Inflammation-Hunter Flashcards
What is the purpose of inflammation?
it is an innate immune response to deal w/ microbes & necrosis (from any cause). Need to get rid of pathogens & need to heal.
T/F Inflammation can be both good & bad–>it is a double edged sword.
TRUE
What are some examples where inflammation is good & an example where inflammation is bad?
Good inflammation: impetigo in response to streptococcus pyogenes; function of vaccines requires inflammation w/ exposure
Bad inflammation: rheumatoid arthritis
What are the features of inflammation that were recognized long ago?
Redness (Rubor) Swelling (Tumor) Heat (Calor) Pain (Dolor) Loss of Function (functio laesa)
T/F Inflammation is in itself a disease.
FALSE. It is a nonspecific response that can be helpful or harmful.
Where is the “mama” of the immune system located? How does this relate to inflammation?
Bone marrow: “mama” of the immune system
produces a bunch of the cells involved in inflammation
Pluripotent hematopoietic stem cells give rise to 2 lineages.
Lymphoid & Myeloid.
Myeloid is our focus. These are released into the blood.
Most important cell of this lineage: neutrophil
Other important cell: monocyte–>differentiates into macrophages!
Mast cells also found here.
What is another name for neutrophils?
polymorphonuclear leukocyte
Where are mast cells usu found?
usu found in the tissues. Often found in CT & lining blood vessels. Less often found in the blood.
What are the primary sensors of acute inflammation? What do these cells do?
mast cells & macrophages (main guy)
these cells recognize tissue damage (from a variety of causes) & can recognize specific microbes (b/c they have receptors on their surface).
They then release mediators & orchestrate the inflammation response.
When the mast cells & macrophages (main guy) orchestrate the acute inflammatory immune response…which players do they get in the game?
hematopoietic cell types neutrophils! plasma proteins (complement) endothelial cells lining blood vessels (to release stuff)
Describe the order of the inflammatory process in general terms.
Inducer damages tissue.
Sensors recognize the damage & release mediators.
Mediators go to the target tissue & eliminate inducers & try to achieve homeostasis.
What are inducers?
exogenous or endogenous signals that report tissue damage, injury, or malfunction
could be trauma, burn, pathogens, toxins, ATP, urate crystals etc.
**they start the inflammatory process b/c they cause the problem
What are sensors?
tissue resident macrophages & mast cells that detect inducers w/ their specific receptors & release mediators for the inflammatory response.
In addition to macrophages & mast cells, what is another sensor?
dendritic cell
What are some examples of mediators & their classes?
cytokines: TNF, IL-1, IL-6
chemokines: CCL2, CXCL8
Vasoactive amines: histamine, bradykinin
Eicosanoids: includes prostaglandins
Direct Activation of a Sensor produces? Indirect activation of a sensor produces?
Direct Activation: good inflammation, get rid of a pathogen
Indirect Activation: bad inflammation, collateral damage of tissue
So, a macrophage senses a pathogen. What does it release to communicate to the endothelial cells lining blood vessels? Why is it important to communicate to these endothelial cells?
Among other things, it releases TNF alpha.
TNF alpha goes to the endothelial cells & says “hey, join the inflammation team!”
Endothelium attracts leukocytes, including neutrophils, & lets them pass into injured tissue.
It also becomes permeable to plasma & lets antibodies & fluid into the damaged tissue.
We have said that the main causes of inflammation (as sensed by macrophages & mast cells) are pathogens & tissue necrosis. What are some specific infections that can prompt inflammation?
bacterial infection viral infection fungal infection parasitic attack microbial toxins
We have said that the main causes of inflammation (as sensed by macrophages & mast cells) are pathogens & tissue necrosis. What are some specific causes of tissue necrosis that can cause inflammation?
Ischemia (MI)
Physical or Chemical Trauma (thermal injury, irradiation, environment chemicals, foreign bodies)
Hypoxia
An MI produces coagulative ischemic necrosis. What type of inflammation does it produce?
sterile inflammation
What are hypersensitivity reactions? What are they also called? What are some examples?
Also called immunopathology
normally protective immune system inflammation rxn damages cells & tissues
Ex: autoimmune diseases & allergies
When inducers are pathogenic microorganisms…what signal do they have & how is they recognized such that they trigger inflammation?
