Disease and Defense Unit 2-class of 2019 Flashcards
what are adaptations (in general)?
reversible changes in size, #, phenotype, metabolic activity, cell function, environment. Can be physiologic or pathologic
what are the 4 main adaptations (of cells)?
Think “Hham”: hypertrophy, hyperplasia, atrophy, metaplasia
hypertrophy
increase in cell size—> increase organ size (limit eventually reached and can no longer compensate—> injury). can be physiologic or pathologic. may be reversible. example: uterus in pregnancy, heart in hypertension.
Can hypertrophy occur with hyperplasia?
YES!
hyperplasia
increase in number of cells (response to stimulus/injury). physiologic=hormonal or compensatory. pathologic=excessive hormonal or GF stimulation (these are very “hyper” cells). increase in cell number. can be physiologic or pathologic. may be reversible. often driven by hormones/growth factors. May be associated with increased risk of neoplasia. eg: mammary gland in puberty, endometrial neoplasia
if stimulation is removed in pathologic hyperplasia, what happens?
abates. doesn’t happen with cancer
atrophy
decrease/shrinkage in size/function capacity of cell. physiologic=loss hormonal stimulation, decreased workload. pathologic=denervation or diminished blood supply.
mechanism of atrophy:
down with the protein synth and up with the protein degradation!!!!!
metaplasia
reversible change where 1 cell type is replaced by another (“it’s so meta!”). typically because 1 cell is sensitive to stress, and another is better able to handle it. change from benign differentiated cell type to another, usually in response to injury. may be associated with increased risk of neoplasia. “in between” state. best observed and most observed in epithelia. seems to have a “field effect”. eg: columnar to squamous metaplasia, barrett esophagus
what is metaplasia named for (the cells)?
what it ends up as
reversible cell injury
if damaging stimulus removed, you can heal if damage isn’t too badly progressed to severe membrane damage/nuclear dissolution
what classifies irreversible injury?
cell death! necrosis/apoptosis, other causes
cellular swelling is caused by what…?
failure of ion pumps in plasma-which disrupts ionic/fluid homeostasis.
what is fatty change?
accumulation lipid vacuoles in the cytoplasm of cells (especially those that do fat metabolism). Due to increased entry/synthesis of free Fa and decreased FA oxidation. non-specific, reversible.
intracellular changes with reversible injury:
plasma membrane alterations, myelin figures, dilation of ER, nuclear alterations
what are myelin figures?
phospholipid masses derived from damaged cell membranes
what are the 2 big irreversible cell injury morphologies?
necrosis and apoptosis
what are some intracellular changes associated with irreversible injury?
cytoplasmic changes (increased eosinophilia), loss of RNA basophilia in cytoplasm
what are some nuclear changes associated with irreversible injury?
breakdown of DNA and chromatin, kayorrhexis (pynknotic nuclear fragments), karyolysis (nucleus dissolution)
pynknosis is what?
nucleus shrinks, increased basophilia
List the 5 patterns of tissue necrosis:
“Cassie Left Connie For Frank”.
Caseous, Liquefactive, Coagulative, Fibrinoid, Fat
coagulative necrosis
GANGRENOUS!!!!!! (involves multiple layers). Architecture of tissue preserved for several days, dead cells are pale/ghost like, characteristic of infarcts, any white/yellow is still live tissue
liquefactive necrosis
seen in focal bacterial/fungal infections, fungal infections. microbes stimulate accumulation of inflammatory cells. leukocyte enzymes digest the bacteria. there are no histeocytes/giant cells unless responding to microbes
caseous necrosis
tuberculosis infections (and histoplasmosis). derived from white apron, necrotic area is fragmented/lysed cells. has histeocytes/giant cells.
granulomas inflammation
amorphous granular debris enclosed in inflammation border. histologically distinctive pattern of chronic inflammation. fibrosis often forms around it
fat necrosis
fat destruction due to activated pancreatic lipases. chest wall trauma, breast tissue, etc. fat hydrolyzed into free FA and precipitated with calcium into chalky, grey material
fibrinoid necrosis
immune rxn where complexes of antigens/antibodies are deposited into artery walls. deposited immune complexes combine with fibrin and produce bright pink/amorphous appearance on H&E
list the 6 mechanisms of cell injury:
ATP depletion, mitochondrial damage, influx of calcium, accumulation of ROS, increased membrane permeability, accumulation of damaged DNA/misfolded proteins.
“ROS CAn MEet MItch After Dinner.”
ATP depletion and cellular injury
Oxidative phosphorylation+ADP=ATP in mitochondria, or via glycolytic path in absence of O2. Tissues with greater glycolitic capacity can survive better. makes tissue susceptible to ischemic injury (think about DELICATE and not as renewable tissue)
mitochondrial damage and cellular injury
failure of oxidative phosphorylation means: ATP depletion, ROS forms, high conductance channels formed destabilizing mitochondria, releasing of proteins and apoptosis
influx of calcium and cellular damage
ischemia and toxins cause release from intracellular stores
accumulation of ROS and cellular damage
damage by free radicals via 2 paths:
1) all cells during REDOX rxn during mito respiration,
2) phagocytic leukocytes.
consequences=damage is based on removal rate. increased production=ineffective scavenging by enzymes=stress. Removal by spontaneous decay.
increased permeability of cellular membranes and cellular damage causes damage where?
Important sites of damage: mitochondria, plasma membrane, lysosome
spontaneous decay in ROS damage
SUPEROXIDE converts H2O2 by SOD. Decomposition to H2O by GLUTATHIONE, PEROXIDASE, CATALASE
what is apoptosis?
programmed cell death where cells activate enzymes to degrade cellular nuclear DNA and nuclear cytoplasmic proteins (fragment/fall off!!!!). Doesn’t illicit an inflammatory response
what are some physiologic causes of apoptosis?
programmed destruction (embryogenesis),
involution of hormone dependent tissues (hormone deprivation),
cell loss in proliferating cell=POP!!!,
elimination of used up cells,
elimination of self-reactive lymphocytes,
death from cytotoxic T-lymphocytes
what are some pathologic causes of apoptosis?
DNA damage with inadequate repair (eliminate instead of propagate),
accumulation misfolded protein (ER stress),
cell injury (viral infection, etc.),
pathologic atrophy in parenchymal organs after duct obstruction
what is the morphology of apoptosis?
picnotic nucleus that darkens (condensed chromatin), fragmentation, apoptotic bodies are phagocytosed or taken up by neighboring cells
what is the mechanism of apoptosis?
1) mitochondrial path and
2) death receptor
describe 3 things mitochondrial apoptosis has:
anti apoptotic mechanisms (BCL2, BCL-XL, MCL1), pro apoptotic mechanisms (BAX, BAK), these lead to activation of initiator caspases (8,9; executioner)
what is autophagy?
where a cell eats its own contents! Yum!. it’s an adaptive response/survival mechanism for times of deprivation. disregulated sometimes (cancer, disease, IDB, neurodegenerative disorders), role in host defense (degrades some pathogens: Mycobacteria, HSV-1, etc)
what are four main paths of abnormal accumulation of substances in a cell?
1) inadequate removal;
2) accumulation of abnormal endogenous substance,
3) failure to degrade due to inherited enzyme deficiencies,
4) deposition/accumulation of abnormal exogenous substances
hemosiderin
hemoglobin derived granular pigment. accumulates with excess of iron. found with Prussian blue
lipofuscin
wear and tear pigment. accumulates with age/atrophy. its a complex of lipid an dprotein
steatosis
accumulation of tryglycerides
cholesterolosis
deposition of cholesterol in macrophages in gallbladder
what is pathologic calcification?
abnormal deposition of calcium salts (and iron, magnesium, other minerals)
dystrophic calcification
dead/dying tissue. absence of systemic derangement in calcium metabolism. appears purple to pink.
psammoma body/calcification
sign of degeneration and cell turnover. laminate of calcification. seen in benign and malignant proliferations (meningioma, papillary thyroid carcinoma, serous carcinoma). outside of cell-aggregate of dead cells and contents.
metastatic calcification
seen in normal tissues. secondary derangement to calcium metabolism. (precipitates and deposits out of tissue). hypercalcemia, hyperparathyroidism, Paget disease, etc.
innate immune system
nonspecific defense mechanism. occurs immediately/very soon.
what are they physical barriers of innate immune system?
skin, mediators in the blood, immune system cells
adaptive immune system
antigen specific response. more complex-requires antigen processing. Specific cells must be made/designed for each antigen. Maintains memory cells for future encounters (for quick response). takes a while to develop!
acute inflammation: onset, cellular infiltrate, tissue injury/fibrosis, local/systemic signs
onset: fast (minutes, hours),
infiltrate: neutrophils,
tissue injury: mild/self limited,
local/systemic signs: prominent
chronic inflammation: onset, cellular infiltrate, tissue injury/fibrosis, local/systemic signs
onset: slow (days),
infiltrate: monocytes/macrophages/lymphocytes,
tissue injury: severe and progressive,
local/systemic signs: less prominent/may be subtle
list the 4 stimuli for acute inflammation:
Infection, Trauma, Foreign Material, Immune Rxn.
“I Try For My Immunity”
list some possible infections:
bacterial, viral, fungus, parasites, toxins
list some possible trauma:
mechanical, chemical, thermal, nuclear, direct physical/chemical damage to cells
list some foreign materials that could cause inflammation:
substance that directly stimulates inflammation and its associated “stuff”. microbes, etc.
list some immune reactions:
host/environment antigens cause inflammation,
immune reactions or hypersensitivity rxns,
inappropriate response to inflammation/environment.
These often persist, tend to be chronic.
inflammation receptors
pattern recognition receptors present on large variety of cells. they pick up stuff (microbe-derived substance, toxins, necrotic cell material, etc).
