Ch.2 Acute inflammation Flashcards
To stimulate and permit inflammatory cells as well as plasma proteins (complement) and fluid to migrate out of blood vessels and into the target interstitial space.
Inflammation
Inflammation helps rid host cell of the ____ cause of cell injury (microbes & toxins) and the _______ of injury (necrotic cells & tissues) + initate _____ of tissues
Rid of initial cause and consequences, initiate repair
What are he two phases of inflammation?
Acute (start) and chronic inflammation
rapid response to infections and tissue damage
Acute inflammation
Presence of edema & neutrophils in tissue=
Acute inflammation
leakage of fluid and plasma proteins into the interstitial or serous cavities. Exudate or transudate
edema
If there is failure to clear the stimulus inflammation progresses to a protracted phase called ____ inflammation
Chronic
longer duration and is associated with continuing tissue destruction and fibrosis (the deposition of connective tissue).
Chronic inflammation
Acute or chronic?
mainly neutrophils
Accute
Acute or chronic?
monocytes / macrophaes & lymphocytes
Chronic
Acute or chronic?
Mild & self limited tissue injury
Acute
Acute or chronic?
May be significant injury
Chronic
Acute or chronic?
no fibrosis
Accute
Acute or chronic?
May be severe/progressive fibrosis
Chronic
Acute or chronic?
Requires gene activation
chronic, slow.
What are the 5 external manifestations of inflammation?
Heat, redness, swelling, pain, & loss of function.
5 Steps of inflammatory run
- Recognition
- Recruitment
- Removal
- Regulation
- Repair
Acute or chronic?
Glomerulunphritis, vasculitis (antibodies & complement, neutrophils)
Acute
Acute or chronic?
Septic shock (cytokienes)
Acute
When cytokines overwhelm the buffering system of body, HYPOTENSION .
Septic shock
Acute or chronic?
Rheumatoid Arthritis (lymphocytes, macro, antibodies)
chronic
Acute or chronic?
Asthma (IgE, eosinophils)
Chronic
Acute or chronic?
Pulmonary fibrosis (Mac, fibroblasts)
Chronic
Acute or chronic?
Acute respiratory distress syndrome (neutrophils)
Acute
Inadequate inflammation is manifested how?
Increased susceptibility to infections
-Reduced production of leukocytes
-Immunosuprrsive ages
-Malnutrition
Are all what?
Things that impair inflammation
Are local and systemic signs of acute inflammation low or high? and why?
High b.c presence of signal still there
Are local and systemic signs of chronic inflammation low or high? and why?
Low/variable because signal strength change over time, so its harder to detect,
-Infection (microbe)
-tissue necrosis (molecules released trigger)
-foreign bodies(sutures, tissue implants)
-Immune reactions (hypersensitivities)
are all what?
Causes of inflamation
The first step is : ____ of microbs and nectrotic cells by cellular receptors and circulating proteins.
Recognition
Most important resident cells who function is to detect the presence of foreign invader, ingest & destroy
Then illicit inflammatory response by recruiting cells & proteins from blood to complete elimination process
macrophages & dendritic cells
Step?
Injury or infection
Releases chemoattractant agent molecules (chemotaxis) that alert immune cell in vicinity of the need of inflammatory cells
Step Zero.
Activation of ___ leads to production of cytokines that trigger inflamation
Toll-like receptors
Macrophages have _____ on their (1) surface, in the (2) extracellular space; in endosomes, into which microbes are ingested; and ion (3) cytosol
TLRs
recruit and activate a multiprotein complex (the inflammasome) which generates the biologically active cytokine interleukin-1 (IL-1).
NOD like receptors (NLRs)
Causes redness (erythema) and warmth in acute
Vasodilation
What is the most important chemical mediator in vasodilatation?
Histamine
Follow vasodilatation
outpouring of protein-rich fluid into the extravascular tissues
increased permeability of the microvasculature
escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities
Exudation
Extravascular fluid that is high in protein and contains cellular debris
Exudate
What does the presence of exudate imply?
That there is increased permeability in small blood vessels typically during inflammatory rxn.
a fluid with low protein content (most of which is albumin), little or no cellular material, and low specific gravity.
