pathology intro Flashcards
Acute vs. chronic inflammation
acute- short duration; exudation of fluid and plasma proteins predominantly neutrophil.
chronic - longer duration - vascular proliferation and scaring/fibrosis - predominantly macrophage and lymphocyte
adaptive immunity cells
lymphocytes and their products:
Humoral immunity - B lymphocytes
cellular immunity - T lymphocytes
Adhesion pairs
Endothelial V-CAM 1 // VLA 4 (integrin) leukocytes
Endothilia I CAM 1 // CD11/CD18 (LFA-1, Mac-1) leukocytes
Apoptosis decision
a balance between the withdrawal of positive signal and the receipt of negative signal
apoptosis is needed for:
- optimal development (tadpole metamorphosis)
- removal of excess cells during embryogenesis (fingers and toe digitation)
- maintain cells with high turnovers
- eliminates autoreactive immune T cells in the thymus
- eliminates damaged cell
- central to hormone depended involution (endometrium, ovary, breast)
- cell death in tumors
atrophy
decrease in organ size WITHOUT the loss of cell number (loss of cell substance)
atrophy is the adaptive response to what? is it reversible?
stress; yes (regain in size when remove stress)
autoreactive clones could result in what conditions?
hemolytic anemia, thrombocytopenia
Ca gradient is maintained by what?
the membrane associated, energy-dependent Ca, Mg, ATPase
cytoplasmic changes in necrosis
denaturation of cytoplasmic proteins tends to be acidophilic, granular mass and have affinity for acid dyes (eosinophilia)
damage results in high conductance channels called?
MPT - mitochondrial permeability transition where cytochrome c and H+ leak out of mitochondria
define cellular aging
progressive decline in the proliferative capacity and lifespan of cells and the effect of continuous exposure to exogenous influences that result in progressive accumulation of cellular and molecular damage
definition of apoptosis
the elimination of unwanted cells by an internally programmed series of events
modulated by dedicated gene products
Diabetes is an acquired or inherited diseases with defects in leukocyte function
acquired: defects in adhesion, chemotaxis, multiple defects
Dysplasia
changes in size, shape, and organization of the cells
most commonly in hyperplastic squamous epithelium and preneoplastic
Dystrophic
deposition of calcium and other minerals in DEAD tissues
edema
excessive accumulation of fluid in tissue or part
elements of wound contraction
12-24 hrs: inflammation and reepithelization (neutrophil, platelets)
3-7 days: angiogenesis, fibroplasia, wound contraction-granulation tissue (neutrophil, macrophage, fibroblast, wound matrix, blood vessel
1-2 wks: tissue remodeling: keratinocyte close off blood clot, complete coverage of granulation tissue, myofibroblasts, wound matrix and blood vessel
endothelial CD-34 pairs with
L-selectin of leukocyte
endothelial E-selectin
Lectin (sialyl-lewis X) of leukocyte
endothelial P selectin pairs with
Lectin (sialyl-lewis X) of leukocyte
example of cellular aging
sequential shortening of telomeres
examples of dystrophic
atheromas
old tuberculosis lesions
examples of endogenous intracellular acuumulations
products of abnormal synthesis and metabolism including lipofuschin, hemosiderin, biliruben
examples of metaplasia
smoking: ciliated columnar to straified squamous
chronic gastric reflux: squamous to columnar
cancer transformation
Extrinsic (Death Receptor initiated) pathway of apoptosis
- Fas ligand binds onto Fas Receptor cause dimerization of death domain
- induction of FADD (Fas associated deadth domain
- Procaspase 8 gets activated into Active Caspase 8
- caspase 8 activate excutioner caspase 3 for apoptosis
exudate
a fluid found in extravascular space derived from blood plasma that traverses the endothelial wall of inflamed small vessels (mostly venules) that is RICH IN PROTEINS AND WHITE BLOOD CELLS.