Toll Like Receptors (TLR)
10 receptors. they detect a variety of MICROBES (on plasma membrane, endosomes). TLR stimulated—> transcription factors—> mediators of inflammation and anti microbial products (stimulates inflammatory cytokines)
Inflammasome
complex of proteins that mediate cell response esp in response to dead/damaged cells or microbes. (stuff=uric acid, ATP, decreased K, DNA). receptors in cytoplasm=important stimulators. Activates capsize 1—> IL1-beta—> inflammation
Pro inflammatory receptors have what 3 locations?
plasma membrane, endosomes, cytosol
vascular changes to inflammation
key component of reaction to bring cells and other material quickly to the site of injury/threat. this directly leads to many early clinical signs of infection
what are the words of antiquity used to describe inflammation?
calor (warmth, increased flow), rubor (increased flow, congested capillary bed, erythema), tumor (permeability, exudate into tissue, swelling)
describe permeability of vessels in inflammation
arterioles dilate, flooding capillaries. Histamine (mediator) acts on smooth muscle to stimulate the dilation (endothelial cells contract).
transcytosis
material is taken from the intravascular space and transported through the endothelial cells via vesicles
list the common cause, protein content, cell content, and specific gravity of Exudate
increased vascular permeability,
increased protein content,
increased cell content and inflammation and RBC,
high specific gravity
list the common cause, protein content, cell content, and specific gravity of Transudate
increased hydrostatic or decreased colloid osmotic pressure,
decreased protein content,
fewer cell content,
low specific gravity
exudate
result of increased permeability/leakiness of vessels related to inflammation—>proteins get pushed out!
transudate
filtering of fluid, result from cardiac failure. decreased blood protein (oncotic pressure) from liver disease can cause. also caused by heart failure. filtered fluid due to vessel being “tight”
lymph drain what???
accumulating edema and debris that inflammation produces
what are the 4 phases of leukocyte recruitment?
margination/rolling, adhesion, transmigration, chemotaxis “MATCh”
what is leukocyte recruitment?
targeting certain areas for migration of leukocytes in 4 phases, low level of natural peripheral movement, but is first step of ACUTE inflammation
margination
leukocytes accumulate on endothelium (laminar flow-slower/larger go to periphery). Vascular permeability thicker, blood moves slower.
rolling
stimulated endothelial cells have adhesion molecules with sugar affinity on leukocytes. endothelium induced to move these surfaces via chemical mediators. local tissues detect threat—>mediators released—>vessel is sticky
what are the chemical mediators for rolling?
histamine—>p selectin. IL1—>E selectin
adhesion
occurs when leukocytes reach area of activation that has been signaled by leakiness. alter interns on surface into a high-affinity state. (Icam-1 binds these). results in stable attachments sites of inflammation
do adhesion and margination overlap?
YES! first margination, then adhesion
transmigration
Think phantom of the opera-“Past the point of no return!!! No going back now!!!” after adhesion arrests leukocyte on endotheium. squeeze btw endothelial cells in venules (diapedesis).
how do those darned leukocytes get through the endothelial cells of the venules?
secrete enzymes like collagenous to break up basement membrane of vessels
chemotaxis
leukocytes move towards site of inflammation by following chemical gradients of greater density. start in vascular space—>diapedese—>move towards gradient. this is tied to the contractile elements of a cell, direction of greatest chemotactic density determines the movement.
can endogenous and exogenous substances be chemotactic?
Heck yes! bacterial products, cytokines, compliment proteins (C5), arachidonic acid metabolites (LTB4)
what are leukocytes?
inflammatory cells
leukocyte activation
activate when encounter certain substances: microbial products, cellular debris, mediators, etc.
what are the 4 things inflammatory cells can do that other cells can’t do?
1) readily phagocytize material,
2) be poised to kill/degrade engulfed materials (nomnonmnom),
3) readily secrete material into extracellular environment to kill or degrade tissue,
4) produce inflammatory mediators to amplify inflammatory process
phagocytosis
recognition/attachment of particle to leukocyte—> engulfment and formation of vacuole—> killing/degrading vacuolated material
what are 2 ways for phagocytes to bind material?
1) receptors for specific products/microbes/necrotic cells,
2) receptors for opsonins
what the heck are opsonins?
host proteins present in blood or produced locally that coat microbes (IgG, C3b, collectins)
what do ROS convert oxygen into when they oxidize NADPH?
SUPEROXIDE ION (toxic oxidizer)
what does superoxide ion spontaneously become?
HYDROGEN PEROXIDE
when in the presence of myeloperoxidase and chloride ions, what does hydrogen peroxide become?
HYPOCHLOROUS RADICAL (strong oxidizer
what toxic compounds kill microbes and break down other materials like elastase and lysozyme?
OTHER LYSOSOMAL ENZYMES
what are NETs?
neutrophil extracellular traps. they are nuclear chromatin that act as scaffolding with embedded antimicrobial compounds providing and area of antimicrobial material that traps microbes. it takes the nucleus, extrudes complex, traps microbes, kills them
what are the 3 general outcomes of inflammation?
resolution, chronic inflammation, scarring
resolution of inflammation
only happens if the tissue can regenerate. occurs in a limited degree of injury (minimal damage). requires termination of inflammatory process
chronic inflammation
generally occurs when the offending agent not removed by acute inflammation so the system transitions to chronic. can be prolonged, followed by resolution or scarring. doesn’t always follow acute inflammation.
scarring
occurs when tissue can’t regenerate, after considerable destruction. results from tissue being filled in by connective tissue elements, can significantly impair function
summarize for me how host tissue damage can occur (3 things)
tissue surrounding infectious agents, cleaning up necrotic tissue by inflammatory process may cause damage, inflammatory process directed against host tissue
what are the general points about acute inflammation?
often presented as sequential steps, but can occur w/ chronic inflammation. mononuclear cell infiltrate (cells with small round nuclei), tissue destruction, repair
what 3 settings are characterized by chronic inflammation?
persistent infections, immune mediated diseases, prolonged exposure to toxins
persistent infections and chronic inflammation
some infections difficult to eliminate or stimulate a response to—> associated with delayed hypersensitivity reaction
immune mediated diseases and chronic inflammation
autoimmune diseases, allergic diseases (endogenous response)
prolonged exposure to toxins and chronic inflammation
exogenous substances that can’t be broken down/removed promote inflammation (constant low grade stimulation). endogenous substances may do this as well
macrophage
blood monocyte. circulates for a day and gives rise to macrophages in tissues throughout body. sometimes given names specific to location (Kupffer cells in liver). All are same origin, basic function
what are the roles of macrophages?
ingest microbes/cellular debris. initiate tissue repair (fibrosis/scar)
classical activation of macrophages:
endotoxin, IFN-gamma, foreign material
classical activation of macrophage production:
ROS, NO, lysozymal enzymes, proinflammatory cytokines
classical activation of macrophage function:
killing microbes, chronic inflammation
alternative activation of macrophage:
IL-4, IL-13 (from eosinophils, T-cells, mast cells)
alternative activation of macrophage production:
growth factors for new vessels, fibroblast activation
alternative activation of macrophage function:
tissue repair, fibrosis
lymphocytes
barely noticeable in cytoplasm, involved large variety of inflammatory responses. many chronic disorders mediated by lymphocytes. activation is a function of adaptive immunity
what are the 3 classes of CD4+T cells that promote inflammation?
TH1 CD4+ T lymphocytes secrete IFN-ɣ: activates classical pathway macrophages.
TH2 CD4+ T lymphocytes secrete IL-4, IL-5, IL-13: activates alternative pathway macrophages; also activates eosinophils.
TH17 CD4+ T lymphocytes secrete IL-17: recruitment of neutrophils and monocytes
eosinophils
bright red granules, bilobed nuclei. recruitment is similar to neutrophils, but includes specific chemokines (eotaxin)
what are the 2 notable scenarios you would notice eosinophils in?
parasitic infections (have major basic protein toxic to parasites), allergic reactions mediated by IgE
mast cells
involved acute/chronic inflammation. network of cells in body, can quickly release mediators (histamine, arachidonic acid, etc), coated with IgE to trigger mediator release. well known for allergic involvement-wide distribution and quick response to infections
granuloma
enlarged macrophages form a nodule, surrounded by lymphocytes. form around organisms and prevent their spread.
can organisms/infections remain viable once sequestered by an granuloma?
YES!
what would a granuloma lead you to investigate further?
inflammatory reactions not eradicated by reactions (leprosy, tuberculosis), some immune mediated diseases (crohns), foreign material, sarcoidosis (last resort diagnosis)
what are the mediators produced that are responsible for many systemic effects?
TNF, IL-1, IL-6
fever
vascular cells in hypothalmus are stimulated by pyrogens to produce prostaglandins (PGE2). Act locally to cause central increase of body temp. exogenous pyrogens cause leukocytes to release endogenous pyrogens (act on hypothalamus vasculature) and can also act directly on hypothalmus vasculature
what is the increased acute phase of proteins in the blood in response to?
IL-6 hepatocytes. produce several proteins in greater abundance. clinically used to detect and monitor progress of inflammatory processes.
what are 2 proteins that adhere to cell walls and act as possible opsonins?
C reactive protein (CRP), Serum Amyloid A (SAA)
fibrinogen
binds RBCs to make them into stacks that sediment. this becomes the basis of the erythrocyte sedimentation rate (ESR) to test for inflammation
leukocytosis
increased leukocytes in the blood. WBC increase systemically in inflammation. TNF and IL-1 cause more to be released from bone marrow. may see increased number of immature WBC (left shift of leukocytes).
continued inflammation leads to increased production of??
colony stimulating factors (CSF). increase bone marrow production of leukocytes
neutrophilia is/is in response to?
increased nuetrophils, bacterial infection
lymphocytosis is/is in response to?
increased lymphocytes, viral infection
eosinophilia is/is in response to?
increased eosinophils, asthma/parasitic infections
leukopenia is/is in response to?
specific infections (eg: typhoid fever)
give me a synopsis of mediators
produced at site of inflammation or by the liver to be activated at site of inflammation. once they are released they have a short lifespan. they are activated by specific receptors, some have broad and non-specific effects
mediators can be:
reformed for secretion, synthesized on demand
what are cell derived mediators?
vasoactive amines, ARACHIDONIC ACID METABOLITES, platelet-activating factor, cytokines, ROS, NO, lysosomal enzymes, neuropeptides
what are plasma protein derived mediators?
COMPLIMENT, coagulation and kinin
vasoactive amines
histamine and serotonin. Stored in cells for quick release/repsonse.
serotonin
vasoconstriction to aid in clotting, present in platelet granules
histamine
arterial dilator and endothelial contractor. Mast cells, basophils, platelets.
when do mast cells release histamine?
physical features (mechanical, temp), immune (IgE bind), compliment (C3a, C5a), histamine releasing proteins (from leukocytes), neuropeptides, cytokines (IL-1 or 8)
arachidonic acid metabolites (AA)
derived from cell membrane phospholipids, transformed into compounds that mediate inflammation and homeostasis. from leukocytes, mast cells, endothelium, platelets.
how is AA deactivated?
spontaneous decay and enzymes
what are the 2 paths that form AA?
