CH2 - Inflammation, Inflammatory Disorders, and Wound Healing Flashcards
What does inflammation allow?
Allows inflammatory cells, plasma proteins (e.g., complement), and fluid to exit blood vessels and enter the interstitial space
Inflammation is divided into what?
Divided into acute and chronic inflammation
What is inflammation characterized by?
the presence of edema and neutrophils in tissue
Inflammation arises in response to what?
infection (to eliminate pathogen) or tissue necrosis (to clear necrotic debris)
innate immunity
Immediate response with limited specificity
What are the mediators of acute inflammation?
Toll-like receptors, Arachidonic acid (AA) metabolites, Mast cells, Complement, Hageman Factor
Toll-like receptors
Present on cells of the innate immune system (e.g., macrophages and dendritic cells)
How are TLRs attivated?
pathogen-associated molecular patterns (PAMPs) that are commonly shared by microbes, CD14 (a TLR) on macrophages recognizes lipopolysaccharide (a PAMP) on the outer membrane of gram-negative bacteria
TLR activation results in what?
upregulation of NF-kB, a nuclear transcription factor
What does NF-kB do?
activates immune response genes leading to production of multiple immune mediators
TLRs and chronic inflammation?
They are also present on cells of adaptive immunity (e.g., lymphocytes) and play an important role in mediating chronic inflammation.
Arachidonic acid (AA) metabolites
- AA is released from the phospholipid cell membrane by phospholipase A2 and then acted upon by cyclooxygenase or 5-lipoxygenase.
Cyclooxygenase
produces prostaglandins (PG) a. PGI2, PGD2 and PGE2 mediate vasodilation and increased vascular permeability. PGE2 also mediates pain.
5-lipoxygenase
produces leukotrienes (LT) a. LTB4 attracts and activates neutrophils. b. LTC4, LTD4 and LTE4 (slow reacting substances of anaphylaxis) mediate vasoconstriction, broncho spasm, and increased vascular permeability.
Where are Mast cells located?
- Widely distributed throughout connective tissue
How are Mast cells activated?
(1) tissue trauma (2) complement proteins C3a and C5a (3) cross-linking of cell-surface IgE by antigen
Mast cells immediate response is?
involves the release of preformed histamine granules, which mediate vasodilation of arterioles and increased vascular permeability
Mast cells delayed response is?
involves production of arachidonic acid metabolites, particularly leukotrienes.
Complement
proinflammatory serum proteins that complement inflammation
Where is complement located?
Circulate as inactive precursors;
Activation of complement occurs via what?
Classical pathway, Alternative pathway, MBL pathway
Classical pathway
C1 binds IgG or IgM that is bound to antigen
Alternative pathway
Microbial products directly activate complement.
Mannose binding lectin pathway
mannose binding lectin (MBL) pathway MBL binds to mannose on microorganisms and activates complement
All pathways of complement result in?
production of C3 convertase (mediates C3?>C3a and C3b, producing C5 convertase (mediates C5?>C5a and C5b)
What forms the MAC?
C5b complexes with C6-C9 to form the membrane attack complex (MAC)
C3a and C5a
(anaphylatoxins)?trigger mast cell degranulation, resulting in histamine-mediated vasodilation and increased vascular permeability
C5a
chemotactic for neutrophils
C5b
opsonin for phagocytosis
MAC
Lyses microbes by creating a hole in the cell membrane
Where is Hageman factor (Factor XII) produced?
Inactive proinflammatory protein produced in liver
How is Hageman factor (Factor XII)?
Activated upon exposure to subendothelial or tissue collagen;
Hageman factor (Factor XII) activates what?
- Coagulation and fibrinolytic systems 2. Complement 3. Kinin system
Kinin system
Kinin cleaves high-molecular-weight kininogen (HMWK) to bradykinin, which mediates vasodilation and increased vascular permeability (simitar to histamine), as well as pain.
What are the cardinal signs of inflammation?
Redness (rubor) and warmth (calor), swelling, pain, fever
What is Redness (rubor) and warmth (calor) due to?
- Due to vasodilation, which results in increased blood flow
How does Redness (rubor) and warmth (calor) occur?
Occurs via relaxation of arteriolar smooth muscle;
Key mediators of Redness (rubor) and warmth (calor) are?
histamine, prostaglandins, and bradykinin
Swelling (tumor) is due to what?
Due to the leakage of fluid from postcapillary venules into the interstitial space (exudate)
What are the Key mediators of swelling?
(1) histamine, which causes endothelial cell contraction and (2) tissue damage, resulting in endothelial cell disruption,
Pain (dolor)
Bradvkinin and PGE2 sensitize sensory nerve endings.
Fever
- Pyrogens (e.g., LPS from bacteria) cause macrophages to release IL-1 and TNF, which increase cyclooxygenase activity in perivascular cells of the hypothalamus, 2. Increased PGE2 raises temperature set point.
What are the steps in neutrophil arrival?
Margination, Rolling, Adhesion, Transmigration and Chemotaxis, Phagocytosis, Destruction of phagocytosed material, resolution
Step 1?Marginatum
- Vasodilation slows blood flow in postcapillary venules. 2. Cells marginate from center of flow to the periphery.
Step 2?Rolling
- Selectin speed bumps are upregulaled on endothelial cells. 2. Selectins bind sialyl Lewis X on leukocytes. 3. Interaction results in rolling of leukocytes along vessel wall
P-selectin is released from where and what does it mediate?
release from Weibel Palade bodies, is mediated by histamine.