Free radical is formed from what?
by product of metabolisms reactions P-450 oxidase in ER; NADPH oxidase in plasma membrane; Peroxisome oxidase in cytosol
goal of inflammation
to deliver leukocytes and antibodies to injury site
initial response –> mediators amplify –. vascular response and cellular response
Heterophagy vs. Autophagy
Heterophagy - when a foreign particle is taken into a cell (phagocytosis or endocytosis) and the primary lysosome form a phagocytic vacuole and the secondary lysosome dismantle particles and exocytose
Autophagy - when the cell’s own organelles is no longer useful, the primary lysosome fuse to form autophagic vacuole and residual body with lipofuscin pigment granule.
histamine is released when there are?
IgE antibodies binding to receptor peptides: anaphylatoxins cytokines IL -1 IL-8 toxins/drugs: mellintin, codein, morphine physical trauma
How do cells naturally neutralized the free radicals?
Cytosol: SOD, vitamin C, Glutathione peroxidase, ferritin, ceruloplasmin
All membranes: vitamins E and A, B-Carotene
Mitocondria: SOD, Glutathione peroxidase
how does cytochrome c induce apoptosis?
cytochrome c act on procaspase 9 and Apaf-1 dimerize to latch on procaspase 9 activating it into active caspase 9, which activate the executioner caspase 3 for apoptosis
how does HPV16 cause cervical cancer?
HPV16 produces E6 –> binds and inactivates p53 –> prevent apopotosis of bad cells
How does the cell nucleus look like when undergo apoptosis vs. necrosis
Apoptosis: pyknosis (condenses); karyorrhexis (fragmentation); non random DNA breakdown
Necrosis: swelling; karyolysis (dissolution); random
How does the EBV cause monnucleosis, NPC, lymphomas?
EBV produces Bcl-2 –> block and resist apoptosis because caspase activation cannot take place
Hyperemia
greater than usual amount of blood in the microcirculation of a tissue or a part
Hyperplasia
increase in number of cells usually resulting in increased volume of the organ or tissue (may or may not increase in size)
Hypertrophy
increase in the size of cells resulting in an increase in size of the organ
NO NEW CELLS, JUST LARGER CELLS
If no new cells form in hypertrophy, what accounts for the enlargement?
the cells increase its metabolic activity and manufacture more proteins causing larger cells
inflammatory cells and their function in chronic vs. acute inflammation
neutrophil - phagocytosis - acute
eosinophil - modulates mast cells function - acute in allergy; chronic in infection
basophil - binds to IgE - acute (anaphylaxis)
platelets - thrombosi, growth factor - acute
monocyte (macrophages) - phagocytosis - chronic
lymphocyte - humoral immunity (B cells); cell mediated immunity (T cells) - chronic
injury summary of mediators in wound healing processes
epithelialization - KGF, TGFa
angiogenesis - FGF, VEGF, angiogenin
fibroblast migration, proliferation - PDGF
ECM synthesis//granulation of tissue formation//wound contraction - TGF-B
bone development - BMPs (BMP-7, IGF-I)
Remodeling (fibroplasia) –> fibrous scar
innate immunity cells
plasma cells, phagocytic cells, NK cells, lung surfactant proteins
Intrinsic pathway (mitochondrial) pathway of apoptosis
death agonists cause changes in the inner mitochondrial permeability transition (MPT) and release of cytochrome c and other pro-apototic proteins into to the cytosol leading do the activation fo caspase
leukocytes give rise to what cells?
granulocytes –> neutrophils; eosinophils; basophils (mast cells)
monocytes –> macrophages
lymphoctyes –> B-lymphocytes and T-lymphocytes
Major differences btw necrosis and apoptosis
Apoptosis: no inflammation (clean); single cell target, cell shrinkage; small areas affected
Necrosis: inflammation (messy); groups of cells affected; swelling; large tissue area affected
margination and rolling involves what pairs of proteins?