1)cyclooxygenase (results in prostaglandins and thromboxanes), 2)lipoxygenase (results in leukotrienes and lipoxins)
prostaglandins
vasodilation
thromboxanes
vasoconstriction
leukotrienes
vascular permeability. mediate specific functions of inflammation. LTB4=chemotactic for neutrophils. LTC4, LTD4, LTE4=vascular permeability
lipoxins
inhibit endothelial adhesion/chemotaxis. generated as leukocytes enter tissue. antagonize leukotrienes-anti inflammatory.
what popular medications block the AA formation paths?
NSAIDs block cyclooxyrgenase, glucocorticoids block phospholipase A2 (shut down whole path)
prostaglandins and thromboxjnes
prostoglandins contribute to pain and fever symptoms. presence of enzymes determines the compounds of a specific AA path.
cytokines
polypeptides that function as mediators in innate and adaptive immune system.
list the 2 important acute inflammatory cytokines
TNF and IL-1
What do TNF and IL1 do?
produced mostly in macrophages, mast cells, endothelial cells. stimulated by microbial products, immune complexes, endothelial cells. cause endothelial activation, induce systemic effects of inflammation
chemokines
subset of cytokines. small proteins separated into 2 groups (CXC, CC) based on structure. function in chemotaxis, also activate leukocytes
CXC
chemotactic for neutrophils
CC
chemotactic for variety of cells
what are 2 important chronic inflammatory cytokines?
IFN-γ, IL-12
IFN-γ
stimulates classical macrophage activation
IL-12
stimulates growth and function of T cells
ROS
released from activated neutrophils and macrophages. NADPH oxidase path. Superoxide ion changes to OH ion. can be reduced to a radical or converted to hypochlorous radical (BLEACH) vial myeloperoxidase in neutorphils.
NO
free radical that can be used to kill microbes. mediator vasodilation (antagonizes platelet activation, reduces leukocyte recruitment/attachment). Made by Nitric Oxide synthase (NOS) from L-arginine.
type 2 inducible NOS
induced by macrophages and endothelial cells. responsible for NO inflammation
type 3 endothelial NOS
constitutively expressed in endothelial cells
Lysosomal enzymes
azurophil granules of neutrophils and granules of monocytes. contain enzymes that can kill microbes and digest ingested materials. can damage host tissues (acid proteases, neutral proteases are active outside cell).
protease inhibitors are present where?
in blood/body tissues to limit damage to host tissues. Alpha-1-antitrypsin (neutrophil elastase inhibitor-emphysema), alpha-2-macroglobullin (inhibits proteinases-eg collagenase)
neuropeptiedes
initiate inflammation, active in vascular tone/permeability. active in lung and GI.
what are some examples of neuropeptides?
Substance P. secreted by nerves/inflammatory cells. binds neurokinin-1-receptor. generates pro inflammatory effects in immune and epithelial cells
complement
large number of plasma proteins involved with inflammation nd immunity. opsonize pathogens and induce inflammatory response to fight infection. final complement forms MAC. increase vascular permeability and leukocyte chemotaxis
the components of complement system (C1-9) circulate as _________ molecules in ______.
inactive. plasma. activated by proteolysis. once activated can proteolyses and amplify the reaction (self activate). Key factor is C3 converts cleaving C3 into a and b.
list the 3 separate paths for C3 converts formation:
1) classical: fixation of C1 to antigen-antibody complex. 2) alternative: microbe cell wall components combine with plasma proteins. 3) lectin: plasma letting binds microbial mannose and stimulates classical path
what are the results of activated complement (5 things)?
C3a, C5a increase vascular permeability (stimulate mast cells to release histamine). C5a stimulates lipogenous path for AA metabolism. leukocytes are activated via C5a, 4a, 3a to increase endothelial adhesion. C3b is opsonin for enhanced phagocytosis. MAC.
how do you block C1 activation and complement?
C1 inhibitor, Decay accelerating factor (DAF), and factor H
what is factor XII (Hageman factor?
an important clotting factor that activates the kinin system, leading to bradykinin (increases vascular permeability, dilation, pain). activates the clotting cascade!
what is Kallikrein?
an intermediate product that is chemotactic. it activates factor 7 but can self activate
Factor Xa
leads to vascular permeability
thrombin
binds protease activated receptors on endothelial cells, activating them. cleaves fibrinogen (to make fibrinopeptides) to increase vascular permeability (chemotactic). cleaves complement factor 5 to form factor 5a.
what is activated when he clotting system is activated?
the fibrinolytic system (active inflammatory mediators)
anti-inflammation
factors serving to antagonize driving/facilitating mediators of inflammation to allow for a baseline. lipoxins, compliment regulatory proteins (C1 inhibitor), IL-10, TGF-beta
lipoxins
antagonize leukotreines (anit-inflammatory mediator)
IL-10
secreted by macrophages. down regulates activated macrophages
TGF-beta
promotes fibrosis. anti-inflammatory as process moves to scarring.
what is the basic definition of tissue repair/healing?
restoration of tissue architecture and function if possible after injury
regeneration of injured cells and tissues involves cell ________ which is driven by growth factors and is critically dependent on _________ of extracellular matrix
proliferation, integrity
what cell types proliferate during repair
remnants of injured tissue (to restore normal structure), vascular endothelial cells (new vessels for repair), fibroblasts (source fibrous tissue to make scar)
list the 3 groups of tissues that have an intrinsic proliferative capacity:
labile (continuously dividing), stable, permanent
labile tissue
continuous turnover from stem cells and proliferation of mature cells. injured cells replaced by residual cells and stem cells if basement layer is intact.
what tissues have labile tissue?
bone marrow, surface epithelia: skin, oral cavity, GI, ducts, urothelium, etc
stable tissues
quiescent tissue (minimal replication even though capable in response to injury/loss). exception is liver since has robust capacity to regenerate. most have limited regeneration capacity.
what are some examples of stable tissue?
parenchyma of most solid organs: liver, kidney, pancreas. also endothelial cells, fibroblasts, smooth muscle
permanent tissue
terminally differentiated, can’t proliferate. limited stem cell replication and differentiation that is insufficient for regeneration. forms scars instead
what are some examples of permanent tissue?
neurons, cardiac muscle
do mature tissues carry variable proportions of the 3 groups of proliferative tissues?
yes! most tissues have some regeneration and scar formation
stem cells summary
characterized by self renewal and asymmetric replication (can make daughter cells that have 2 fates), embryonic and adult
embryonic stem cells
most undifferentiated, present in inner cell mass of blastocyst. can form ecto,endo, meso
adult stem cells
tissue stem cells. less undifferentiated than ES cells, found in organ or tissue. self renewal capacity. more restricted lineage potential. important for tissue homeostasis
sources of cells to covered injured epithelium
skin: adjacent epithelial cells, hair follicle: follicles in skin
growth factors
proteins that stimulate survival/proliferation of particular cells. may promote migration, differentiation, other cell responses.
what (might) produce growth factors?
macrophages, lymphocytes, or parenchymal/stromal cells
autocrine vs paracrine vs endocrine growth factor signalling
directly in cell, adjacent cells, distance/remote cells
ECM definition
complex of several proteins that assembles into a network surrounding cells and makes up a large portion of any tissue. regulates proliferation, movement, differentiation of cells. is required for tissue regeneration and if it is damaged only a scar can form.
list 3 components of ECM
1) fibrous structural proteins,
2) water hydrated gels,
3) adhesive glycoproteins
what are the 2 basic forms of ECM?
interstitial matrix and basement membrane
interstitial matrix
spaces btw connective tissues. made by mesenchyme. made of fibrillar and non fibrillar collagens. scaffolding (collagens, ellastins, proteoglycans)
basement memberane
beneath epithelial, endothelial, smooth muscle cells. made by epithelium and mesenchyme. made of amorphous non-fibrilar type 4 collagen and laminin
liver regeneration
robust. 40-60% of liver can be removed for transplant, can regenerate. can also regenerate if other injury/insults happen if framework intact. priming—> g0—> g1—> proliferation—> regeneration!
scar formation
results when repair not possible by regeneration alone. replaces non-regenerated cells with connective tissue. sometimes just scar or combo of scar and cell regeneration
what can cause scars?
tissue injury is severe or chronic, parenchymal cells and epithelia are damaged, non dividing cells are inured
list the steps of scar formation (3):
angiogenesis, migration and proliferation of fibroblasts and deposition of connective tissue and agencies, maturation and reorganization of fibrous tissue
give a very basic outline of angiogenesis:
vasodilation (triggered by NO), permeability by VEGF, separation of pericytes from albumin surface, sprout and migration to area of injury, proliferation, remodeling, recruitment of periendothelial cells, suppression
what orchestrates the deposition of CT/scar?
locally procuced cytokines and GF: PDGF, FGF-2, TGF-BETA!!!!!
what is the most important cytokine for synthesis and deposition of connective tissue proteins?
TGF-beta
degradation of collagens/ECM components is accomplished by _________
MMP. matrix metalloproteinases. produced by a variety of cells, include interstitial collagenases, gelatinases, stromelysins. important for remodelling
nutritional factors that influence tissue repair
impair collagen synthesis if shot tin protein and Vitamin C
metabolic factors that influence tissue repair
delay repair if you have diabetes, are on glucocorticoids (inhibit TGF-beta production and diminish fibrosis)
vascular factors that influence tissue repair
ischemia, venous drainage (poor perfusion if lack of resources). Thrombosis, arteriosclerosis and artherosclerosis, varicose veins
what are 2 major considerations regarding whether repair will be effective or not?
if the inciting insult has been terminated or persists, if a new insult (infection) has been introduced
what are some aberrations of cell growth and ECM production in healing?
hypertrophic scar (regresses from going outwards originally), keloid (does not regress)
keloid
goes outside the bounds of initial repair. occurs in groups and families. pink/ropy collagen
hypertrophic scars
look like keloids, but they regress. can cause contracture
healing by first intention
epithelial regeneration is principal repair mechanism. superficial, clean wounds, not large. fibrous but not contracture. neutrophils—> fibrin clots—> angiogenesis—> granulation—> epithelial regeneration
healing by second intention
combination of regeneration and scarring. contracture occurs via myofibroblasts to contract tissue together. inflammation is more intense, larger area to fill in and regrow
NSAID (non-steroidal anti-inflammatory drug)
drugs whose therapeutic action is to reduce pain and inflammation caused by COX1 and 2, as well as decrease production of inflammatory prostaglandins and thromboxjnes
can NSAIDs have undesirable side effects?
yes. prostaglandins mediate physiologic maintenance functions, and inhibition can cause predictable side effects in tissues (we know what it will do though so that’s good)
what are some major therapeutic uses of NSAIDs?
analgesia, antipyretic effect, anti inflammatory, antithrombogenesis
analgesia
inhibits inducible COX2 at injury site. low to moderate intense pain relief. intermediate dose, prn dosing.
antipyretic effect
inhibits inducible COX2 in hypothalmus. fever reduction! (anti-pyretic, anti fire!) intermediate dosing, prn dosing.
anti inflammatory
inhibition of inducible COX2 at sites of inflammation. treats RA. hi doses, scheduled dosing, based on half life
antithrombogenesis
inhibits COX1 in platelets. primary and secondary MI risk reduction. low dose, daily.
