Chapter 3 Robbins/Pathoma Flashcards
C reactive protein is involved in what pathology?
Fibrinogen does what? what is this the basis of?
increased risk for myocardial infarction
causes RBCs to form stacks (rouleaux) that sediment more rapidly –> basis for erythrocyte sedimentation rate
What are the growth factors associated with angiogenesis
VEGF-A –> migration and proliferation of endothelial cells
NO –> vasodilation and formation of vascular lumen
FGF-2 –> proliferation of endothelial cells and helps get macrophages and fibroblasts to the area
Angiopoietins 1 and 2 –> structural maturation of new vessels
Eosinophils are abundant in immune reactions mediated by what?
what else do they have that helps destroy helminths?
IgE
major basic protein
when fibroblasts are added to the scarring tissue, what do some become and what does this help do?
they become smooth muscle like, and are called myofibroblasts –> contribute to the contraction of the scar over time
**contraction meaning reduction in size
What are the different CD4 cells and what do they produce?
Th1 –> IFN-gamma –> activates macrophages in the classical pathway
TH2 –> IL4,5,13 –> activate eosinophils and is needed for alternative pathway
Th17 –> IL-17 –> recruit neutrophils and monocytes
1) what’s the biggest cause of delay in healing?
2) what is the most important systemic cause of abnormal wound healing?
3) pirates??
4) what mechanical factors can you think of?
Infection –> the biggest one
Diabetes –> most important systemic causes of abnormal
Vitamin C deficiency –> low collagen synthesis so good luck closing that wound
someone on bedrest that doesn’t listen and opens their knee wound
what is PGE2 famous for?
what else can lead to one of these symptoms?
Pain and fever
bradykinin
Which macrophage initiates tissue repair?
which ingests and eliminates microbes?
which secrete mediators of inflammation?
M2
M1
M1
Explain the creation of prostaglandins from arachidonic acid, the different types and what they do?
(4 major things)
arachidonic acid uses cyclooxygenase –> COX1 is constitutively expressed, but COX2 is upregulated during inflammation
PGD2, PGE2 –> vasodilation
PGI2 (prostacyclin) –> vasodilator and potent INHIBITOR of platelet aggregation
Thromboxane A2 –> platelet aggregating agent and vasoconstrictor
explain Leukocyte adhesion deficiency
1) what is the problem
2) hallmarks?
3) what is the clinical feature?
autosomal recessive defect of integrins –> CD18 subunit specifically.. so you can’t adhere to the surface and be pulled in
1) delayed separation of the umbilical cord (normally the tissue dies and falls off on its own but it’ll be delayed without neutrophils
2) Increasing circulating neutrophils (half of the pool is usually adhered in the lungs.. called the marginated pool.. but they’re not adhered anymore
3) recurrent bacterial infections that LACK PUS
What is Serous Inflammation?
what is an example?
exudation of cell poor fluid into spaces created by cell injury
**skin blister resulting from a burn or viral infection represents accumulation of serous fluid beneath the damaged epidermis
Explain engulfment and what is involved
bound to phagocyte receptor –> pseudopods extend around it to become a phagosome –> binds with a lysosome –> now called a phagolysosome –> degrades it.
What do CD4 cells recognize? (mnemonic)
how does the CD4 cell bind to the APC? (mnemonic)
what about CD8?
4 x 2 = 8
CD4 recognizes MHCII
CD28 on the T cell binds to B7 on the antigen receptor cell. 28 / 7 = 4.. CD4
8 x 1 = 8
CD8 recognizes MHCI
Explain the production of ROS starting from O2
1) starting from O2, what is this step called? what enzyme is famous here?
2) from here, what is created?
3) finally, how does this get to bleach?
4) which one of these steps is the most efficient system for neutrophils?
