Path: Inflammation 1&2 Flashcards
List the most common and most important cells of inflammation.
1- neutrophils 2- bands 3- macrophages 4- lymphocytes 5- plasma cells 6- eosinophils 7- mast cells 8- multinucleated giant cells
Normally, what percent of the leukocytes measured in the blood are neutrophils?
40-70%
Normally, what percent of peripheral blood leukocytes are bands?
<5%
What cell type is the most important innate immune system defense against extracellular pathogens?
Neutrophils
What are the dominant cell players in CHRONIC inflammation?
Macrophages
The point in the cycle where macrophages replace neutrophils in the inflammatory response, starts around day _____ and is sometimes called “ ________”.
day 3; “subacute”
T cells carry out cell-mediated or humeral immunity?
Cell-mediated immunity
B cells carry out cell-mediated or humoral immunity?
Humoral immunity
Lymphocytes are identifiable in a peripheral smear by their ________ nuclei and _____ cytoplasm. They look like little blue dots under the microscope.
small, round, dense nuclei; scant cytoplasm
Plasma cells are derived from ___________ cells.
Activated B cells
Plasma cells produce large amounts of ______-specificity antibodies.
single-specificity antibodies
Plasma cells are distinguishable under a microscope by their “_______” appearance due to nuclear chromatin clumped around the periphery.
“clockface”
_______ are prominent in many allergic and parasitic diseases.
eosinophils
The granules contained in eosinophils contain _______________ (toxic to parasites, but also to host cells).
major basic protein
The eosinophil granules avidly take up red ______ dye, hence their name.
red eosin dye
Eosinophil nuclei frequently have ____ (#) lobs?
2
______ cells are bone-marrow-derived cells around blood vessels, nerves and skin.
Mast cells
Mast cells have cytoplasmic granules loaded with:
histamine, chemotactic factors, proteases, heparin, serotonin, and more
Mast cell granules avidly take up _______ (blue dye) and other basophilic dies.
Hematoxylin (blue dye)
Multinucleated giant cells are a fusion of several __________.
Macrophages
Name the two morphological types of multinucleated giant cells
foreign body type and Langhans type
Describe the foreign body type of multinucleated giant cells
Foreign body type giant cells have haphazardly arranged nuclei
Describe the Langhans type giant cells
Langhans type giant cells have nuclei arranged peripherally in a semicircle and are associated with immune granulomas.
What is a granuloma?
An aggregate of activated macrophages
Describe the two common types of granuloma.
1- foreign body granulomas generally represent the inflammatory reaction to a persistent material too large or undigestible for clearance.
2- Immune type granulomas generally represent the inflammatory response to a persistent antigen that induces a cell-mediated immune reaction.
Granulomatous infections are generally due to intracellular or extracellular pathogens?
Intracellular pathogens
What are the two types of inflammatory cells that are numerous and easily sen with routine stains under a microscope?
neutrophils and lymphocytes
Lymphocytes can be differentiated from other cells in a smear by looking at their nuclei. Their nuclei are round, and the same size as _______, also found in the field.
RBCs
Which are larger under the microscope, neutrophils or macrophages?
Macrophages
Acute inflammation has a rapid onset, ___________ (time span), and short duration ___________ (time span).
seconds to minutes; minutes to a few days
Acute inflammation has 4 cardinal signs and symptoms. List them.
1- redness (rubor) 2- swelling (tumor) 3- heat (calor) 4- pain (dolor) Also sometimes, loss of function (Latin translation not a valuable memory aid)
What are PAMPs, anyway?
pathogen-associated molecular patterns (PAMPs), are certain microbial components shared among related microbes that are essential for infectivity. Cells of our innate immune system recognize PAMPs with Pattern Recognition Receptors (PRRs) on their own surfaces, this is where the innate immune response begins.
What in Sam Hill are DAMPs?
Damage-associated molecular patterns (DAMPs) are certain molecules released from injured or dead cells.
What are Toll-like receptors (TLRs)?
pattern recognition receptors on cellular plasma membranes and endosomal vesicle membranes of macrophages, dendritic cells and various epithelial cells and leukocytes that recognize PAMPs and DAMPs
What is an inflammasome?
A multi-protein complex that forms when receptors on any host cell surface recognize DAMPs or other molecules released by injury (ATP, DNA, uric acid). This induces the production of IL-1.
What are cytokines?
The intercellular messenger substances secreted by cells of the immune system (innate and acquired) that tell other cells what to do.
How do cytokines get leukocytes to the site of infection?
Pro-inflammatory cytokines upregulate the expression of endothelial cell adhesion molecules that bind leukocytes, directing them to the site of infection.
List the 5 distinct forms of inflammation.
1- purulent (suppurative) 2- abscessing (necrotizing) 3- fibrinous 4- serous 5- granulomatous
List the 3 component responses of inflammation.