GI side effects NSAIDs
inhibits constitutive COX1 in gastric cells=ulceration, bleeding, nausea
increased incidence of bleeding problems side effects NSAIDs are due to?
COX1 inhibit in platelets
renal side effects NSAIDs
inhibition of COX 1, 2 in kidney cells=acute renal failure and interstitial nephritis
uterine side effects NSAIDs
inhibition of COX2 in smooth m.= interference uterine contractions late term pregnancy
increased thrombotic events side effects NSAIDs
unopposed inhibition of COX2 in vascular endothelial cells=potential for increased cardiovascular events, including MI and stroke
traditional NSAIDS (reversible vs irreversible, action/classes)
reversible, COX1 AND 2. chemical classes are: “SOAPPy” (Salicylates, Oxicam derivatives, Acetic/carboxylic acids, Propionic acid derivatives, PYrazolone derivatives)
salicylates
analgesic, antypyretic, anti-inflammatory
pyrazolone derivatives
analgesic, antipyretic, anti inflammatory. more potent/longer lasting than aspirin, serious toxicities with misuse/chronic use
acetine/carboxylic acids
analgesic, antipyretic, anti inflammatory. fewer toxic rxns than pyrazolone, but many more adverse rxns related to idomethicin. limited generally to arthritis that don’t respond
oxicam derivatives
anlagesic, antiipyretic, anti inflammatory. potent, long half life (15-50hrs)
propionic acid derivatives
analgesic, antipyretic, anti inflammatory. tolerated well, some OTC
acetaminophen (reversible vs irreversible, action/classes)
NO inhibition COX1, 2 in PERIPHERY. inhibits COX2 in CNS. analgesic, antipyretic properties. less GI side effects
COX2 selective inhibitors (reversible vs irreversible, action/classes)
Seslective, reversible COX2 inhibition. analgesic, antipyretic, anti inflammatory. less GI side effects.
asprin (reversible vs irreversible, action/classes)
irreversible inhibition of COX1, 2. analgesic, antipyretic, anti-inflammatory, antithrombotic
list some traditional NSAIDS:
ibuprophen, naproxen, ketoprofen
traditional NSAID actions
anti inflammatory, antipyretic, analgesic effects. rapidly/completely absorbed (>90% protein bound, renal excretion or liver metabolism). as effective as ASA or acetaminophen for mild/moderate point.
traditional NSAID side effects-GI
interfere with gastric cytoprotection via COX1 PGE sytnesis—> sypepsia and gastric ulceration. lowest risk with ibuprophen, highest with naproxen. food or antacids can help. PPI protect against gastroduodenal toxicity
traditional NSAID side effects-Platelets
interfere with platelet aggregation by inhibition cox1 thromboxane a2 synthesis (promotes bleeding). effect is 4-7 days ( life of platelet). should keep patients on regular NSAID use off of anticoagulants or vice versa
traditional NSAID side effects-Kidney
cause renal vasoconstriction by inhibiting COX1, COX2 PGE synthesis and loss of vasodilator actions-reversible renal insufficiency. can cause fluid retention, which can exacerbate heart failure. avoid if hypertension if diabetes, ckd, heart failure. lowest cardiovascular risk with naproxen.
how do cox 2 selective inhibitors work? (celecoxib/celebrex in particular)
all possess anlageisc, antypyretic anti inflammatory action. selectively reversible for COX 2 over 1 by 5-7 fold for celexoib. well absorbed and well exreted. metabolized by cyp2c9, long half life. used for RA, osteoarthritis, acute pain. less gastroduodenal toxicity to doses that provide pain relief than non selective NSAIDS. could reduce antithrombotic PGI2 activity. increases risk of CVD and HF in dose dependent manner. can precipitate acute renal failure, avoid use in at risk patients. can trigger sulfa allergy
how do cox 2 selective inhibitors work (acetaminophen in particular)
equal to aspirin as analgesic/antipyretic. less anti inflammatory properties, possibly selective for inhibition of CNS prostaglandin synthesis. mild to moderate pain. inadequate alone for inflammatory conditions. peak absorption is in 30-60 min, related to gastric emptying. metabolized in large doses=liver toxic (depletes glutathione stores). hepatotoxicity is biggest and most common concern. limit to less than 4000 mg in 24hrs.
how do cox 2 selective inhibitors work? (aspirin in particular)
inhibits COX1 and 2. reduces mild to moderate pain of inflammatory origin. less effective in visceral pain. initial RA therapy and other inflammatory conditions, reduces elevated body temp, inhibits platelet aggregation. rapid absorption from small intestine. GI irritation minimized if pH >3.5. high plasma protein binding-may lead to displacement. avoids in: ulcers, alcoholics, older NSAIDs (warfarin), pregnancy, chronic renal insufficiency, asthma.
aspirin poisoning
once frequent in children. mild is headache, dizzy, tinnitus, visual disturbances, mental confusion, drowsiness, sweating, thirst, hyperventilation, diarrhea. acute is: vomiting, fever, sweating, respiratory alkalosis, metabolic acidosis, death
cyclooxygenase
critical enzyme in path for production of prostaglandins and thromboxanes from arachidonic acid. PGG/PGH synthase. no drugs currently inhibit isomerases/synthases.
COX2 induced by?
cytokines, shear stress, GF, or up regulated as needed or for specialized functions. located inflamed/activated tissues.
areas of pain/inflammation (PGE2/PGI2)
enhance edema formation, leukocyte infiltration via vasodilation
hypothalmus/fever (PGE2)
increase heat generation and decrease in heat loss
kidneys (PGE2/PGI2)
renal adaptation to stresses via maintenance of renal blood flow. most critical in elderly
NSAIDS that inhibit COX1 result in:
potential side effects: GI ulceration, prolonged bleeding time, acute renal failure
NSAIDS that inhibit COX2 would result in:
therapeutic actions (relief pain, fever reduction, inflammation reduction), potential side effects (acute renal failure, thrombotic events, prolonged gestation
5-lipoxygenase
enzyme in path for production of leukotrienes from AA. LTB4—> mast cells, eonsinophils, basophils, macrophages—> becomes CysLTs LTC4, LTD4, LTE4—>mediated by receptors.
LTB4 stimulates what?
neutrophil chemotaxis, aggregation, transmigration through endothelium
LTC4/LTD4/LTE4 stimulate what?
increased vascular permeability, bronchoconstriciton, vasoconstritction. role in asthma, psoriasis, arthritic process.
glucocorticoids
involved in carb and protein metabolism and anti-inflammatory response. cortisol is prototype hormone. only glucocorticoids have anti-inflammatory activity
mineralocorticoids
involved sodium retention. aldosterone is prototype hormone
adrenal androgens
increased release occurs in concert with cortisol, but not aldosterone. DHEA and androstenedione have weak androgen activity, some is converted to testosterone and estradiol outside of adrenals
regulation of secretion and synthesis of adrenal corticosteroids
ACTH release controlled by corticotropin-releasingg factor from hypothalmus. glucocorticoids and androgens are controlled by AcTH action last adrenal cortex.
diurnal rhythm of basal steroidogenesis
entrained by higher neuronal centers that release CRH from hypothalmus in response to sleep wake cycles
negative feedback regulation via circulating corticosteroids
endogenous hormones and exogenous agents used in therapy. hypothalmus and pituitary decrease ACTH release and steroidogenesis.
what can suppress HPA axis and result in adrenal crisis?
chronic use of pharmacologic doses of glucocorticoids
glucocorticoid path is a ______limited system with synthetic enzymes in excess that provide for rapid responsiveness.
substrate. rate limiting is cholesterol—>pregnelonone. ACTH stimulates this in zone fasted and reticularis. inhibited by metyrpone and mitotane
mineralocorticoid path in ______ has 18-OH-steroid dehydrogenase enzyme that converts corticosterone to aldosterone.
zona glomerulosa.
renin angiotensin system stimulates conversion of cholesterol to pregnenolone and cortiosterone to aldosterone.
what is the mechanism of action of glucocorticoids?
most actions are mediated by widely distributed glucocorticoid receptors. cortisol as CBG enters cell—> binds to systolic receptor to release Hsp90 for dimerization of S-R complex (transcription regulated)—> effects on protein synthesis result in delayed onset
does secretion of glucocorticoids change circadian rhythm?
YES! ACTH pulses govern cortisol changes (peak post mea and in AM)
how is glucocorticoid removed from circulation?
via the liver.
Describe the regulation of glucocorticoid secretion by the hypothalamic-pituitary-adrenal gland axis, especially as it relates to the mechanism of glucocorticoid drug-induced suppression of adrenal gland function
• Diurnal rhythm of basal steroidogenesis,
entrained by higher neuronal centers that
release CRH from hypothalamus in response to
sleep-wake cycles —>ACTH release —>cortisol
release
• Negative feedback regulation by circulating
corticosteroids (both endogenous hormones
and exogenous agents used in therapy) at the
hypothalamus and pituitary decreases ACTH
release and steroidogenesis.
NOTE: Chronic use of pharmacologic doses
of glucocorticoids can suppress the HPA axis
and result in adrenal atrophy and insufficient
adrenal response to environmental stressors
—> adrenal crisis.
• Stress (injury, hemorrhage, severe infection,
surgery, hypoglycemia, cold, pain, fear) can
override negative feedback and produce
marked increases in steroidogenesis.