Inducer: pathogen–>has danger signal/PAMP
Sensors/Phagocytic Cells (macrophages): have PRR that bind PAMP.
Intracellular signaling pathway & activation of macrophages.
They release mediators for inflammation & get goin’ on their phagocytosis.
Then you get rid of the pathogen & you get tissue regeneration & repair.
What does PAMP stand for?
What does PRR stand for?
PAMP: pathogen-associated molecular patterns
PRR: pattern recognition receptors
What are some specific examples of PRRs found on sensor cell surfaces?
TLR: toll like receptors *found on plasma membrane & intracellularly Ex: TLR-5--sees flagellum. Other: Dectin-1: recognizes beta glucans. Fights fungi. CRD/mannose receptor Complement Receptor Scavenger Receptors: SR-A, MARCO Lipid Receptor: CD36
Describe how inflammation is induced by tissue injury.
Danger signals in the form of alarmins or DAMPs come from tissue that has experienced necrosis.
Phagocytic cells have DAMP receptors.
Cells release mediators & get inflammation going
Get tissue regeneration & repair.
What does DAMP stand for? What are some examples of DAMPs?
damage-associated molecular patterns Ex: HMGB-1 S100A8/A9 ATP
T/F Tissue that has experienced apoptosis releases DAMPs.
FALSE. Only tissue that has experienced necrosis. Apoptosis does NOT prompt inflammation.
What is collateral damage? What are some examples of this?
the bad effects of inflammation
chronic diseases: rheumatoid arthritis, atherosclerosis, lung fibrosis
hypersensitivity to insect bites, drugs, toxins
**have to use anti-inflammatory drugs
So…it seems cyclical: tissue damage–inflammation–collateral damage–inflammation. How is this cycle stopped?
stopped via the body’s anti-inflammatory mechanisms
stopped when the microbe or dead tissue is removed.
**trickier w/ autoimmune diseases
What is the trade off of anti-inflammatory medications?
more susceptible to infections
Describe what collateral damage might look like in the following tissues: Brain Lung Cardiovascular System Kidney Liver GI Microcirculation
Brain: confusion Lung: respiratory distress Cardiovascular System: shock Kidney: oliguria, anuria Liver: excretory failure GI: loss of fcn, ileus Microcirculation: capillary leak edema, DIC
Describe a general order to tissue repair. Note: tissue repair peaks after injurious agent has been removed.
Inflammation
Granulation Tissue
Wound Contraction
Collagen Accumulation Remodeling.
What is acute inflammation?
this is inflammation that has a fast onset & short duration (up to a couple of days)
ends when the offending agent is broken down
when it is over, mediators are broken down
Ex: sunburn
What is chronic inflammation?
can sometimes follow acute inflammation
longer duration (more than a few days)
sometimes occurs when the stimulus can’t be removed.
Ex: psoriasis
Which are more short-lived: macrophages or neutrophils?
neutrophils!
What accounts for the redness & swelling in acute inflammation?
Redness-hyperemia: b/c of vasodilation to arterioles, capillary bed, & venules w/ acute inflammation. More blood flows there.
Swelling-edema: b/c of increased vascular permeability @ capillaries. Fluid, leukocytes, & plasma proteins get out.
Once again, as a result of increased vascular permeability during times of acute inflammation…what substances get into damaged area?
leukocytes
plasma proteins (complement)
fluid
In general terms, describe the journey of the leukocyte that is a part of inflammation?
In the blood.
Recruited to a capillary bed.
Adheres to the endothelium of the blood vessel.
Transmigrates across the blood vessel into surrounding tissues.
Gets to damaged area via chemotaxis.
May or may not be a part of phagocytosis of bad stuff there.
With acute inflammation, there is vasodilation. But this is often preceded by _______. How does this happen?
preceded by vasoconstriction. This is neurogenic response to the acute injury.
How does vasodilation happen?
the injured tissue has some macrophages or phagocytic cells that release mediators. Histamine & NO will go to the smooth muscle of the arterioles, capillaries & venules & relax them. Then, these blood vessels will dilate.