O2 –> O2- (this is called the respiratory burst, and uses NADPH Oxidase
O2- –> H2O2 (spontaneous)
H2O2 –> HOCL (bleach) via Myeloperoxidase (MPO)
MPO/HOCL system is most efficient
What is Leukocytosis?
why is there so many of these?
what kind of leukocytes are there more of? what is this called physiologically
also referred to as Leukemia reactions –> they are similar to the white cell counts observed in leukemia and have to be distinguished from that.
there’s an accelerated release of bone marrow post mitotic reserve pool (caused by IL1 and TNF)
tons of immature neutrophils –> left shift
What is Purulent (suppurative) inflammation?
common example of this?
what are localized collections of purulent inflammatory tissue called? what do they look like histologically?
characterized by production of pus, an exudate consisting of neutrophils, liquefactive debris of necrotic cells, and edema fluid
acute appendicitis
abscesses –> central region that appears as a mass of necrotic leukocytes and tissues, surrounded by a layer of preserved neutrophils
How does fever happen?
IL1 and TNF get into the blood stream, hit the perivascular cells of the hypothalamus
they up regulate COX activity which increases PGE2, raising the set point of the hypothalamus
What is the most successful therapeutic for people with chronic inflammatory disease?
what are examples of this?
TNF inhibitors.. it’s preventing leukocyte recruitment!
RA or psoriasis or IBD
why is nitric oxide considered a free radical?
how is NO created?
which is the only one associated with microbial killing?
NO + O2- superoxide –> ONOO-
via NOS –> eNOS (endothelial), nNOS (neuronal), iNOS (inducible)
iNOS
why can neutrophils be found in a chronic state? what’s an example?
neutrophilic exudate can persist for many months.
Osteomyelitis
called “acute on chronic”
Explain Liver regeneration
1) start with hepatocyte proliferation.. what is this triggered by and what are the phases?
Hepatocyte proliferation in the regenerating liver is triggered by:
1) priming phase –> IL6 is released from Kupffer cells to prime hepatocytes
2) growth factor phase –> HGF and TGF-a act on primed hepatocytes to put them into the cell cycle (because they’re quiescent remember)
3) Termination phase –> after divisions, they return to quiescent.
What are the five cardinal signs of inflammation?
rubor (redness) tumor (swelling) calor (heat) dolor (pain) functio laesa (loss of function)
What is an ulcer?
where is it most commonly encountered?
local defect, or excavation, or the surface of an organ that is produced by the sloughing of inflamed necrotic tissue
mucosa of the mouth, stomach, intestines, GI (peptic ulcers)
lower extremities of people who have circulatory disturbances
What are the major signs of acute inflammation?
what is causing each?
redness and warmth –> vasodilation, mediated by histamine, PGI2,D2,E2, bradykinin
swelling –> leakage of fluid from post capillary venules (histamine and tissue damage)
pain –> PGE2 + Bradykinin
Fever –> macrophages releasing IL1 and TNF
What are the 3 main growth factors helping to lay down connective tissue for scars?
where do they come from?
what’s the most important one?
PDGF, FGF-2, and TGF-B
M2 macrophages
TGF-B
What is exudate?
what is causing it?
what is an example?
what is transudate?
what is causing it?
what is an example?
extravascular fluid high in protein and contains cellular debris.. this is due to fluid and protein leakage.
**pus is a purulent exudate consisting of dead leukocytes and microbes
Transudate is a fluid with LOW protein content and LOW cellular material.. fluid leaks out due to an increased hydrostatic pressure or decreased oncotic pressure
**edema is considered an ultra filtrate
Most bacterial infections have local inflammation. in rare cases it can go systemic. what is this this called?
Sepsis, which is a form of systemic inflammatory response syndrome
What are the phagocytic receptors?
why are the ones on macrophages not self reactive?
what enhances the phagocytosis of stuff? what if this weren’t around? what are the specific ones to know?
Mannose receptor on the macrophage –> mammalian glycoprotein do not have terminal mannose on their cell membranes, bacteria do
Mac-1 –> integrin on macrophages that may also bind.
opsonins –> IgG and C3b
nonselective without it, kind of directs it to the area.
What is the oxygen independent form of microbial killing?
what two things should we know?
is it more or less effective for oxygen dependent?
secondary granules contain lysozyme and major basic protein
less effective by a lot.
What does IL6 do? where does it come from?
What about IL17?