Describe the metabolic and mineralocorticoid effects of associated with glucocorticoids and explain how these effects can result in serious adverse effects when they are used as pharmacotherapeutic agents.
structural changes can be made to produce glucocorticoid drugs with altered protein binding, prolonged half life, separation of mineralocorticoid and glucocorticoid activity. Carbohydrate stimulate gluconeogenesis—> increased blood glucose (increased insulin release)—> gluconeogenesis—> liver glycogen deposition. protein increased aa uptake into liver/kidney—> decreased protein synthesis—> net aa transfer from muscle to liver (muscle wasting). lipid inhibit uptake glucose by fat—> lipolysis—> lipogenic effect in central tissue. net physiologic result: maintenance of glucose supply to brain. anti inflammatory effects (decreased synthesis of inflammatory and immune mediators), immunosuppressive effects (suppress t cell activation, decreased healing/immunity), reduced vasodilation, reduced accumulation of activation of cells (decreased leukocytes in acute inflammation, decreased monocytes/lymphocytes in chronic inflammation, decreased clonal expansion T/B cells.
Hydrocortisone (Solu-Cortef®) describe
• Mechanism of anti-inflammatory and immunosuppressive actions
• Metabolic pathways – activating vs inactivating
• General clinical uses
• Dosing considerations / formulations
• Toxicities (distinguish acute vs chronic vs withdrawal)
Common use in physiologic doses for replacement therapy and emergencies; glucocorticoid and mineralocorticoid actions [1:1]; administered orally and parenterally
Prednisone —> Prednisolone describe
• Mechanism of anti-inflammatory and immunosuppressive actions
• Metabolic pathways – activating vs inactivating
• General clinical uses
• Dosing considerations / formulations
• Toxicities (distinguish acute vs chronic vs withdrawal)
Most commonly used oral agent when steroid burst therapy desired; glucocorticoid and mineralocorticoid actions [13:1]; activated to prednisolone in liver. NO topical activity, not activated until first pass hepatic metabolism.
Methylprednisolone (Solu-Medrol®) describe • Mechanism of anti-inflammatory and immunosuppressive actions
• Metabolic pathways – activating vs inactivating
• General clinical uses
• Dosing considerations / formulations
• Toxicities (distinguish acute vs chronic vs withdrawal)
Used if parenteral administration desired for steroid burst (no better than oral prednisone in acute exacerbations of asthma); minimal mineralocorticoid action. Oral (Medrol) and parenteral (Solu-Medrol)
Dexamethasone (Decadron®) describe
• Mechanism of anti-inflammatory and immunosuppressive actions
• Metabolic pathways – activating vs inactivating
• General clinical uses
• Dosing considerations / formulations
• Toxicities (distinguish acute vs chronic vs withdrawal)
Most potent anti-inflammatory agent, used in cerebral edema, chemotherapy-induced vomiting; no mineralocorticoid action, greatest suppression of ACTH secretion at pituitary.
Triamcinolone (Kenalog®) describe
• Mechanism of anti-inflammatory and immunosuppressive actions
• Metabolic pathways – activating vs inactivating
• General clinical uses
• Dosing considerations / formulations
• Toxicities (distinguish acute vs chronic vs withdrawal)
Potent systemic agent - excellent topical activity; no mineralocorticoid action
Explain the rationale for alternate day therapy and tapered withdrawal following chronic therapy with glucocorticoids
Consider seriousness of disease, minimal amount for desired effect, duration of therapy.
Always reduce dosage as soon as therapeutic objectives are obtained. If using large doses, advisable to use shorter-acting agent with little mineralocorticoid effect. Alternate day schedule can minimize adverse effects (lessens growth-suppressive effects
because anti-inflammatory actions apparently outlast suppressive effect on HPA axis); make gradual transition to alternate day schedule after control of disease achieved. Terminate administration gradually if taken longer than 7-10 to 28 days, otherwise may cause severe rebound of disease or symptoms of adrenal insufficiency (adrenal crisis).
physiologic actions of mineralocorticoids
aldosterone binds to cystolic receptor, migrates to nucleus to induce mRNA formation to synthesize proteins. insertion of protein into membrane increases sodium reabsorption, increased secretion of H and K.
mineralocorticoid activity vs glucocorticoid activity
mineralocorticoid=salt retaining action at kidney. glucocorticoid=metabolic effects.
metabolism of glucocorticoids
liver: 11beta-HSD1 converts cortisone to cortisol (activating. also prednisone to prednisolone). kidney 11beta-HSD2 converts cortisol to cortisone (inactivating). fetus placental 11beta-HSD2 is active but not HSD1 (liver isn’t functional), so use agent that is poor substrate for 11betaHSD2
rheumatoid arthritis is managed with what 3 categories of drugs?
nonsteroidal anti inflammatory drugs, glucocorticoids, disease modifying antirheumatic drugs (DMARDs)
early RA is controlled with what?
NSAIDS. then DMARDS are added when the diagnosis is certain
what is used as a “bridge” to reduce disease activity in slower acting DMARDS when treating RA?
low dose glucocorticoids. also used as adjunctive therapy when active disease persists through DMARDS
mineralocorticoid toxicities effects (acute, short course, high dose)
na and h20 retention—>edema—> increased BP, hypokalemia
glucocorticoid toxicities effects (acute, short course, high dose)
glucose intolerance, mood changes, insomnia, GI upset
glucocorticoid effects high dose sustained therapy side effects (more than 2 weeks)
iatrogenic cushings syndrome, hypothalmic-pituitary-adrenal axis suppression, mood disturbance, impaired wound healing, increased susceptibility to infection
possible effects with large, cumulative doses of glucocorticoids
osteoporosis, posterior capsular cataracts, skin atrophy or loss of collagen support, growth retardation, peptic ulceration
hemodynamics
hydrostatic and osmotic forces are nearly balanced. want a controlled movement of fluid from tissues into the body cavities. eg: if high capillary hydrostatic pressure fluid and salts into the interstitial space. venous area has concentration of proteins to pull back in. usually fairly equal pressure, only a small amount of fluid is leftover and collected by the lymph
problems with hemodynamics
extravasation (buildup of fluid in tissues—>edema, and natural spaces—>effusion). due to decreases in plasma oncotic pressure, increased permeability, lymph drainage exceeded.
transudate
vascular wall=intact. increased hydrostatic pressure, reduced oncotic pressure. usually just fluid without extra proteins and such
exudate
increased permeability of vascular wall. inflammation—> endothelial cells contract to make small gaps. direct damage to endothelial cells. proteins move across into interstitial space. can cause damage b/c things moving across that shouldn’t be
transudate: etiology, specific gravity, protein concentration, protein fluid/serum ratio, LDH fluid/serum ratio, glucose fluid/serum ratio, WBC
ultrafiltrate of plasma (increased hydrostatic pressure and/or reduced oncotic pressure).
less than 1, less than 3, less than 0.5, less than .6,
greater than 0.5, few WBC.
essentially: less (except glucose)
exudate: etiology, specific gravity, protein concentration, protein fluid/serum ratio, LDH fluid/serum ratio, glucose fluid/serum ratio, WBC
increased vessel permeability due to inflammation.
greater than 1, greater than 3, greater than .5,
greater than .6, less than .5, many WBC.
essentially: more (except glucose)
which should have a higher specific gravity, exudate or transudate?
exudate
increased blood volume
too much blood volume systemically or in a specific area.
hyperemia
physiologic: active! (inflammation, exercise, etc.).
arteriolar dilation,
oxygenated blood: red
congestion
pathologic: passive.
impaired venous outflow (obstruction causes backup into capillaries/arterioles).
deoxygenated blood: pale or red/blue.
low nutrient/oxygen blood that can’t move.
get ischemia of adjacent tissue since not getting enough oxygen
what are the 3 organs that cause issues if fluid problems in body?
heart, kidney, liver
L heart failure
mostly due to scar tissue. not good output=peripheral tissue is not perfused well. fluid buildup in lungs. Kidney hates this, not enough fluid in vasculature so it holds onto fluid, dilutes out proteins and decreases oncotic pressure. fluid gets stuck in legs and move up the body from there. Lungs and Legs and Kidney
R heart failure
backs up into venous system. liver/portal circulation backs up you get portal congestion/liver congestion. oral system from gut goes to liver/spleen. fluid backs up into spleen. GI tract varies-dilated veins. then lots of fluid in organs, moves out of serosal surfaces—>acites. venous to liver to spleen to gut to organs to acites
hemorrhage
blood outside of the vasculature into surrounding tissue. due to vessel damage (platelets and coag. factors can’t fix it). commonly due to trauma. impaired integrity of vessel walls, can be fixed if small but otherwise not. can’t keep up with constant capillary damage. Concern is WHERE damage is occuring. low level function of platelets, low level function of coagulation factors
petichia
small, pinpoint hemorrhages. tiny capillary breaks
purpura
> 3mm.
ecchymoses
bruise 1-2 cm
hematoma
within tissue. placental abruption is example
thrombosis
builds up in flowing blood occurs in layers (tell if pre/post mortem). out of control is when layers keep building up and up. layers=lines of Zahn (platelet, red cells, platelet, red cells, etc.) can be driven by Factor 5 leiden.
Virchow triad
used for thrombosis. Endothelial injury, abnormal blood flow, hypercoagulability
thromboembolus
most common type of embolus. largely driven by stasis. DVT (immobility: recent surgery, estrogen, pregnancy/post partum, previous/current cancer, coagulation abnormalities, limb trauma/orthopedic procedures, obesity).
embolis
fluid/gas/solid mass floating in blood that shouldn’t be! pro-coagulant states push this. travels through big vessels to small ones of the pulmonary vessels. severity depends on what is blocked and how large the block is
do you get thrombi in arterial flow areas?
not typically since flow is really fast
can thrombosis and hemorrhage occur simultaneously?
yes! initially starts with too much clotting, something in vessels floats around in bloodstream damaging vessels. continued vessel damage can lead to lack of sufficient platelets/clotting factors, so you bleed. otherwise issues can lead to thrombosis.
disseminated intravascular coagulation (DIC)
lots of little clots. symptoms from multiple organ systems (respiratory insufficiency, MSC, convulsions, acute renal failure, peticiae/purpura, GI, oral hemorrhage). shock. hemolytic anemia, thrmobocytopenia, low fibrinogen, elevated D-dimer and other fibrin degradation products
infarction
tissue death (necrosis) caused by vessel occlusion. typically coagulative necrosis caused. liquefactive necrosis is caused in the brain. damaged tissue gets replaced by scar tissue (generally), doesn’t work so well anymore…
white infarction
dense tissue where you block off an artery. single blood supply. no reperfusion. dense tissue.
red infarction
involved blood flow. temporarily block off, it comes back and you get hemorrhage. dual blood supply. reperfusion. loose tissue.
shock
not enough blood, heart isn’t pumping enough blood to tissues. circulating blood volume is inadequate to perfuse tissues (can lead to multigrain dysfunction/damage).
cardiogenic shock
myocardial pump failure. myocardial damage, extrinsic compression, outflow obstruction
hypovolemic shock
low blood volume. severe dehydration, hemorrhage, burns
can you have hypovolemic and cariogenic shock?