E-selectin is induced by what?
TNF and IL-1.
Step 3?Adhesion
- Cellular adhesion molecules (ICAM and VCAM) are upregulated on endothelium by TNF and IL-1 2. Integrins are upregulated on leukocytes by C5a and LTB4 3. Interaction between CAMs and integrins results in firm adhesion of leukocytes to the vessel wall
Leukocyte adhesion deficiency
is most commonly due to an autosomal recessive defect of integrins (CD18 subunit)
What are the clinical features of LAD?
delayed separation of the umbilical cord, increased circulating neutrophils (due to impaired adhesion of marginated pool of leukocytes), and recurrent bacterial infections that lack pus formation.
Step 4?Transmigration and Chemotaxis
- Leukocytes transmigrate across the endothelium of postcapillary venules and move toward chemical attractants (chemotaxis).
Neutrophils are attracted by
bacterial products, IL-8, C5a, and LTB4
Step 5?Phagocytosis
- Consumption of pathogens or necrotic tissue; phagocytosis is enhanced by opsonins (IgG and C3a). 2. Pseudopods extend from leukocytes to form phagosomes, which are internalized and merge with lysosomes to produce phagolysosomes.
Chediak-Higashi syndrome
is a protein trafficking defect (autosomal recessive) characterized by impaired phagolysosome formation.
Clinical features of Chediak-Higashi syndrome include
Increased risk of pyogenic infections, Neutropenia, Giant granules in leukocytes, Defective primary hemostasia, Albinism, Peripheral neuropathy
Why is there Neutropenia in Chediak Higashi syndrome?
(due to intramedullary death of neutrophils)
In chediak higashi there are Giant granules in leukocytes because?
due to fusion of granules arising from the Golgi apparatus
In chediak higashi Defective primary hemostasia is due to?
abnormal dense granules in platelets
Step 6?Destruction of phagocytosed material
- O2-dependent killing is the most effective mechanism. 2. HOCl generated by oxidative burst in phagolysosomes destroys phagocytosed microbes.
How does O2 dependant killing occur?
O2 is converted to O2. by NADPH oxidase (oxidative burst). O2. is converted to H202, by superoxide dismutase (SOD). H202 is converted to HOCl (bleach) by myeloperoxidase (MPO).
NADPH oxidase
O2 is converted to O2. by (oxidative burst).
SOD
O2. is converted to H202, by superoxide dismutase
MPO
H202 is converted to HOCl (bleach) by myeloperoxidase (MPO).
CGD is characterized by?
poor O2-dependent killing.
CGD is Due to?
NADPH oxidase defect (X-linked or autosomal recessive)
What does CGD lead to?
recurrent infection and granuloma formation with catalase-positive organisms, particularly Staphylococcus aureus, Pseudpmonas cepacia, Serratia marcescens, Nocardia, and Aspergillus
Nitrobiue tetrazolium test
is used to screen for CGD. Leukocytes are incubated with NBT dye, which turns blue if NADPH oxidase can convert 02 to O2. but remains colorless if NADPH oxidase is defective.
MPO deficiency results in?
defective conversion of H202 to HOCl
MPO deficiency symptoms?
Increased risk for Candida infections; however, most patients are asymptomatic.
MPO deficiency and NBT?
normal; respiratory burst O2. to H2O2 is intact.
O2-independent killing
less effective than O2-dependent killing and occurs via enzymes present in leukocyte secondary granules (e.g., lysozyme in macrophages and major basic protein in eosinophils).
Step 7?Resolution
Neutrophils undergo apoptosis and disappear within 24 hours after resolution of the inflammatory stimulus.
Macrophages
Macrophages predominate after neutrophils and peak 2-3 days after inflammation begins.
What are macrophages derived from?
monocytes in blood
How do macrophages arrive in tissue?
via the margination, rolling, adhesion, and transmigration sequence
What do macrophages do?
Ingest organisms via phagocytosis (augmented by opsonins) and destroy phagocytosed material using enzymes (e.g., lysozyme) in secondary granules (02-independent killing)
What are the outcomes for macrophages managing the next step of the inflammatory process?
Resolution and healing, 2. Continued acute inflammation, Abscess, Chronic inflammation
Macrophages induce Resolution and healing by?
Anti-inflammatory cytokines (1L-10 and TGF-(Beta) are produced by macrophages.
Macrophages induce Continued acute inflammation by?
persistent pus formation; IL-8 from macrophages recruits additional neutrophils.
Macrophages induce Abscess by?
acute inflammation surrounded by fibrosis; macrophages mediate fibrosis via fibrogenic growth factors and cytokines.
Macrophages induce chronic inflammation by?
Macrophages present antigen to activate CD4+ helper T cells, which secrete cytokines that promote chronic inflammation
Chronic inflammation is characterized by?
presence of lymphocytes and plasma cells in tissue, its a delayed response but more specific (adaptive immunity) than acute inflammation
Chronic inflammation stimuli include
(1) persistent infection (most common cause); (2) infection with viruses, mycobacteria, parasites, and fungi; (3) autoimmune disease; (4) foreign material; and (5) some cancers.
T lymphocytes are produced where?
Produced in bone marrow as progenitor T cells
Where are T lymphocytes further developed?
Further develop in the thymus where the T-cell receptor (TCR) undergoes rearrangement and progenitor cells become CD4+ helper T cells or CD8 cytotoxic T cells