Made by macrophages –> local and systemic reactions
IL-17 –> produced by T lymphocytes –> neutrophil recruitment
What are the four causes of inflammation?
Infection –> most common cause
Tissue necrosis –> remember inflammation follows necrosis
foreign bodies (splinters, dirt, sutures)
immune reactions (hypersensitivity reactions and autoimmune diseases) –> this is more for chronic
What are neutrophil extracellular traps?
what happens to the neutrophils because of these traps?
extracellular fibrillar networks that provide a high concentration of antimicrobial substances at the site of infection and prevent spread of infection by trapping them to the fibrils.
nuclei are lost during the formation of the nets, so their death
What is the response of lymphatics in inflammation? why is it happening?
what is a telltale sign of an infection in the wound with regards to lymphatics? diagnosis?
lymph flow increases to help drain edema fluid
red streaks near a skin wound –> lymphangitis (inflamed lymphatic vessels)
What is “the acute phase response”
what is included within this?
cytokine-indued systemic reactions
Fever Acute-Phase proteins Leukocytosis increased BP/pulse sepsis if severe
which CD4 cell is important for defense against helminths?
Th2
What cell plays a central role in repair by clearing offending agents and dead tissue? Be specific!
Macrophages (M2)
what do we use to inhibit thromboxane A2 or prostaglandins?
what if we want to inhibit just COX2? is that good or bad?
COX1 and COX2 inhibitors (or aspirin)
bad –> cox-2 is used primarily for prostacyclin, so if you inhibit that it could tip the scale to more thromboxane A2 leading to more vascular thrombosis
Wound contraction happens primarily in what kinds of wounds
large wounds
Regardless of what complement pathway, start from C3. what happens from there?
C3 converts is generated, cleaving C3 to C3A and C3B
C3B joins to help make C5 convertase, which cleaves C5 to make C5A and C5B
C5B joins with C6-C9 to form the MAC
Explain Liver regeneration: from progenitor cells
1) why would this occur if there is the other way of hepatocyte proliferation? examples?
in situations where proliferative capacity of hepatocyte, such as chronic liver injury or inflammation
What are the dominant cells in most chronic inflammatory reactions?
where are they derived from?
what does the classic pathway involve?
Macrophages
bone marrow hematopoietic stem cells
Classical M1 –> activated by microbial products like endotoxin and IFN-gamma –> engage TLRs and other sensors –> and produce
1) NO and ROS –> killing stuff
2) IL-1 (TNF too), IL-12, IL-23 –> inflammation
Explain the creation of leukotriene and lipoxins from arachidonic acid, the different types and what they do? (5 things)
arachidonic acid + 5-lipoxygenase –> major products
Leukotriene B4 –> chemotactic activator for neutrophils
LTC4, LTD4, and LTE4 –> bronchospasm, intense vasoconstriction and increased permeability of postcapillary venules
Lipoxins –> SUPPRESS inflammation by inhibiting recruitment of leukocytes
What are the steps of neutrophil arrival and function?
what is the basic idea and basic molecules associated with each?
Margination –> vasodilation slows blood in the post capillary venules, so they “marginate” from the center of flow to the periphery
Rolling –> the marginated cells need to be slowed down and they do so by rolling over “selections”
Adhesion –> we want to grab the leukocyte tightly and stop it. this is done by CAMs (on endothelial cells) and Integrins (which are on neutrophils)
Transmigration and chemotaxis –> makes sense
Phagocytosis –> consumption of the pathogens once they get there.
To prevent against the harm of free radicals, what are the 5 things that are going to be used to prevent damage in the cell?
Superoxide dismutase
catalase
glutathione peroxidase
ceruloplasmin (for copper)
transferrin (for iron)
In more detail: transmigration
1) what is another name for this process?
2) where is it mainly occurring?
3) what 2 molecules are helping bring them in?
4) what enzyme are they associated with?