What are the tradeoffs of having vasodilation & greater blood volume to an injured area?
stasis: the blood doesn’t move as quickly, it kind of just stays there.
Vascular congestion: you have a lot more blood in that area.
There are both good causes & bad causes of increased vascular permeability related to inflammation. What is the good cause?
Good Cause:
macrophages @ site of injury release mediators (including NO, histamine & leukotrienes). These target b.v. (esp venules) & contract endothelial cells (increasing inter endothelial spaces). These allows for more vascular leakage.
There are both good causes & bad causes of increased vascular permeability related to inflammation. What are the bad causes?
severe injuries that directly hurt the endothelium (burns, microbes)
neutrophils that adhere to the endothelium don’t know what to do & release their contents, causing more collateral damage to the endothelium.
What is the difference b/w transudate & exudate? They both result in edema.
transudate: fluid w/ low protein content, ultra filtrate of blood plasma. gets there b/c of imbalance b/w hydrostatic & osmotic pressure–not b/c of inflammation or increased vascular permeability
exudate: fluid w/ high protein conc’n & cells, gets there b/c of inflammation & increased vascular permeability.
What are examples of situations where you would see excess transudate?
Too high hydrostatic pressure b/c of congestive heart failure. Too low osmotic pressure b/c of starvation. Results in edema.
If you see a red streak along the site of a wound…what does it likely mean?
It means that there is a problem. This is an infection moving across a lymphatic channel. Microbes find their way into the lymph during inflammation.
What is lymphangitis? What is lymphadenitis? Why are lymph nodes enlarged in some of these cases?
lymphangitis: secondary inflammation of lymphatics
lymphadenitis: secondary inflammation of draining lymph nodes
* *lymph nodes enlarged b/c of hyperplasia of the lymphoid follicles & increased numbers of lymphocytes & macrophages.
How do macrophages recruit leukocytes to the injury site?
Among other things, macrophages release chemokines. This includes CXCL8: interleukin-8. This calls neutrophils.
What is extravasation of leukocytes & what are the sub-steps of this process?
extravasation: movement of leukocytes from lumen of blood vessel into interstitial tissue
* margination
* rolling
* adhesion (to endothelium via adhesion molecules)
* diapedesis (migration across vessel walls)
* chemotaxis (migration toward inflammatory stimulus of tissues).
How do adhesion molecules get added to endothelial cells of blood vessels?
macrophages @ the site of injury release a variety of mediators for the inflammatory response.
One set is cytokines (TNF alpha as an example). These add adhesion molecules to endothelial cells of blood vessels.
What are the different types of adhesion molecules & what role do they play in the recruitment of leukocytes?
Addressins on leukocytes bind selectins on endothelial cells. These bind w/ a low affinity & allow rolling of the leukocytes along, looking for injury site.
The immunoglobin superfamily adhesion molecules (LFA as an ex) are attached to leukocytes & bind integrins (ICAM as example) on endothelial cells tightly. This stops the leukocytes & tells them to get to that injury site!
Once the leukocytes have been stopped in their tracks, what happens?
They squeeze thru the inter endothelial spaces that have been created by some of the mediators secreted by macrophages. Note: this is in venules. Called diapedesis.
Once the inflammation is done, how do you get rid of the adhesion molecules?
once the blood vessels are no longer dilated, the blood flow will increase (no more stasis) & sheer force will get rid of the adhesion molecules.
How do the leukocytes get past the basement membrane of the blood vessel?
they secrete collagenase: creates a little damage to the blood vessel.
What is involved in chemotaxis?
leukocytes get to the site of injury by following chemoattractants (going up the conc’n gradient of this, almost chasing a snack)
Chemoattractants can be both endogenous & exogenous. What are examples of endogenous chemoattractants?
Endogenous:
chemokines (CXCL8)
complement (C5a)
leukotrienes (LTB4)
Chemoattractants can be both endogenous & exogenous. What are examples of exogenous chemoattractants?
Exogenous:
bacterial products
N-formylmethionine (f-met-leu-phe)
lipids
Explain the process of phagocytosis.
internalize stuff as a vacuole (called phagosome)
this fuses w/ a lysosome=phagolysosome
Bad stuff digested via NADPH oxidase (creates ROS)
Digested bad stuff is released to external environment via exocytosis.