1- vascular response
2- leukocyte response
3- systemic response (total body response)
What characterizes the vascular response of inflammation?
Vasodilation soon followed by increased permeability
What compound primarily mediated vasodilation during inflammation?
Histamine
What compounds mediate the increased vascular permeability during inflammation and what change to they cause in endothelial cells of capillaries and post-capillary venules?
Histamine, bradykinin, leukotrienes.
Cause cells to contract, opening space between them.
What can cause increased vascular permeability to persist beyond 2-12 hrs?
Burns, radiation and certain bacterial toxins
List the 3 types of fluid that can leak from capillaries and describe their various viscosities.
Serous (thin, serum, no clotting factors due to coag. formation upstream)
Fibrinous (thick with abundant protein)
Purulent (thickest with protein and inflammatory cells)
Describe the difference between exudate and transudate.
Exudate is a thick, cellular inflammatory fluid while transudate is a thin, acullular fluid.
Please, describe pus.
A purulent exudate rich in neutrophils, cellular debris and commonly microbes.
A localized area of tissue necrosis with purulent exudate is an _________ .
Abscess
What is an empyema?
A collection of pus in the pleural space.
Necrotizing inflammation at or near the surface of an organ or tissue can cause the necrotic inflamed tissue to slough off, creating a localized defect or excavation. This is an _______.
Ulcer
Superficial sloughing of epithelium (without necrosis through basement membrane into subepithelial tissue) is called ________ .
Erosion
What is margination?
When leukocytes move to the periphery of a blood vessel’s lumen where they can begin diapedesis via selectins and integrins.
Leukocytes express these receptors for binding to endothelial selectins:
L-selectins
Normally, P-selectins (for platelets) found on the surface of endothelial cells, are stored in cytoplasmic granules called:
Weibel-Palade bodies
What are LFA-1s?
Integrins found on neutrophils, monocytes and T cells.
What are Mac-1s?
Integrins found on monocytes
What are VLA-4s?
Integrins found on monocytes and T cells
TNF and IL-1 induce endotheial cell expression of ligands for _______ during acute inflammation.
integrins- to bring leukocytes to site of infection
What are leukocytes looking for between endothelial cells to initiate their transmigration from blood vessels to the inflamed tissue during inflammation?
PECAM-1 (CD31) to bind to their PECAM-1
What is chemotaxis?
Migration of leukocytes in tissue to a site of inflammation.
List the 3 most important classes of endogenous chemoattractants.
1- cytokines
2- complement system proteins
3- arachidonic acid metabolites
Name the most important cytokine chemoattractant (chemokine).
IL-8
What is the most important complement protein chemoattractant?
C5a
What is the most important arachidonic acid metabolite?
Leukotriene B4 (LTB4)
What are the “first responders” of acute inflammation?
neutrophils
Do segmented (matured) neutrophils proliferate (divide/replicate) once they get to a site of infection?
No.
Can macrophages proliferate (divide/replicate) once they get to a site of infection?
Yes.
What are the first cells to arrive in viral infections?
Lymphocytes, not neutrophils.
If spinal tap of a patient with symptoms and signs of acute meningitis yield CSF with neutrophils, what do you suspect is the source of infection, virus or bacteria?
Bacteria.
Autoimmune inflammation is commonly lymphocytic, eosinophilic or neutrophilic?
Lymphocytic
Allergic inflammation is commonly lymphocytic, neutrophilic or eosinophilic?
Eosinophilic
A macrophage has ______ receptors that bind _______ or fructose residues of glycoproteins and glycolipids, which are prevalent in microbes, but not human glycoproteins and glycolipids.
Mannose receptors; bind mannose
Macrophage integrins, particularly _______ may also bind microbes in addition to the mannose receptors.
Mac-1
Phagocytosis of microbes is greatly enhanced when they are coated with ______ that adhere to microbes or molecules and then bind to phagocytes, facilitating recognition and attachment.
Opsonins
The major opsonins are:
Various IgG antibodies, C3b complement, and mannose-binding lectin
We defend ourselves against leaked contents of macrophage/neutrophil lysosomes with the antioxidants:
enzyme superoxide dismutase
enzyme catalase
enzyme glutathione peroxidase
ceruloplasmin (serum copper-transporting protein)
transferrin (serum iron-transporting protein)
What compound reduces oxygen to the effector molecule, superoxide anion, that is lethal to microbes?
NADPH
What is the most efficient bacteriocidal system of neutrophils?
the hydrogen peroxide-myeloperoxidase-halide system.
If the peroxide-myeloperoxidase-halide system fails due to a myeloperoxidase deffiiency in a neutrophil, what else can do the job?