Transudate
What is produced as a result of osmotic or hydrostatic pressure imbalances across vessel wall?
not associated with vas. permeability or inflamation
Trasudate
A purulent inflammatory exudate, rich in leukocytes (neutrophils) debris of dead cells, microbs
Pus
Contraction of endothelial cells, creating inter0endothelial opening
is the primary mechanism to what?
Increased vascular permeability
Histamine, bradykinin, leukotrienes + others all elicit what?
rapid after exposure, short lived.
Increase vascular permeability
What does increased vascular permeability result in?
-slower blood flow
-Higher viscosity of blood b/c more RBCs
-Localized redness of tissues
Normal condition= blood has laminar flow, red cells incenter, leukocytes towards vessel walls.
Stasis (early inflammation) -> increase caliper of vessels, blod flow slows, leukocytes are larger than red cells, slow down more.
Leukocytes assume a peripheral position along endothelial surfacem
Step 1, Margination
When endothelial cells are activated by cytokines/other mediators produced locally, they express adhesion molecules to which _____ attach loosely
What step?
Leukocytes
Step 2: rolling
receptors expressed on leukocytes and endothelium that have an extracellular domain that binds carbohydrates
Selectins
Edothelial cells express two selectins, ___ - and ___-selectins, as well as the ligand for L-selectin, whereas leukocytes express L-selectin
E and P selectin
They are expressed in low amount but unregulated after stimulation by cytokines
If endothelium area has not received signal for activation (cytokines) then ____ and ____ are not there or expressed in low amounts
E and P selectin
binding of _____ is largely restricted to endothelium at sites of infection or tissue injury (where the mediators are produced)
Leukocytes
Found primarily in intracellular membrane-bound vesicles called Weibel-Palade bodies
BUT
Following exposure to mediations (histamines), traffics to cell surface.
P-selectin
___ and ___ _induced after stimulation by the cytokines IL-1 and tumor necrosis factor (TNF) from tissue macrophages .
Mediate initial weak leukocyte binding to endothelium
Not normally expressed on normal endothelium
__ is stimulated on the leukocyte
E-selecting and P-selectin endothelium ‘
L-selectin on leukocyte
_____ mediated interaction have low affinity, easily shut off by flowing blood so, there’s a bind & detach process until proper adhesion can occur
Leukocyte (sialyl lewis X) bind selecting, handshake !
Selectin- mediated interactions
What does this show ?
Multistep process of leukocyte migration through vessels
Mediate firm adhesion of leukocytes to endothelium.
leukocyte surface protein family
Integrins
transmembrane two-chain glycoproteins that mediate the adhesion of leukocytes to endothelium and of various cells to the extracellular matrix
Integrins
What activates intengrin to switch to high affinity form for leukocytes?
Chemokies
chemoattractant cytokines that are secreted by many cells at sites of inflammation, bind to endothelial cell proteoglycans
Chemokines
Cytokines that activate endothelial cells to increase their expression of ligands for integrins.
TNF and IL-1
C5a and LTB4 do what to integrins?
They mediate firm adhesion of leukocyte to endothelium following weak connection btwn leukocyte and selectins
Up-regulate them to become high affinity
What is the result of impaired leukocyte adhesion and defective inflammation.
result in recurrent bacterial infections
-Delayed separation of umbilical cord
-High # of circulating neutrophils
-Recurrent bacterial infection, can’t form pus
All results of what? Autosomal recessive
Leukocyte adhesion disorder (LAD) that affects their adhesion to endothelial surface.
extravasation of leukocytes following adhesion
Transmigration (diapedesis)
Cellular adhesion molecule expressed on leukocytes, mediate the binding event needed for leukocyte to traverse the endothelium.
PECAM-1 (CD31)
locomotion along a chemical gradient produced by chemotactic agents that started the process.
chemotaxis
Bacterial product Peptides, cytokines, C5a from complement, and leukotrienes are all what?
chemoattractants
What is produced in response to infections and tissue damage and during immunologic reactions,
bind G-protien leukocyte receptors
Chemoattractants
neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hours
(left red= neutrophils) (right red= macrophages)
Acute inflammation
What causes cellular infiltrate:
dominated by continuously recruited neutrophils for several days
Pseudomonas bacteria
What causes cellular infiltrate:
lymphocytes may be the first cells to arrive
Viral infections
What causes cellular infiltrate:
dominated by activated lymphocytes, macrophages, and plasma cells (reflecting the immune response
Hypersensitivities
What causes cellular infiltrate:
eosinophils may be the main cell type.