What is the purpose of phagocytosis?
to get rid of bad microorganisms & dead & dying tissue
What are the 3 stage of histopathology of acute inflammation?
- Normal tissue
- vascular congestion, hyperemia, stasis w/ vasodilation.
- leukocytic infiltrate
What kinds of leukocytes are mainly involved in acute inflammation?
neutrophils.
What are some examples of injuries that can cause acute inflammation?
trauma
toxins
infarction
bacterial infections
What are some examples of injuries that can cause chronic inflammation?
viral infections
chronic infections
persistent injuries
autoimmune diseases
What are the 2 roads to chronic inflammation?
Road #1: acute inflammation that is prolonged
Road #2: a type of injury that immediately produces chronic inflammation
What does acute inflammation look like? Where can it go from there?
neutrophils predominant vascular changes limited tissue injury **can resolve & bring tissue back to normal **can form an abscess
How does an abscess heal? What do it look like?
has pus formation
heals via fibrosis (tissue injury, collagen deposition & some loss of function)
What are the features of chronic inflammation & how does it heal?
angiogenesis mononuclear infiltrate fibrosis progressive tissue injury **heals by permanently changing the tissue, probably fibrosis
What is found in the mononuclear infiltrate found in chronic inflammation?
mainly macrophages & lymphocytes, not as many neutrophils. plasma cells also present
What is another name for neutrophils? What does this mean?
polymorphonuclear leukocytes
**means that their nuclei have multiple lobes.
You see a bunch of cells w/ multiple lobar nuclei that are neutrophils. You are looking @ acute inflammation.
What are some pathogens that can lead to chronic inflammation?
mycobacteria (TB)
some persistent viruses, fungi, parasites
The pathogens that cause chronic inflammation often display ______________.
delayed type hypersensitivity.
Ex: TB skin test, mycobacteria if present will show delayed hypersensitivity & you will see a bump on your skin w/i 72 hours.
What are some triggers of chronic inflammation that only cause collateral damage, have no good components?
autoimmune diseases
allergic diseases
Prolonged exposure to what can lead to chronic inflammation?
toxic exogenous agents: silica–silicosis
toxic endogenous agents: plasma lipids–atherosclerosis
What are the macrophages in the brain called? In the liver? Where do macrophages come from?
Brain: microglia
Liver: Kupffer cell
*bone marrow releases monocytes into the blood.
monocytes go from the blood into the tissues where they become macrophages.
How do macrophages get into the surrounding tissues?
via adhesion molecules & chemotaxis
**predominant around 2 days
What cell type mainly secretes things to activate macrophages in tissues? What types of things activate macrophages?
sensitized T lymphocytes secrete things
Thing: microbial products, cytokines (IFN gamma)
Macrophages once they are activated secrete things. What types of things & what is their effect?
Tissue Injury/Inflammation when they secrete: ROS proteases cytokines coagulation factors arachidonic acid metabolites Tissue Repair when they secrete: growth factors fibrinogenic cytokines angiogenic factors remodelling collagenases
If you are looking @ a slide of tuberculous granuloma…what process is at play & what do you see?
chronic inflammation w/ delayed type hypersensitivity
see mononuclear infiltrate: lymphocytes, macrophages
Macrophages becoming 2 things: multinucleate giant cells & epithelioid cells
T/F The mediators of inflammation are long-lived so that you assure the pathogen has been removed.
FALSE. the mediators are short-lived & potent.
What are the 2 ways that cells produce/release mediators?
- some mediators are already made & sequestered in granules in the cell ready for exocytosis
Ex: histamine in mast cell granules. - some mediators are synthesized from nothing when they are needed & secreted in response to a stimulus
Ex: prostaglandins, cytokines
T/F Some mediators are derived from plasma proteins.
True.