Hydrogen peroxide can be converted to hydroxyl radical, which is also efficacious in killing bacteria
What is iNOS?
inducible nitric oxide synthetase. This compound is responsible for creating the nitric oxide precursor of the reactive nitrogen species, used in executing invading microbes, from arginine.
If a person lacks both iNOS and NADPH in their neutrophils, what will happen?
They will be overwhelmed by bacterial infection and fucking die.
How does lysozyme work?
It hydrolyzes the glycopeptide coat of all bacteria.
What are defensins?
Cationic arginine-rich peptides toxic to bacteria. Is a phagocyte effector molecule.
What is an acid protease?
degrade bacteria and debris when the phagolysosome environment is acidified by proton pumps in their membranes. A phagocyte effector molecule
These proteases degrade bacteria and debris in phagolysosomes, but if released outside phagocytes, degrade collagen, basement membrane, fibrin, elastin, cartilage; cleave complement C3 and C5 to cause anaphylaxis.
neutral proteases
What do neutrophil elastases do?
Degrade bacterial toxins
What are cathelicidins?
Antimicrobial proteins found in phagocytes
Some patients develop antibodies to this proteinase, called cytoplasmic anti-neutrophil cytoplasmic antibodies (c-ANCA). This is an autoimmune disease called granulomatosis with polyangiitis (Wegener’s).
Proteinase-3
We protect outselves against leaked proteases by antiproteases. The most important of these is ____________, which is the major inhibitor of neutrophil elastase.
alpha-1-antitrypsin
Congenital deficiency of alpha-1-antitrypsin results in uncontrolled elastase. The organ most severely affected by elastin destruction is ________.
Lung
List the 4 most important of the systemic effects of acute inflammation.
1- fever
2- tachycardia
3- hyperventilation
4- leukocytosis (elevated WBCs in blood)
What are the main cytokines that mediate the acute phase response of inflammation?
IL-1, TNF, and IL-6
The acute phase response to inflammation includes increases in plasma protein levels, namely:
C reactive protein, amyloid A, fibrinogen
If the liver is busy making acute phase reactive proteins, you may see a deficit of this protein’s level in the blood.
Albumin.
T/F: Inflammation switches the body from catabolism to anabolism.
False. Anabolism to catabolism. Building to breakdown of proteins.
T/F: In acute phase inflammation, levels of epinephrine, norepinephrine, cortisol and glucagon go up.
True
How is it that a patient goes into a negative nitrogen balance during the acute phase of inflammation?
Skeletal muscle is broken down faster than the liver is making proteins of inflammation. This leads to elevated nitrates in the blood and thus in the urine output. This equals a negative nitrogen balance.
Usually and especially in clinical research, only a temperature of ______ celsius or _______ degrees F is counted as a fever.
38 C or 100.4 F
The main pyrogens (fever inducers) are:
TNF-alpha & IL-1
Which prostaglandin mediates fevers, acting directly on the hypothalamus?
PGE2
At what elevated temperature does a person become comatose?
43 C
A fully anesthetized patient is poikilothermic, meaning:
They have an ambient temperature. (same as surroundings)
The normal WBC count in adults is:
4,500-11,000/cu mm
Typically, infections (particularly bacterial) tend to cause leukocytosis of: (how many cells per cu mm)
15,000-20,000/cu mm but can be as high as 100,000/cu mm
WBC counts of between 40,000-100,000/cu mm are much more commonly due to ________ than an inflammatory response.
Leukemia
What is a leukemoid reaction?
A leukocytosis of between 40,000-100,000/cu mm due to inflammation.
Leukocytosis consisting of neutrophils (most common) is called:
Neutrophilia - most commonly associated with bacterial infections.
Leukocytosis consisting of lymphocytes is associated with bacterial or viral infections?
Viral infections
Leukocytosis consisting of eosinophils is associated with:
Allergies and parasitic infections
What are Dohle bodies?
Patches of dilated ER, which appear as “sky-blue peripheral cytoplasmic puddles”) in neutrophils during severe acute inflammation.
Why does there appear to be a leukocytosis, specifically a neutrophilia, in patients on steroid therapy?
steroid therapy causes decreased margination of WBCs, so more neutrophils will be counted in a blood sample that does not represent an infection response
What is a left shift?
an increased number of immature granulocytes in the blood; mediated by TNF and IL-1
How would you tell if a patient on glucocorticosteroid therapy had an infection?
WBC count would be >20,000/mm3 and there would be left shift
What are acute phase reactants?
proteins produced in abundance with inflammation; these include clotting factors, complement proteins, serum A, C-reactive protein, alpha-1-antitrypsin and other antiproteases, ferritin, and hepcidin
What is ESR and what reactant causes it?