YES! low cardiac output+low BP=vasoconstriction, increased heart rate, recall conservation of fluid. skin is cool and pale, tachycardia, low urine output
SIRS (systemic inflammatory response syndrome)
type of shock we go into due to significant inflammatory shock. eg: septic shock (microbial infection, subset of SIRS). often not responsive to IV fluids. arterial vasodilation, vascular leakage, venous blood pooling
development from organism perspective
early on=highly orchestrated, dynamic program. results in formation of specialized tissues, organs, systems. very dynamic state
development from cellular perspective
dramatic change in: proliferation (1 to billions), death (apoptosis), differentiation (totipotent—>organs/tissues), programmed cell death creates spaces, cell migration, cell-cell interactions
adult organism homeostasis
highly orchestrated, static program that provides optimal function of specialized tissues/organs/organ system. once you have adult, goal is to NOT proliferate, resulting in functional organs
continuously dividing tissues
constant turnover (benign and malignant neoplasm). skin, gut, epithelia, hematopoietic system
quiescent tissue
normally little/no turnover. capacity to turnover if needed. hepatocytes, liver
non dividing tissues
little to no proliferative capacity. brain development = post mitotic. CNS neurons, cardiac muscle
mechanisms of maintenance: external environment interactions
physical environment, infectious agents, inhaled/ingested substances
mechanisms of maintenance: cell extrinsic; macroenvironment
circulating factors, hormones, cytokines
mechanisms of maintenance: cell extrinsic; microenvironment
extracellular matrix, stroma, growth factor, inflammatory mile
mechanisms of maintenance: cell intrinsic
differentiation program. age of cell
mechanisms of maintenance-pathology
when homeostatic balance is disturbed, pathology results.
list the 3 disorders of cell growth
hypertrophy, hyperplasia, neoplasia
neoplasia
new formation. progressive, unchecked increase in cell number. non invasive, non metastatic=benign. clonal process. pathologic and irreversible. “tumor”. disruption of normal homeostatic mechanisms
neoplasia-global mechanistic hallmarks
altered cell-autonomous mechanisms (activate oncogenes, inactivate tumor suppressor), cell non autonomous mechanisms (altered microenvironment: contribution of immune system can be important driving force. altered macroenvironment: breast cancer is example, hormonal force if counteracted impacts tumor growth)
bengin neoplasms
don’t invade/metastasize. caused injury via compression/interference. treatment is surgical in most cases. tumor in essential spot, nowhere for organs to go (brainstem) can be fatal even though not invading. circumscribed/encapsulated. necrosis uncommon
malignant neoplasms
invade and METASTASIZE. cancer. cause injury with local tissue destruction and distant dissemination and tissue destruction. clinically very significant. how most cancers kill you. invasive, necrosis common
microscopic pathologic features benign neoplasia
relatively well differentiated. low rate cell turnover. cytologic uniformity. boundary btw. tumor and adjacent tissue maintained
microscopic pathologic features malignant neoplasia
variable differentiation. high rate of cell turnover. cytologic pleomorphism (cells differ markedly). loss of boundary btw tumor and tissue
classifications by tissue of origin: benign neoplasia
epithelial, mesenchymal
classifications by tissue of origin: malignant neoplasia
epithelial (carcinoma, subset adenocarcinoma), mesnchymal (sarcoma), hematopoietic (lymphoma, lukemia)
clinical correlates benign neoplasia
treated by surgical resection alone. may recur. do not progress to malignancy except for benign, premalignant neoplasms (colonic adenoma)
overview cancer pathology for me:
cancer cells change over time (neoplasm/tumors). heterogeneous population of cells, makes targeted therapies difficult. ongoing genetic alterations+selection=clonal evolution
what’s the most common cancer?
carcionomas (cancers of epithelia)
dysplasia
disordered growth. applied to epithelia, hallmark of early premalignant neoplasia. lose cytologic uniformity, lose normal histologic maturation, loss of architectural orientation. usually given a grade (low grade=less abnormal)
what is carcinoma in situ?
looks like cancer but can’t yet demonstrate invasiveness
histologic grades
degree of histologic differentiation. low grade-more differentiation, greater resemblance to normal. higher grade-less differentiation and resemblance to normal. grading scheme varies by tumor. low mitotic activity-low grade. can be predictive of biologic behavior, overall less reliable than disease stage
what does tumor stage and clinical outcome risk/threat go up with?
N and M involvement of the TNM stage scale. lowest T stage is non-invasive. the deeper the tumor invades, the worse the prognosis, so higher T stage is worse prognosis. goes up with lymph involvement
pediatric neoplasms
childhood neoplasms arise out of developing tissue-so they are different. origin n developmental (proliferative/migratory) precursors. recapitulate aspects of developmental program of tissue of origin. short latency and early metastasis. fewer mutations, prominent role for oncogenic fusions and epigenetic dysregulation. relative chemosensitivity
what are the 2 characteristics of malignant tumors?
invasion and metastasis.
invasion
infiltration of adjacent tissues by malignant cells
metastasis
transfer of malignant cells from primary site to non -connected/secondary site. discontinuous with primary tumor
carcinoma in situ
pre invasive stage. stays above basement membrane. common in skin, breast, other sites. precursor to cancer
malignant tumors are ______ demarcated from surrounding tissue.
poorly. why it got name cancer (crab). invasive and can penetrate organ walls. surgical resection is difficult/impossible
methods of cancer dissemination
1) direct seeding of body cavities/surfaces; 2) lymphatic spread; 3) hematogenous spread.
list the steps of the metastatic cascade
invasion (through basement memb./ECM), intravasation (get into blood/lymph), extravasation (exit vessel at new site), colonization (grow in new site)
why do cancers leave their original area of formation?
when conditions are crowded/harsh/ there is waste buildup.
what are some additional hallmarks of cancer?
it has the capacity to modify cellular metabolism, it can evade immunological destruction (EMERGING hallmarks). It also has genomic instability and inflammation from immune cells can become tumor promoting (ENABLING CHARACTERISTICS).
in the metastatic cascade, how do cancer cells interact with the ECM?
carcinoma cells must breach the basement membrane, traverse the connective tissue, intravasaste.
_______ of ECM is an active process that involves several steps.
Invasion! loosens up E-cadherin, degrades ECM, attaches ECM components, the cells migrate
how do cancers dissociate cells from each other?
they alter molecular adhesions. Ecadherin is down regulated, which facilitates detachment.
how is the basement membrane and interstitial tissue degraded by cancer cells for invasion?
proteolytic enzymes are secreted or stromal cells are induced to make them. Matrix Metallo Proteases (MMPs) remodel insoluble components, and release ECM sequestered growth factors. when collagen is cleaved, proteoglycans have chemotactic, angiogenic, and growth promoters that get released
how do cancer cells move
ameboid migraion or by cutting basement with proteases
how do cancer cells change their attachment to ECM and the proteins there?
tumor cells are resistant to apoptosis. cleavage of basement membrane allows for new binding sites that stimulate migration. receptors are not as important in cancer cells as in normal cells for maintaining the cells in a resting state
cancer cell motitlity
cleavage products of matrix components and IGF have chemotactic tumor activity. movement can be potentiated by tumor cell derived cytokines like autocrine motility factors. move collectively, mesenchymally, ameboid
when you lose Ecadherin, what does it mean about your cancer phenotype?
it’s invasive! E cadherin is lost through: LOH, inactivation mutation, silencing, repression
what transcription factors promote epithelial to cell mesenchymal transition by repressing Ecadherin?
SNAIL, TWIST, ZEB 1/2
list the steps of epithelial to mesenchymal transition that is used inappropriately by cancer cells.
palatogenesis, neural crest formation and movement, cardiac valve formation, myogenesis
do cancer cells self destruct when not attached to a basement membrane?
No!
what changes are associated with EMT (epithelial to Mesenchymal Transition)?
downregulation epithelia proteins (ecadherin, cytokeratins). upregulation mesenchymal proteins (vimentin, fibronectin, n-cadherin, motility/invasiveness, increased protease secretion, fibroblast-like morphology
What does EMT help cancer cells resist?
chemo
tumor microenvironment
ECM+growth facors+ fibroblasts + immune cells. cross talk between these. not a static barrier, an area instead where reciprocal signaling can affect tumor suppression, promotion, progression
what are tumor cells vulnerable to when they are in circulation?
destruction!!!! by: mechanical shear stress, apoptosis by adhesion loss (can resist), immune system defenses. Typically they bind/aggregate to enhance survival/implantability. can bind and activate coagulation factors.
how do tumor emboli extravasate?
adhere to endothelium, egress through basement membrane via adhesion molecules
what are/where are tumor associated macrophages found?
found in tumor margin. they help tumors intravasate into their new tissue home
do natural pathways of drainage explain distribution of cancer metastases?
nope.
what are the 2 theories about why metastasis is preferential to certain areas?
seed and soil theory (needs of cancer cell for specific environment), and the mechanical arrest theory (cells arrest in first capillary bed encountered). these theories are not mutually exclusive.
breast cancer cells express chemokine receptors such as ____ sense chemical gradients and lead cancers to favorable sites.