What are cells that can release mediators?
platelets neutrophils monocytes/macrophages mast cells mesenchymal cells (smooth muscle cells, endothelial cells, fibroblasts)
Histamine comes from what cell type?
mast cells
basophils
platelets
What is the action of histamine?
vasodilation
increased vascular permeability
endothelial activation
Serotonin comes from what cell type?
platelets
What is the action of serotonin?
vasodilation
increased vascular permeability
Leukotrienes & prostaglandins are both:
eicosanoids
Leukotrienes come from what cell type?
mast cells
leukocytes
What are the actions of leukotrienes?
increased vascular permeability
chemotaxis
leukocyte adhesion
vasoconstriction
Prostaglandins come from what cell type?
mast cells
leukocytes
What are the actions of prostaglandins?
vasodilation
pain
fever
Platelet activating factor is very potent & comes from what cell type?
platelets leukocytes basophils mast cells neutrophils macrophages endothelial cells
What are the actions of platelet activating factor?
vasodilation increased vascular permeability leukocyte adhesion chemotaxis degranulation oxidative burst boost the synthesis of other mediators, esp eicosanoids
ROS come from what cell type?
leukocytes
What are the actions of ROS?
killing microbes
tissue damage
NO comes from what cell type?
endothelium
macrophages
What is the action of NO?
vascular smooth muscle relaxation
microbial killing
What are some examples of cytokines? What cell types do they come from?
Ex: TNF alpha, IL-1 Come from: macrophages endothelial cells mast cells
What are the actions of cytokines?
local endothelial activation (to express adhesion molecules) fever pain anorexia hypotension decreased vascular resistance
Chemokines come from what cell type?
leukocytes
activated macrophages
What are the actions of chemokines?
chemotaxis
leukocyte activation
What are the 3 categories of plasma protein-derived mediators?
Complement
kinins
coagulation pathway proteases
What are some examples of cells of the complement? Where do they come from?
Ex: C5a, C3a, C4a
Come from:
plasma (produced in the liver)
What are the actions of cells of the complement?
leukocyte chemotaxis & activation
vasodilation (thru mast cell activation)
What are some examples of cells that are kinins? Where do they come from?
Ex: bradykinin
Come from: plasma (produced in the liver)
What are the actions of the kinins?
increased vascular permeability
smooth muscle contraction
vasodilation
pain
Where do coagulation pathway proteases come from?
plasma (produced in the liver)
What are the actions of coagulation pathway proteases?
endothelial activation
leukocyte recruitment
What are the 2 vasoactive amine mediators?
histamine
serotonin
How are vasoactive amines released?
they are pre-produced & stored in intracellular granules. They are released via exocytosis. Histamine: mast cell degranulation. **they are the first responders b/c they are pre-produced.
Histamine is the principle mediator of what?
immediate transient phase of increased vascular permeability
Mast cell degranulation occurs, releasing histamine, in response to what stimuli?
Physical Injury: trauma, thermal
Allergic Rxn: antibodies bound to mast cell
Complement anaphylatoxins
Cytokines
Endogenous mediators prompt release of arachidonic acid from _______, mainly via the enzyme: _________. This produces a class of actors called______.
membrane phospholipids
phospholipase A2
Eicosanoids
Eicosanoids can be modified via 2 enzymes that produce different end substances. Describe these 2 pathways.
Pathway #1: cyclooxygenase -prostaglandins -thromboxanes Pathway #2: lipooxygenase -leukotrienes -lipoxin
Eicosanoids can mediate almost every step of the inflammation pathway. What communication pathway do they use?
G protein coupled receptors on cells.
What is platelet activating factor derived from?
phospholipids
T/F Platelet activating factor is more potent than histamine.
TRUE! This is why it is such an important drug target. It has a huge role in inflammation.
What produces ROS? What is their fcn? What is the downside?
NADPH oxidase system produces them
fcn: these radicals are toxic to microorganisms
downside: collateral damage if released into host tissue
T/F NO has a long half life.
False. Super short half life. Seconds it is a gas! It works on only nearby cells.
Describe how NO comes to be. What is its effect?
Cytokines go to a macrophage or something & it then produce NO via inducible nitric oxide synthase (iNOS). This then causes vasodilation & is microbicidal.
Aside from vasodilation & its microbicidal effects, what are the counterintuitive effects of NO?
anti-inflammatory effects: reduces platelet aggregation reduces platelet adhesion reduces mast-cell inflammation reduces leukocyte recruitment
If you have too much TNFalpha what happens?
If you have too little TNFalpha what happens?
You die-sepsis.