ESR = erythrocyte sedimentation rate, caused by fibrinogen - the cells sediment faster when they are stuck together; not a very specific or sensitive test for inflammation but it is quick and cheap
CRP stands for ____, which binds ____ and serves as ____, thereby initiating ____. Its synthesis is induced by ____, especially ____.
C-reactive protein; binds phosphocholines on bacteria; as a ligand for C1 thereby initiating the complement cascade; synthesis is induced by cytokines, esp. IL-6
What are the 4 criteria for SIRS, 2 or more of which indicate SIRS if present? (SIRS=Systemic Inflammatory Response Syndrome)
- temperature >38˚C
- HR >90/min
- respiratory rate > 20/minute or pCO2 12,000/cu mm or 10% bands
Sepsis is defined as _____.
SIRS due to proved or suspected infection, with 25 additional parameters (added after the consensus conference of 2001)
What are the 5 main cytokines involved in the acute phase response?
(1) TNF-alpha
(2) IL-1
(3) IL-6
(4) interferon-gamma
(5) TNF-beta
The combined effects of glucocorticoids and cytokines on what cells result in the acute phase response changes?
hepatocytes
What 3 cell types are involved in first producing inflammatory mediator molecules?
- macrophages
- dendritic cells
- mast cells
Histamine is a ____ amine stored in ____ of ____ cells. They function by binding the ___ receptor on endothelial cells.
vasoactive; granules; mast; H1
What 3 cell types are most important for secreting cytokines, and what other 3 cell types can secrete cytokines too?
primary:
1. activated lymphocytes; 2. macrophages; 3. dendritic cells
secondary:
1. epithelial cells; 2. endothelial cells; CT cells
Activated endothelial cells, in addition to producing some cytokines, also become ____ which promotes ____.
procoagulant; promotes the formation of clots
Which molecule is responsible for promoting lipid and protein mobilization and decreasing appetite in the inflammation process?
TNF
The subset of cytokines that act primarily as chemoattractants for leukocytes are
called ____.
chemokines
The 40 chemokines are classified into 4 groups on the basis of the arrangement of cysteine residues in them. What are they?
- C-X-C
- C-C
- C
- CX3C
Chemokines act by binding to what type of receptor? What can be said about these receptors’ ligand specificities?
GPCRs, they have overlapping ligand specificities because the chemokines have such important actions
IL-8 is secreted by activated ____ and ____ cells. The most important inducers of its production are ____(3 things). The primary effect of IL-8 is activation and chemotaxis of ____.
macrophages and endothelial cells; microbial products, TNF, and IL-1; neutrophils
The C chemokines act primarily on what cells?
lymphocytes
What is “mottling” of the skin?
Irregular mixture of colors, usually a sign of ischemia
Fractalkine is a chemokine that signals for migration of:
Monocytes & T-cells
MCP-1 stands for:
Monocyte chemoattractant protein-1
MIP-1alpha stands for macrophage inflammatory protein-1alpha and is a chemoattractant for: (hint: more than macrophages)
monocytes, lymphocytes, eosinophils, & basophils
__________ is the neutrophil police dispatcher, chemoattractant for neutrophils.
IL-8
What is the memory aide for the 5 modifiable risk factors for atherosclerosis?
SHODDy Smoking Hypertension Obesity Diabetes Dyslipidemia
What type of inflammatory cells dominate interstitial tissues during acute vs chronic inflammation?
Acute: neutrophils
Chronic: Lymphocytes
CD14 is a ____ (receptor type) present on ________ (cell type) that recognizes the _____ (surface antigen) of gram negative bacteria.
TLR; macrophages; LPS (a DAMP)
TLR activation by a PAMP results in upregulation of ________ (transcription factor), the “on switch” that turns on the inflammatory response.
NF-kappaB
Arachidonic acid is released from the _____________ by ___________ .
phospholipid cell membrane; phospholipase A2
Once arachidonic acid is released from the PM, it is then acted on by either of these two pathways:
Cyclooxygenase or lipoxygenase
Generally speaking, the cyclooxygenase pathway produces these mediators of inflammation:
prostaglandins (PGI2, PGE2, PGD2)
The prostaglandin products of the cyclooxygenase pathway mediate these events of acute inflammation:
vasoDilation and vascular permeability
In addition to vasodilation and vascular permeability, PGE2 mediates:
Fever and pain
Generally speaking, the lipoxygenase pathway produces these mediators of acute inflammation:
Leukotrienes
LTB4- attracts and activates neutrophils
LTC4, LTD4, LTE4- mediate vasoConstriction, bronchospasm, increase vascular permeability
What are the 4 key mediators of neutrophils?
C5a, LTB4, IL-8, bacterial products
List 3 ways mast cells are activated.
1) Tissue trauma
2) Complement proteins C3a & C5a
3) Cross-linking of cell surface IgE by antigen
Where does increased vascular permeability occur?
Post-capillary venule