selectins from endothelial cells and silaylated oliogsaccharides from leukocyte
Mechanisms of apoptosis
- intrinsic (mitochondrial) pathway - withdrawal of growth factors, hormones
extrinsic (death receptor-initiated) pathway- receptor ligand interactions (FAS, TNF receptor)
cytotoxic T lymphocytes directly propagates teh process by activate granzyme B - control and regulations by the Bcl-2 family
- executational caspases activate latent cytoplasmic endonucleases/proteases
- cytoplasmic bud to form apoptotic body and ligand for phagocytotic cell receptors
mechanisms of cell injury
- ATP depletion (hypoxia)
- mitochondrial damage
- intracellular influx of Ca++/loss of Ca++ homeostasis
- accumulation of free radicals (oxidative stress)
- defects in membrane permeability
Melonomas inhibit what?
expression of Apaf1 which is needed for activation of procaspase 9 for intrinsic pathway of apoptosis
Metaplasia
conversion of one differentiated cell type to another
metaplasia is most commonly seen in what cell types?
most common in epithelium and less in mesenchymal cells
Metastatic
calcium deposition in NORMAL tissue in HYPERCALCEMIC states
mitochondrial injury is caused by what factors?
inc incytosolic Ca, oxidative stress, lipid peroxidation, and leakage of cytochrom c into the cytosol
monocytes vs macrophages
monocytes within circulation and macrophages are moncytes that have found residents in the tissues
Name 2 immune privileged sites
the EYES and the TESTICLES
name some of the anti inflammatory mediators
IL-1 receptor antagonist
IL-4, IL-10, TGF-B, TIMPs, LXA4
name some proinflammatory mediators
IL-1, IL-6, TNF-a, Interferon (IFN-y), PGE2, MMPs
Name the chemokines in inflammation
IL-8, MCP-1, eotaxin
Necrosis
Gross and histological cell death from irreversible exogenous injury
Always pathologic etiology
morphologic appearance due to denaturation of intracellular protein
Nuclear changes in Necrotic cell death
Pyknosis - condensation of chromatin
Karyorrhexis - fragmentation of cell nucleus (non random in apoptosis, but random in necrosis)
Karyolysis - dissolution of cell nucleus//basophilia of chromatin fades
*normally normal nucle is basophilic (purple/blueish) and the cytoplasm is more pinkish, but in necrosis nuclei tends to be eosiphillic (pinkish)
opsonins
specific: antibodies
nonspecific: C3bi, C5b, collectins, fibronectin
patterns of necrosis: caseous
subset of coagulative specific to tuberculosis lesion in the lung
cheese like
unlike coagulative necrosis, tissue architecture is completely obliterated
patterns of necrosis: coagulative
outlined of dead cell intact, firm tissue
increasing intracellular acidosis - dentatures structural proteins
ex. myocardial infarction, renal infarction (except in brain)
patterns of necrosis: fat necrosis
enzymatic digestion of fat
trauma induced
ex. fat necrosis by pancreatic enzymes
patterns of necrosis: gangrenous necrosis
secondary to ischemia
superimposed infection
not a distinctive pattern of necrosis
ex. distal limb in diabetes mellitus
patterns of necrosis: liquifactive
dead cell disintegrates affected tissue liquifies (brain) digestion greater than denaturation progressive catalysis of cell surface ex. cerebral infarction
platelets
not cells; fragments of megakaryocytes
Reactive oxygen species include
O2-; H2O2; OH-
regeneration and the cell cycle
regeneration has to be activated for labile cells (skin)
regeneration is reduced in permanent cells (neurons, heart)
regeneration is enhanced in stable cells (hepatocytes)
regulators of the cell cylce
cyclin A -cdk2 @ synthesis
cyclin B -cdk1 @ mitosis
cyclin D - cdk4/6; cyclin E -cdk2; RB-P-E2F –> RB-PPP +E2F; CKI:p21/p27/p15 @ G1 phase
Some cancer cells can either produce decoys levels of this protein to competively bind to the receptors of cells mark for apoptosis
FasL - the decoys competitively binds to the dead domain receptors so that the real Fas ligands could not bind and could not initiate extrinsic pathway
some cancer cells produce real fasL to target what cells?
the cytotoxic T cells so that these T cells will die of apoptosis and can not go after the cancer cells.