Allergic reactions or certain parasites
Blocking of what cytokine?
is extremely useful therapeutics for chronic inflammatory diseases such as rheumatoid arthritis
TNF
the ingestion of particulate material by cells.
Phagocytosis
Neutrophils (short lived) & macrophages (long-lived, slower response) are what ?
Phagocytes
antibodies (IgG), the C3b cleavage product of complement, and certain plasma lectins which
all coat microbs and allow for more efficient phagocytosis
Opsonins
Membrane bound vesicle that inject micron and fuses with lysosome=
Psuedopodes extend from leukocytes to form these
Merging with lysosome=
phagosome
Phagolysosome
Problem in protien trafficking (autosome recessive) which affects formation of phagolysososme
Clinical features similar to LAD, more pyrogenic infection (pus forming), BUT (neutropina, death of neutrophils)
Chediak-Higashi Syndrome
Inter medullary death of neutrophils, low count in blood.
Neutropina
Killing of microbes and destruction of ingested materials are accomplished by
Reactive oxidative species (ROS) & nitrogen species (RNS)
What method of killing I most effective mechanism for killing microbes?
O2 Dependent killing (done by Neutrophils)
Neutrophil or macrophage?
1-2 days, rapid short lived, O2 killing, prominent secretion of lysosomal enzymes
Neutrophil
Neutrophil or macrophage?
Days/weeks, slow, dependent on gene transcription activation of cytokine genes.
Macrophages
What 3 things do neutrophils and macrophages share in common?
-Phagocytois
-Migrate through blood vessels
-Chemotaxis
O2 converted into O2- by NDAPH oxidase
this processes is called what?
Oxidative Burst
What does an oxidative burst do?
Supply electron to an NADPH oxidase in the phagosomal membrane
Once a neutrophil is activated what enzyme is rapidly assembled in the membrane of the phagylosome to bind in O2 dependent killing?
NADPH oxidase
Following oxidative burst, O2- Is converted into H2O2 via what enzyme?
Superoxide Dismutase (SOD)
H2O2 is finally converted to HOCL (bleach) by what enzyme in O2 dependent killing?
Myleperoxidase MPO
A potent antimicrobial agent that destroys microbes by halogenation or via oxidation of proteins and lipids
HOCL
What inflammatory cell up regulates NOS in order for it to participate in microbial Killing?
Macrophages
1 of the 2 types of granules in Neutrophils
contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase.
Specific (secondary) granule
1 of the 2 types of granules in Neutrophils
contain myeloperoxidase, bactericidal factors (such as defensins), acid hydrolases, and a variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases, proteinase 3).
Azurophil (primary) granule
Macrophages contain _____ filled with
acid hydrolases, collagenase, elastase, and phospholipase, all of which can destroy ingested materials and cell debris
Lysozymes
activated neutrophils liberate chromatin components, including histones, which form fibrillar networks called
neutrophil extracellular traps (NETs)
NETs in blood during sepsis Is a consequence of what?
Widespread neutrophil activation
Disease characterized by by poor O2 dependent killing pathway
due to NADPH oxidase defect.
Chronic Granulomatous Disease (CDG) (X-linked or AR)
CDG leads to recurrent infection and granuloma formation with what kind of organism?
Catalase (+) organisms
ex. Staph Aureus , Serratia Marcessens, Aspergillus
____ definceny results in defective conversion of H2O2 to HOCL
MPO
MPO definceny causes increase risk of what kind of infections, with no symptoms?
Candida
Less effective killing, uses 2nd enzymes housed in leukocyte 2nd granules ex. lysozyme in macrophages & eosinophils
O2 INdependent killing
What is the final step once all infection has been cleared in acute inflammation?
Neutrophils undergo apoptosis within 24hr of dissipation of initial inflammatory signal.