CXCR4
are tumor cells efficient at colonizing distant organs?
no….tumor cells shed each day can be detected in the bloodstream. to compensate they can lie dormant. it seems that tumor cells secrete cytokines, growth factors, ECM molecules that act on stream cels that make a metastatic site habitable for cancer cells
direct metastases
invasive masses which interfere with normal function
indirect metastases
“paraneoplastic syndrome” paracrine/endocrine effects. occur in 7-15% of patients
paraneoplastic syndrome
consequence of cancer presence, but not due to local present of cancer cells. neither direct or indirect cuase. thought to be the result of hormones/cytokines secreted by tumor cells and or immune responses the tumor triggers. can trigger: ectopic hormone production, cutaneous lesions, arthropathies, myopathies, myopathies, neuropatheis, thromboses, nephrosis, cachexia, DIC
what are the main causes of death in cancer (non-lukemic)
in order: infection, organ failure, thromboembolism, hemorrhage, emaciation
_____% of all malignant neoplasms are caused by environmental factors.
80%. this is shown by regional differences in cancer rates, worldwide differences in cancer rates, and especially shown when migration to a new country happens (within a few generations you switch to being at risk for THAT countries cancers)
what causes the environmental risk factors for most types of cancer?
that is unknown. Tobacco causes 30% of all cancer deaths (with 85% of lung carcinoma related to tobacco use).
tobacco has been implicated as a risk factor for what cancers?
cancer of oral pharynx, larynx, pancreas, bladder, esophagus.
what cancers are highest death rates for men and women in US?
men=lung cancer (34% of cancer deaths) then prostate (12%) then colo/rectal (11%). women=lung (21%), then breast (18%), and colon (13%)
what is the cumulative lifetime risk of cancer for men and women in Colorado?
1/2 for men and 2/5 for women
when are you most likely to get cancer?
in the 7th/8th decades
is Colorado lower or higher cancer incidence that US?
2-5% lower than US rates recently. in the last decade, its 10-13% lower
what’s the most common cancer diagnosed in men and women?
breast in women, prostate in men.
who identified polycyclic aromatic hydrocarbons as active carcinogens in tar?
Kenneway and Heiger.
who found that croton oil promotes but doesn’t initiate skin tumors?
Berenblum
environmental carcinogens (4)
1) polycyclic aromatic hydrocarbons;
2) aromatic amines;
3) nitrosamines;
4) aflatoxins. all must be activated to a carcinogenic form by microsomal enzymes (cytochrome P450).
“PAANA-cotta is delicious, but may be a carcinogen!”
how do polycyclic aromatic hydrocarbons form?
from incomplete combustion of fossil fuels. they become the diol epoxide
how do aromatic amines form?
industrial and consumer products. N-hydroxylation and sulfating are required.
how do nitrosamines form?
when 2 amines in food react with nitrous acid in stomach. hydroxylation leads to carbonium intermediate.
how does aflatoxin form?
moldy grains and ground nuts, particularly when no refrigeration. produced by aspergillum flavus. microsomal expoxidation required
what is the general theory on chemical carcinogenesis? (3 things)
chemical carcinogens are usually metabolized by microsomal enzymes to be active. the metabolite is an electrophile. the electrophilic species can modify protein, RNA, and DNA
what are the direct acting carcinogenic compounds?
alkylating agents (n-mustards, chemotherapeutic agents). acylating agents (dimethylcarbamyl chloride)
if adducts created by electrophilic attack are not excised from DNA, what happens
these bulky adducts cause mutations (eg: mispairing, frameshift)
what are some other carcinogens that account for a small percentage of known cancers?
metal vapors, arsenic, thorotrast (liver cancer from radiology), exposure to vinyl chloride, asbestos, benzene exposure (ML), radon gas
ames test
measures the ability of things to mutagenize a set of strains of salmonela typhimurium
principles of cancer established by administration of suspected carcinogens (8):
1) effect of chemical is dose dependent,
2) specific carcinogen=specific cancer,
3) time is required,
4) cell proliferation is required (rapid turnover is more risk),
5) changes transmit to daughter cells,
6) malignant risk is in stem cells,
7) malignant cells are incorrectly differentiated stem cells,
8) cancers develop through initiation and promotion
is promotion due to carcinogens?
no it is the effect of a non-carcinogen.
what are promoters of cancer?
mutagens or carcinogens. often irritants but not all irritants are promoters. often cause inflammation, Phorbol ester is best experimental example-activates kinase which activates cell proliferation
what are some types of inflammation that promote cancer? (6)
ulcerative colitis, atrophic gastritis, cholecystis, chosteomyelitis (may cause scams cancer), schistosomiasis of urinary bladder, chronic hepatitis
how do chemicals cause cancer?
they cause mutations that accumulate in DNA! all carcinogens are mutagens, human cancers have lots of mutations, DNA repair mutations can lead to cancer, chromosomal aberrations and aneuploidy can affect/activate genes, loss of growth suppression causes
epigenetic effects of chemicals
chemicals cause perterbuations in cell cell interactions and communication. carcinogens can modify protein and RNA, resulting in things like activation. many chemical carcinogens are toxic to cells, they may therefore promote improper cell growth.
what are the four major forms of cancer seen frequently and are often fatal?
lung, pancreas, colon, prostate. they are carcinomas (malignant tumors) derived from organ’s epithelium.
“invasion” means what with cancer?
somewhere along the edge of the growth of the carcinoma in the epithelium, small groups of tumor cells broke through the basement membrane to invade connective tissue storm
what must you do before planning any type of cancer treatment?
do a biopsy! to identify as carcinoma or something else
what are 2 features that need to be determined about a carcinoma?
grade and stage. both contribute to a prognosis and treatment planning
stage
extent of tumor spread at diagnosis time. strongest predictor of prognosis. Now we use a TNM classification. T (1-4)=size of tumor, N (1-4) is lymph node involvement, M is presence of metastasis (Mo or M1)
what does Tis mean
tumor in situ
grade
state of differentiation of tumor cells seen in histological sections. low grade-well differentiated. high grade-don’t resemble normal epithelia
low grade tumors produce what?
squamous carcinoma= spindle shaped, produce keratin, have desmosomal connections. adenocarcinomas= form primitive glands and produce mucin.
signs and symptoms stem from _____ effects of the cancer at the site where it developed, or ______ effects from metastasis.
local, distant. advanced stage=weight loss, fatigue, extreme cachexia, infection (usually acute bronchopneumonia)
lung carcinoma
present with cough, difficulty breathing, secondary pneumonia, chest pain, facial swelling, wight loss, distant mets. diagnose with imaging, biopsy, VATS (video assisted thoroscopic biopsy), cytology, meidastioscopy. 124,000 deaths from cancer from smoking each year. risk is age, duration of smoking and level, occupational history, air pollutant exposure, family history.
squamous cell carcinoma lung cancer
25-40% of cases. linked to cigarette smoking. arise from squamous metaplasia and dysplasia in bronchial tree. epithelium replaced with squamous epithelia over time. often large, necrotic, hemorrhagic near center of lesion. cancer cells are moderately-well differentiated. keratin pearls, P53 mutations, loss of Rb, p16 inactivation
adenocarcinoma lung cancer
25-40% of cases. most common type in women, nonsmokers. many are smokers. arise centrally. form primitive gland-like structures, positive for mucin. K-Ras mutations common. has bronchioloalveolar carcinoma (best prognosis, not linked to smoking)-cells grow along alveolar septa and airspace w/ little storm. Treat with surgery and radiation
large cell carcinoma lung cancer
10-15% of cases. undifferentiated high grade cancer where anapestic cancer cells may not produce keratin or mucin.
small cell carcinoma lung cancer
20-25% of cases. linked to smoking. arises anywhere in lung. only chemo. no differentiation. small, dark cell clusters that metastasize widely in the body. Bad news bears.
lung cancer is associated with _______ syndromes.
paraneoplastic. (1-5% of cases). hormones and hormone like production by cancer cells.
pancreatic cancer
back pain, jaundice (due to bile duct block), cachexia, migratory thrombophlebitis. arises in all stages, mostly in cola areas of pancreatic ducts/ductules (intraepithelial neoplasias). cancer grows silently so diagnosed too late-already metastasized widely. diagnose with imaging, biopsy. treat with surgery (rare), radiation and chemo. most are differentiated adenocarcinomas. K-ras mutations. synthesize prominent connective tissue storm. Stent sometimes to prevent ascending cholangitis (leads to septic, infection, shock)
colorectal carcinoma
second leading cause of death in men and women. moderately well differentiated adenocarcinomas arising in mucosal layer of bowel wall. arise in pre-existing adenomatous polyps. spread via lymph/blood. 2 major types: (neoplastic colonic polyps), tubular adenoma and villous adenoma=risk for cancer. size of polyp correlates to risk. found a lot on the R side (large growths protruding into lumen), and some on L (apple core lesion, creates constipation). often metastasizes to liver. over 50, colonoscopy.
prostate carcionoma
leading cause of cancer in men, second leading cause of cancer death. arise in periphery, can be felt on exam. firm mass, produce difficulties voiding urine. most common in African Americans, least common in Asians. androgens may play a role, cause is largely unknown. diagnose with ultrasound/biopsies. PSA can be elevated. progresses via loss of tumor suppressor genes. often treated by radical prostatectomy. advanced stage=anti-androgen therapy. Gleason system grading, subordinate pattern and predominant pattern are added. 8-10 is aggressive cancer.
BPH, benign prostatic hypertrophy
enlarges central, peri-urethral region of gland. produces problems with voiding
primary induction chemotherapy
drug treatment= primary treatment strategy, no surgery radiation. may be curative in some cases (germ cell cancers, Wilms tumor, etc.). used also for patients who present with advanced/metastatic disease with no other effective treatment. goal is to palliate tumor related symptoms, improve quality of life, prolong time btw. progression, improve survival
neoadjuvant chemotherapy
used in patients with localized cancer when localized therapies (surgery/radiation) may not be completely effective. used BEFORE surgery/radiation, can help spare vital organs (may shrink tumor to make surgery more effective, etc). may kill micrometastatic disease. goal is to increase effectiveness of the surgery/radiation, maximize tumor destruction, minimize normal tissue damage. used to treat anal, bladder, breast, esophageal, head and neck, gastric rectal cancers, osteogenic, soft tissue sarcomas
adjuvant chemotherapy
used in patients AFTER local treatment modalities (surgery/radiation). goal is to reduce incidence of localized/systemic recurrence-kill metastatic tumor cells. can increase effectiveness, improve survival rate. used to treat breast, colorectal, gastric, non small cell lung, melanoma. primary tumor removal makes it difficult to measure response to drug-relapse free survival
does conventional cancer chemotherapy have a small or large window?
small. smallest in therapeutic medicine. variable pharmacokinetics mean differences in treatment with same agent (efficacy and toxicity), small changes can have large effect
polymorphisms in what region/gene are associated with toxicity by irinotecan treatment?