1) diapedesis
2) post capillary venules
3) PECAM1 and CD31
4) collagenase (makes sense they need to break through the basement membrane)
In the early stages of inflammation, what gets the neutrophils to come in? not any signaling, just generally
leakage of fluids leads to concentration of blood and a slow blood flow. so an increased viscosity
this leads to “stasis”, which allows for neutrophils to accumulate
What are the 5 R’s of the inflammatory response
recognition recruitment removal regulation resolution
what does histamine do?
what is it the principal mediator for?
what can inhibit it?
causes dilation of arterioles and increases permeability of post capillary venules
immediate transient phase of increased vascular permeability
anti-histamine drugs binding to the H1 receptors
Leprosy, syphilis, cat-scratch disease, sarcoidosis, and chron’s disease are examples of what?
diseases with granulomatous inflammation
what is fibrosis?
what’s the difference between this and scarring?
major cytokine involved?
what cells produce collagen for kidney fibrosis? liver?
excessive deposition of collagen and other ECM components in a tissue
fibrosis occurs to abnormal deposition of collagen in INTERNAL ORGANS and is PATHOLOGIC
TGF-B
myofibroblasts, stellate cells
Function of Kallikrein?
cleaves plasma glycoprotein precursor to give rise to bradykinin
this leads to pain and increased vascular permeability, dilation of blood vessels.
What are the two major vasoactive amines?
what releases the first one? what 3 stimuli?
Histamine and serotonin
Histamine –> by mast cells
1) physical injury
2) binding of antibodies to mast cell (cross linking)
3) anaphylatoxins C3a and C5a
Serotonin is present in platelets and neuroendocrine cells. neurotransmitter in the GI and vasoconstrictor
When might you see foreign body granulomas?
Talc (intravenous drug abuse)
Sutures
Healing by Second intention
what is the principal mechanism of repair in this case?
what’s to note about the inflammatory response here vs first intention?
tissue loss is more extensive, such as in large wounds, abscesses, ulcerations
there is actually both regeneration and scarring
more intense because a greater volume of necrotic degrees, exudate, and fibrin must be removed (makes sense)
to note about M1 and M2 macrophages together?
they inhibit one another depending on the stimulus.
Labile, Stable, Permanent tissues?
for each one, what are they, what are some examples, and can they regenerate
Labile –> continuously dividing –> example is hematopoietic cells in the bone marrow and surface epithelia.. –> they can regenerate after injury as long as stem cell pool is reserved
Stable –> cells “quiescent” and stuck in G0. have minimal proliferation normally –> can divide in response to injury, but limited capacity (kidney, pancreas, parenchyma of most solid tissues)
Permanent tissues –> terminally differentiated and nonproliferation –> heart, neurons, kind of skeletal muscle –> ALWAYS results in scar.. cannot undergo regeneration
Remodeling of CT for a scar is done by what? what subtype of enzyme are they?
what does it do?
say we have over degradation of the CT, what’s going to stop it immediately?
Matrix Metalloproteinases (MMPs) –> collagenase
degrade the ECM to permit remodeling and extension of the vascular tube.
Tissue inhibitors of Metalloproteinases (TIMPs)
Explain fever:
1) what are the substances that cause it called?
2) endogenous ones? exogenous?
1) pyrogens
2) TNF, LPS
What are the two complications involving scarring?
examples of each?
wound dehiscence –> rupture of a wound –> after abdominal surgery and you vomit or cough.
ulceration –> can break down due to inadequate vascularization
What’s involved in the classic pathway?
Alternative?
Lectin pathway?
GM makes classic cars –> classic deals with C1 fixation to antibodies IgG or ism.
triggered by microbial surface molecules like LPS
plasma mannose binding lectin binds to carbs on microbes to activate C1
What two things happen when you have excessive formation of scars?
Hypertrophic scar –> raised scar but STILL in the same boundaries
Keloid –> grows beyond the boundaries of the original wound and does not regress –> common in African Americans.
Intracellular destruction of microbes and debris is mainly accomplished by what? what is it derived from?
ROS
NO
why would you think that neutrophils are only at the beginning of inflammation and macrophages are at the end?
neutrophils are short lived after they enter tissues.
Macrophages/monocytes survive longer and proliferate in the tissues.