The cells of the immunopriveged sites express high levels of what at all times?
FasL - so antigens reactive T cells expressing Fas enter these sites are killed
the execution phase of apoptosis, what does the cytoplasm caspases digest?
cytoskeleton
The removal of dead cells by phagocytosis is so efficient and without a trace of inflammation. T/F
True
Transudate
fluid in extravascular space derived from blood plasma that traverses the endothelial wall of normal non-inflamed capillaries and venules, having a LOW CONCENTRATIONS OF PROTEINS AND FEW OR NO CELLS.
Unlike hypertrophy, what has to involve for hyperplasia?
Mitosis - hyperplasia only takes place if the cell is capable of synthesizing DNA, and completion of mitosis (cell cycle and checkpoints)
what accounts for the rapid decline in CD4+ cells?
A few of the CD4+ cells are infected by the HIV virus in which it takes over the genomic marchinary, it begins to elaborate the production of fas Ligand that will come to the other uninfected cells and mark them for apoptosis. The majority of the cells death is not due to infection of the virus, but by the apoptosis mechanisms from the increase production of FasL forcing the healthy cells to die.
What are caspases?
proteases first discovered in Nematodes; the caspase families sites of action include cytoskeleton, nucleus, mitochondria, with intrinsic and extrinsic triggers
what are some examples of hyperplasia?
physiological: -hormonal ex. breast/pregnancy -compensatory ex. liver regeneration pathological: -hormonal ex. endometrial hyperplasia, benign prostatic hyperplasia -wound healing
what are the 2 ways ATP is produced?
oxidative phosphorylation (major) glycolytic pathway (minor)
what are the cardinal signs of acute inflammation?
redness (rubor) swelling (tumor) heat (calor) pain (dolar) loss of function
what are the functions of inflammation
localizes and eliminates injury;
dilutes, neutralizes, sequesters harmful agents
removes damaged/necrotic cells and tissues
initiates/interwoven with repair events
what are the negative signals for apoptosis?
- increased level of oxidants within a cell
- DNA damage by oxidants/agents (UV, Xrays, chemo)
- accumulation of malfolded proteins
- inc death activators (TNFa, lymphotoxin, FasL)
what are the positive signals for growth?
GF for neurons
IL-2 essential for mitosis of lymphocytes
what are vasoactive amines?
histamine and serotonin
what can block the cyclooxygenase reaction but not the 5 lipooxygenase reaction that makes the arachinodonic acid metabolites?
aspirin, indomethacin, ibuprofen (NSAID) drugs
what can block the phospholipase producing arachindonic acid?
steroids
what cause fatty liver?
when protein manufacturing shuts down during hypoxia, the liver mobilized glycogen to the mitochondria for glycolyis
free fatty acids for enter liver and form triglycerides and oxidation to ketone bodies, phospholipids, cholesterol esters and lipoproteins that all lead to lipid accumulation
what cell inuries caused by free radicals?
Attack the lipid membrane directly
DNA fragmentation
protein cross linking and fragmentation
what changes in cellular injury are reversible?
cellular swelling
fatty change
what complements are endogenous chemotactic factors?
C3a, C5a, C567
What does atrophy cause?