UGT1A1, phase 2 enzyme is responsible for inactivating the active metabolite
is more or less better for combining chemotherapy drugs?
more is probably better. single drugs rarely cure cancer. mutations can cause drug resistance, which makes them harder to kill with 1 drug.
what are some general principles for combining chemotherapy drugs?
drugs that are partially effective against same tumor alone should be combined! when several members of a class of drug are available, choose ones that have toxicities that don’t overlap with other agents (more side effects but less lethal interactions). use drugs in optimal doses and schedules. use intervals as short as possible. avoid removal or dose reduction from combination since this may allow resistant cells to grow
how do you treat with cancer chemotherapy?
try to find a cytotoxic agent that can kill tumor cells (death via apoptosis). identify the maximally tolerated dose (MTD) and treat as close to this as possible. hope you kill all tumor cells with as few side effects as possible. choose drug based on tumor site
BH3 profiling
BCL domains are mediated by BH3. this helps to determine if cells are near or far to death threshold. mitochondria are exposed to titrated doses of BH3 peptides to make mitochondrial outer membrane permeabilization (MOMP). primed=low dose and lots of MOMP. unprimed=high dose and little to no MOMP
why does chemo work?
despite the fact that disruption of apoptosis/cell death is a hallmark of cancer, tumor cells are closer to apoptosis threshold than most normal cells. BH3 profiling measures this proximity where death will occur
in AML, how doe BH3 profiling work?
pretreatment BH3 predicts a clinical response to chemo in AML. This is done by testing how easily tumors cells undergo apoptosis
what are some problems with current chemo therapeutics?
kill normal cells along with tumor ones. window is small. affects dividing cells, we aren’t often targeting defect that caused the tumor
how do we hope to treat with cancer chemotherapy in the future?
identify particular defect that cause patient’s cancer, predict what to go after. use drug that targets that/causes death or growth arrest in tumor with the defect. determine Optimal Biological Dose (OBD) for inhibiting biological target. combine agents based on understanding how they work.
what are some common mechanisms of chemoresistance?
reduced uptake of drug into tumor cells/increased efflux pumps. leads to MDR (multiple drug resistance). reduced apoptosis machinery. mutations alter cellular targets. repair of cellular damage. tumor stem cells regenerate. Cancer cells are unstable and evolve to resist treatment. Inactivate the drug. Some of these processes work for one drug, but a different drug may also be needed for different resistance mechanisms (single or multiple drugs).
alkylating agents that react with DNA:
form covalent chemical adducts and inter strand crosslinks. if they don’t repair, no replication. apoptosis
cyclophsophamide
nitrogen mustard. alkylating agent. most frequently used. used for breast cancer and lymphomas, child tumors, solid tumors. inactive, must be metabolized. metabolite is ALDH substrate. cells with high levels ALDH are resistant. *think about how drug metabolized to understand how it works. *
alkylating agents: resistance mechanisms
reactions with cellular molecules. GSH tripeptide with free cysteine sulphydryl reacts with inactive alkylating agents. DNA repair removes alkyl group from guanine. cross link repair-high levels NER to remove crosslinks
alkylating agents: toxicity
hematopoeitic toxicity. dose limiting. nausea, vomiting, gonadal toxicity, alopecia, carcinogenesis. increased risk of cancer.
cisplatin and analogues
anti cancer drug. derivatives are less toxic. crosslink DNA making replication impossible-apoptotic response. effective testicular and ovarian, head and neck, lung, bladder cancer
platinum compounds: resistance
reduced accumulation (decreased uptake, increased efflux), inactivation, increased NER repair, more repair proteins, increased tolerance DNA damage. inhibition of aopoptotic response.
platinum compounds: toxicity
cisplantin-nephrotoxic (aggressive hydration helpful). nausea, vomiting, ototoxicity. damage inner ear. neurotoxicity. carboplatin (myelosuppression, platelet toxic), oxliplatin (sensory neuropathy). different toxicities with different PK.
antimetabolites: 5-fluorouracil
pyrimidine analogue. activates intracellular FdUMP by Thymidine kinase. (causes dTTP deletion and inhibits DNA synthesis). Inhibits DNA synthesis and activates apoptotic response because of DNA damage. GI, breast, head/neck, ovarian
5-FU: resistance mechanisms
target enzyme is altered. point mutations=reduced affinity FdUMP. regulation of translation, TS suppresses mRNA translation. inactivation of normal feedback TS level mechanism
5-FU: toxicity
primarily on rapidly growing normal cells. myelosuppression, gastrointestinal toxicitgy. alopecia, derm problems
topoisomerase interacting agents
topoisomerases help package chromatin. form temp. single/double strand breaks in DNA and religation. derived from natural products.
topoisomerase interacting agents: mechanism of action
stabilize cleavable complex btw. topoisomerase and DNA, inhibiting relegation to leave the breaks. damage=apoptosis. used in breast, ALL, AML, lymphoma, sarcoma, other.
topoisomerase interacting agents: resistance
increased drug efflux. important for etoposide, doxorubicin. mutations confer resistance don’t alter enzyme activity
topoisomerase interacting agents: toxicity
myelosuppression. can result cardiotoxicity and acute and chronic effects. associated with chelating ability, damage due to levels of ant-oxidant enzymes (catalse) lower in heart. iron chelators may protect. can cause secondary malignancies (esp. in AML)
antimicrotubule agents
polymers of alpha and beta tubulin. stabilizes or destabilizes microtubule dynamics to activate apoptosis
antimicrotubule agents: vinca alkaloids
naturally occurring (vinblastine, vincristine). used pediatric malignancies, hematopoietic tumors, solid tumors. bind tubulin and cause depolymerization
vinca alkaloids-resistance
increased drug efflux. MDR transporters (MDR1). cross resistance other drugs. mutations in tubulin and alter binding
vinca alkaloids: toxicity
neurotoxicity, damage to nerve cells (esp. wi/vincristine). myelosuppression, neutropenia
microtuble targeted agents: taxanes
paclitaxol, docetaxel. occurring compounds from pacific yew tree bark. used breast, ovarian, lung, solid. bind interior of microtubule and stabilize against depolymerization by altering dissociation rates. blocks mitosis
taxanes: resistance
drug efflux: MDR family ABC transporters. cross resistance other drugs. mutations in tubular prevent binding. inhibition apoptosis
taxanes: toxicity
myelosuppression-neutropenia. peripheral neuropathy. alopecia
hormonal agents cancer treatment
treat hormonally responsive cancers (breast, prostate, endometrial)
tamoxifen
estrogen receptor inhibitor
antiandrogens
bind androgen receptor and inhibit transcription factor
aromatase inhibitors
catalyze synthesis of estrogen from androgens. inhibits this
gonadotrophin releasing hormone (GNRH)
inhibit testosterone production
hormonal agents: toxicities
side effects are associated altered steroid hormone signaling. hot flash, bone density change, gynecomastia
antibodies in cancer treatment
rituximab (anti CD20, B cell tumor treatment), perception (anti-her2 breast cancer), avastin (anti-VEGF colon cancer), inhibit function of target. some deliver toxins, chemotherapeutic drugs, radioisotopes
retuximab
antibody recognizes antigen displayed on B cell tumors derived from progenitor cells at different stages of differentiation
kinase inhibitors
targeted to defects that cause tumor development. less toxic. may be highly effective. we have few examples were they cure alone. resistance is almost always guaranteed.
chronic myelogenous lukemia
caused by single oncogenic event (fusion of Bcr-Abl), translocation makes active tyrosine kinase Bcr-Abl. Imantinib inhibits the active site of the enzyme. majority of resistance is appearance of resistant alleles. Most Imatinib resistant patients have mutations that alter drug binding. Dasatinib works in CML patients with mutated Bcr-Abl (resistant to Imatinib)
how do immune checkpoint inhibitors circumvent tumor strategies to avoid immune system?
CTLA-4 reduces T cell activation to maintain self-tolerance (negative signals sent in response to dendritic activation). if you block this you enhance T cell activation. PDL-1 mechanism inhibits T cell effector function, if tumors have unregulated PDL-1 they can avoid immune destruction
Contrast and compare differences and purposes of different kinds of chemotherapy- adjuvant, neoadjuvant and primary chemotherapy.
Adjuvant- after local treatment, trying to kill micrometastases. Neoadjuvant- before localized treatment such as surgery, trying to make that treatment more effective and less damaging. Primary- on its own with no other therapy in a few cases curative, more often for palliation of symptoms in patients with advanced disease.
Describe major differences between “targeted therapies” and conventional cytotoxics.
Conventional agents damage normal cells as well as tumor cells- therapeutic window is largely based on tumor cells being closer to their apoptotic threshold, MTD relevant for conventional agents less so for targeted agents, which are usually less toxic, resistance mechanisms different. Remember: conventional cytotoxics hit specific targets (e.g. Topoisomerase/DNA) just like “targeted” agents do- difference is that with the newer “targeted” agents we aim to hit a target that is different/faulty in tumor cells but not normal cells.
Discuss the basis for combining anti-tumor agents.
Combine agents that work to at least some extent on their own, avoid overlapping toxicities, use drugs at optimal doses, keep treatment-free schedules as short as possible. Works because of the heterogeneity in the tumor cell population- some tumor cells respond to drug A some to drug B.
Describe the mechanism of action, major toxicities and resistance mechanisms of prototypical drugs for each class of anti-tumor agent.
DNA damaging agents, toposiomerase interacting agents, microtubule interacting agents, hormonal agents, antibodies, kinase inhibitors. Some resistance mechanisms generally applicable- e.g. drug efflux through transporters, resistance to apoptosis.
Some resistance mechanisms specific to agent- e.g. mutations in drug target, activation of repair mechanisms, other ways to activate steroid receptors. Many drugs have similar toxicities- usually associated with damage to fast growing cells- GI toxicity, myelosuppression. Specific toxicities depend upon mechanism of action- e.g. neurotoxicity associated with microtubule-interacting agents.
drug tailoring is important for anti cancer drugs. describe how pharmacogenetics is important for this?
small differences in drug handling can have major effects. polymorphisms can can affect toxicity and activation dramatically.
examples of cancer chemo
DNA damaging agents, topoisomerase interacting agents, antimetabolites, microtubule interacting agents, hormonal agents antibodies, kinase inhibitors, immune checkpont inhibitors
