperplasia, hypertrophy, Metaplasia, and dysplasia can be predispositions to neoplasia, but only Meta and Dysplasia can persist in neoplastic tissue
Simple cellular hypertrophy
number of cells DOES NOT increase
-can synthesize more organelles, larger organelles or both
-more prominent in cells that undergo little replication (stable or permanent cells)
Physiologic vs Compensatory hypertrophy
Physiologic: occurs as a result of a physio process (increased work load)
Compensatory: occurs b/c compensation is needed (opposite kidney when one is removed)
Hyperplasia
increase in the number of cells; increased mitotic division is implied; increases the size of tissues and organs; hyperplastic cells themselves can be hypertrophic but is not a requirement
Hyperplastic Cell Types
Only some can be hyperplastic; labile and stable cells (either proliferate normally or can be stimulated to proliferate)
Permanent cells cannot undergo hyperplasia unless you are a neonate, a frog, fish, or bird (these have regenerative capabilities in their cardiac myocytes)
2 types of hyperplasia
Physiologic: hormonal (mammary gland epithelium before lactation) or compensatory (epidermal response to skin abrasion)
Pathologic: hormonal or in response to chronic irritation
*Some physiological processes can progress into pathologic processes (goiter)
Causes of Metaplasia
-chronic irritation from particles and chemicals inhaled into the respiratory tract
-vitamin A deficiency
-Ammonia toxicity in chicken bronchi
-E2 toxicity: urinary and prostatic epithelium
-healing of mammary gland epithelium following mastitis
-blockage of ducts in salivary gland, biliary tract, and pancreas
-conversion of soft tissue to bone following injury (osseous metaplasia--very common)
-extramedullary hematopoiesis in spleens and livers following bone marrow injury or insufficiency (myeloid metaplasia--very common)
-formation of cartilage or bone in mammary gland tumors of dogs (chrondroid or osseous metaplasia)
Hypoplasia
failure of organs or tissues to obtain full size DURING development
Aplasia
a complete failure of an organ to develop
Involution
decrease in size of a tissue caused by reduction in the number of cells, usually by apoptosis (or PCD) and usually refers to physiological processes
-thymus and bursa involute with age
-uterine involution following parturition
Causes of Atrophy
-deficient nutritive supply
-decreased workload
-disuse
-pressure
-loss of endocrine stimulation
-senility
Serous atrophy
important necropsy finding that indicates starvation; grossly fat deposits are completely or partially depleted and a clear or yellowish gelatinous material remains; most common in epidural and perineal fat but may affect fat depot in bone marrow; common in neonates
3 main substances that accumulate in cells
1. normal cellular constituent: water, lipids, proteins, and CHOs in excess
2. Abnormal substance: either exogenous, such as a mineral or product of infx agents, or endogenous such as a product of normal synthesis or metabolism
3. Pigment accumulates
5 mechanisms leading to Fatty liver
1. Excessive delivery of free FA either to the gut or adipose tissue
2. Decreased B-oxidation of FA to ketones and other substances because of mitochondrial injury (toxins, hypoxia)
3. Impaired synthesis of apoprotein (CCL2 toxicity)
4. Impaired combination of TGs and proteins to form lipoprotein
5. Impaired release of lipoproteins from the hepatocyte