REDUCED FUNCTIONAL DEMAND
mechanism is an imbalance between protein synthesis and degradation
what effect does cytochrome c has?
it aids in apoptosis
what effects does ATP depletion has?
dec. ATP pump - inc influx of Ca, H2O, and Na//inc efflux of K+ - swelling
inc anerobic glycolysis - dec. glycogen//dec. pH - clumbing of chromatin
What effects incr in cytosolic Ca have?
with extracellular Ca moving in, and intracellular moving out of mito into cytosol caused increased in cytosolic Ca, which activates enzymes, ATPase (dec in ATP), Phospholipase and Protease (membrane damage), endonuclease (nucleus chromatin damage)
what factor involves the interrelationship among clotting, kinin, fibrinolytic and complement systems?
factor 12 to 12a
what give us the signs that a cells is aging?
when find a lot of lipofuscin in a cell
What happen when ATP depletion from hypoxic and chemical injury?
protein synthesis decreased (detachment of ribosomes)
lipogenesis (fatty deposition)
deacylation and reacylation in phospholipid turnover
what happens in AIDS?
Decline in CD4+ T cells
what inflammatory mediators are in fever?
IL-1, IL-6, TNF-a
what inhibit the extrinsic (death receptor initiated) pathway?
FLIP, produced by some viruses and normal cells, which binds to procaspase 8 but cannot cleave/activate procas 8 because FLIP lacks enzyme activity
what is an important function of NO?
free radical; cytotoxic, bactericidal
what is increased in hypersensitivity reaction?
IgE
what is involved in anaphylatoxins reaction and what is not?
IgE is NOT involved, but C3a, C5a more than C4a are produced by basophil/mast cells.
what is the first point of attack?
plasma membrane
what is the function of the plasma membrane?
- maintain contant ionic environment: K inside (protein synsthesis), Ca outside (prevents membrane damage)
- regulates what is taken into the cell: receptor mediated, pinocytosis, phagocytosis
- envelop and compartmentalized metabolic reactions
what is the goal of acute inflammation?
to deliver leukocytes, antibodies to injury site
what is the mechanisms for hyperplasia?
physiological: increased in local production fo GFs, and GFRs; activation of intracellular signaling such as production of transcription factors
what is the normal CD4+ count?
500 to 1000 cells/mm^3
If less than 200 cells = AIDS
what is the process that takes place on apoptotic cells with macrophages?
opsonization - macrophages secrete substances that bind specifically to apoptotic cells but not to live cells, and opsonize these for phagocytosis
what is the sequence of duration of injury?
Reversible cell injury show dec in cell function
Irreversibel cell injury show incr in cell death with structural changes:
-Ultrastructural changes - min to hours
-Light microscopic changes - hrs to days
-Gross morphologic changes - days
what molecules is involved in transmigration?
immunoglobulin superfamily PECAM -1 (CD31) from both endothelial and leukocytes pair to activate surface receptors CD44 on leukocyte
what regulatory enzyme inhibit apoptosis and how?
Bcl-2 can block the release of cytochrome c and block Apaf-1 from latching onto procaspase 9 preventing it from activating to active caspase 9
what signs are indication of metabolic derangement in cells?
intracellular accumulations in abnormal amounts
- excess of normal cell constituents
- abnormal exogenous, endogenous
- pigments
what specific chemokines are chemotactic factors?
IL-8: PMN
eotaxin: eosinophil
MCP-1: monocytes
what triggers the alternate pathway of the plasma proteases?
endotoxins, cobra venom, aggregated IgA
What types of caspases relevant to our courses?
Caspase 8, 9, 3, 6
whatcondition that has a germline mutation that is found in the apoptosis pathologic process of the immune system?
Autoimmune Lymphoproliferative Syndrome (APLS) - present with spleen enlargement because of the accumulation of non useful lymphocytes
where did plasma cells come from?
Plasma cells come from differentiated B -lymphocytes, terminally differentiate and only produce antibodies
where does histamine release from?
mast cells/basophils
where does the intracellular Ca reside?
Ca sequestered in the mitochondria and ER
which tissues in the oral cavity have unlimited capacity for regeneration and which tissues has limited capability?
unlimited: gingiva, PDL, alveolar bone
limited: cementum (periodontium)