Other than contraction of endothelial cells, what two other mechanisms lead to increased vascular permeability?
endothelial cell injury, resulting in endothelial cell necrosis and detachment
increased transport of fluids and proteins (transcytosis) stimulated by VEGF (vascular endothelial growth factor)
What causes heat and redness in inflammation?
vasodilation of arterioles and increased permeability of post capillary venules
Explain in more detail: adhesion
1) what is on the endothelium and what induces these to pop up?
2) what specific types should we know?
3) what is on the neutrophil that binds to these for tight adhesion? Important one to know?
4) what up regulates them?
on the endothelium, we have CAM molecules that are induced by IL1 and TNF.. they are going to grab and take hold of the integrins
VCAM and ICAM
the integrins (CD18 is important) are on the neutrophils and are unregulated by C5a and LTB4…
Labile, Stable, Permanent tissues?
for each one, what are they, what are some examples, and can they regenerate
Labile –> continuously dividing –> example is hematopoietic cells in the bone marrow and surface epithelia.. –> they can regenerate after injury as long as stem cell pool is reserved
Stable –> cells “quiescent” and stuck in G0. have minimal proliferation normally –> can divide in response to injury, but limited capacity (kidney, pancreas, parenchyma of most solid tissues)
Permanent tissues –> terminally differentiated and nonproliferation –> heart, neurons, kind of skeletal muscle –> ALWAYS results in scar.. cannot undergo regeneration
what two tissue types can undergo regeneration?
in each, what growth factors are driving it? examples?
labile + stabile
labile –> hematopoietic stem cells –> colony-stimulating factor
stabile –> no one knows –> kidney removal, the other kidney undergoes hyperplasia and hypertrophy
Most common mechanism of vascular leakage?
what elicits it?
if leakage is happening immediately, what is this reaction called? what are examples?
what if it’s happening with a delay? what is an example?
contraction of endothelial cells resulting in increased inter endothelial spaces
histamine, bradykinin, leukotrienes
immediate transient response –> burns, irradiation, bacterial toxins
delayed prolonged leakage –> late-appearing sunburn
What are the three morphologic features of chronic inflammation?
infiltration with lymphocytes and plasma cells
tissue destruction thanks to persistent infection
attempts at healing –> fibrosis or angiogenesis seen on slide
When do Scars form?
when regeneration alone cannot repair the tissue –> leads to connective tissue replacement.
in more detail: chemotaxis
1) what is the most common exogenous chemoattractant?
2) what are the 4 most common endogenous chemoattractants?
1) n-formylmethionine
2) IL-8, C5a, LTB4,
what is granulomatous inflammation a form of?
what is it characterized by?
why is it creating this granuloma?
what’s a hallmark in the staining?
what’s the classic disease process?
chronic inflammation
collections of activated macrophages, often with T lymphocytes
attempt to contain the offending agent that is tough to get rid of
pink granular cytoplasm with indistinct cell boundaries called EPITHELIOID CELLS.. then there’s a collar of lymphocytes and then you can see giant cells (groups of macrophages fused)
mycobacterium tuberculosis
What is acute inflammation characterized by?
what immunity is it?
when does it onset?
what’s to note about specificity?
what are the four types of stuff in the body associated with this immunity?
edema and neutrophils
innate
fast: minutes or hours
nonspecific
epithelium that covers body surfaces, mucus, complement system, cells (like mast cells, neutrophils, etc)
What do Mast cells have on their surface and what does it bind?
what happens when this thing binds to it?
FCeR1
binds the Fc portion of the IgE antibody
release histamine and prostaglandins
TNF and IL1 contribute to local and system reactions of inflammation: what is their role on systemic acute-phase responses?
they induce systemic acute phase responses including fever and implicated in sepsis.
What are the steps of scar formation?
1) what’s the first step? what’s to note about this?
1) Angiogenesis –> forming new blood vessels. they’re leaky due to VEGF which is why you have edema that persists in wounds
2) Formation of Granulation Tissue –> this is the pink, soft mass underneath the scab –> characterized by fibroblast proliferation and new thin-walled, delicate capillaries.
3) Remodeling of Connective Tissue –> maturation and reorganization of the connective tissue produces the STABLE fibrous scar.
Contracture?
what can it result in?
over exaggerated contraction leading to deformities of the wound and surrounding tissue
can result in joint problems
What four things activate neutrophils HIGH YIELD
LTB4, C5a, IL8, bacterial products (n-formylmethionine)
What is Fibrinous inflammation?
what is the conversion of this to scar tissue called?
fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant stimulus
characteristic in the lining of body cavities
**organization, leading to fibrosis
Of the complement products, what triggers mast cell degranulation?
What triggers opsonization for phagocytosis?
what is chemotactic for neutrophils?
C3A and C5A
C3B
C5A
How do we get arachidonic acid? what does arachidonic acid then split to?
Cell membrane phospholipids + phospholipase A2 = arachidonic acid
arachidonic acid –>
cyclooxyrgenase which includes all Prostaglandins
or
5-lipoxygenase which includes leukotrienes and lipoxin!
What is IL-1 and TNF doing for neutrophils?
inducing selectins
inducing CAM
inducing production of NO
Healing by First Intention?
what is the principal mechanism of repair in this case?
example of this?
when the injury involves only the epithelial layer
regeneration
healing of a clean, uninfected surgical incision
Where are acute phase proteins synthesized?
what are the three best known?
these three are stimulated by what cytokines?
Liver
C-reactive protein, fibrinogen, serum amyloid A
IL5 (for C-reactive and fibrinogen)
IL-1 or TNF (for SAA)
What does the alternative macrophage pathway involve?
activated by IL-13 and IL-4
responds by producing:
1) growth factors and TGF-B to aid in tissue repair
2) IL-10 and TGF-B for anti-inflammatory effects
What are the 3 outcomes of acute inflammation?
complete resolution (perfect world)
Healing by connective tissue replacement (scarring or fibrosis)
Chronic inflammation –> if the other two options will not resolve it
What are the major causes of chronic inflammation?
persistent infection
hypersensitivity reactions (including autoimmune disease, allergic diseases like asthma)
prolonged exposure to potentially toxic agents
What are the three major components to acute inflammation (physiologically)
dilation of small vessels (arterioles) increasing blood flow
increased permeability (of the postcapillary venules)
emigration of leukocytes from this location
Someone’s worked in a sand factory for years, what kind of inflammation would you think they present with and what is it called?
silicosis –> particulate silica that’s inhaled.
chronic inflammation
What is the cause of hereditary angioedema (hint: relates to complement)
what about paroxysmal nocturnal hemoglobinuria (PNH)?
deficiency of the C1 inhibitor
deficiency of DAF or CD59 –> DAF prevents C3 convertase formation and CD59 prevents MAC formation
In more detail: explain rolling
1) what is the reasoning of it?
2) what is on each component and where do they come from?
3) what induces these speed bumps?
the neutrophil comes in because of margination, it’s slowing down but it needs to roll over speed bumps
that’s where P and E selectin come in. they are binding and letting go of Sialyl Lewis X on leukocytes to create the rolling
P selectin comes from Weibel-Palade bodies in the endothelial cell.
E selectin is also from endothelial cells, but not from the Weibel Palade bodies
both are induced from IL-1 and TNF
say we want to cause bronchospasm. what is more effective: histamine or leukotrienes?
leukotrienes
What is Exuberant Granulation?
what is it blocking?
what is it also called?
what do physicians have to do in this case?
formation of excessive amounts of granulation tissue –> protruding above the surrounding skin. –> blocks reepithelialization
Proud flesh
remove it in order to let the wound heal.
What can we use to inhibit phospholipase? (coincidentally this thing also inhibits transcription of genes of everything else
corticosteroids (broad-spectrum anti-inflammatory
What are the two ways in which tissue is repaired?
Regeneration by proliferation of residual cells (uninjured) and maturation of tissue stem cells
deposition of connective tissue to form a scar
Acute inflammation: what are the primary cells associated with this?
Chronic inflammation?
Neutrophils
Lymphocytes
