=local reaction of vascularized tissue to injury, itself is NOT a disease, but a normal response of the body to trauma or foreign organisms
what is the singular and plural suffix to indicate inflammation?
Processes of Inflammation:
Increased blood flow to injured site
exudation of fluid from vessels
Attraction of leukocytes to the injury: leukocytes engulf intrusive agent, if any
Activation of chemical mediators
Proteolytic removal of extracellular debris
Restoration of injured to tissue to normal structure and function: depends on the regenerative capacity of the tissue
What causes erythema and warmth in inflammation?
vascular dilation and increased blood flow
What causes edema associated with inflammation?
extravasation and extravascular deposition of fluid and proteins
Three steps in initial acute inflammation: 1- vascular dilation and increased blood flow, 2- extravasation and extravascular deposition of fluid and proteins, and 3- leukocytes emigration and accumulation at the site of injury
Fundamentally, what is the purpose of inflammation?
it is a protective response to rid the organism of the initial cause of cell injury (microbe, toxin) and get rid of the consequences of injury, like necrotic cels and tissue
How can inflammation and repair be potentially harmful?
Inflammatory responses underly common chronic disease
Uncontrolled inflammatory reactions can lead to life-threatening hypersensitivity reactions (asthma)
Repair can produce restrictive scarring and limb immobilization due to the deposition of collagen, leading to a potential loss of function (burn victims)
Examples of when inflammation is "not our friend" 3
3. Rheumatoid Arthritis
What are the 6 cardinal signs of inflammation:
1. Calor- heat
2. Dolor- pain
3. Tumor- swelling
4. Rubor- redness
5. Functio laesa- loss of function
6. Systemic changes
What causes heat associated with inflammation?
increased blood flow to the site of injury
What causes redness associated with inflammation?
Increased blood flow
What causes swelling associated with inflammation?
accumulation of water and cells
What causes pain associated with inflammation?
pressure of fluid and effect of mediators
What causes loss of function associated with inflammation?
secondary to heat, redness, swelling, and pain
What causes systemic changes associated with inflammation? examples?
release of humoral factors
Fever and malaise are examples of systemic changes
6 causes of inflammation:
Tissue death- inflammation arises in living tissue adjacent to necrotic areas
2 examples of physical injury that cause inflammation:
2 examples of Chemical injury causing inflammation:
what is an example of inflammation without infection?
what is an example of infection without inflammation?
4 outcomes of ACUTE inflammation:
Healing by scarring
Progress to chronic inflammation
when does acute inflammation heal by scarring?
After substantial tissue destruction, and in tissue that cannot regenerate (i.e. lung)
When does an abscess form as an outcome to acute inflammation?
infections with pyogenic (pus-causing) organisms
When does acute inflammation progress to chronic inflammation?
when an infectiuon cannot be cleared easily, such as viral or autoimmune
The outcomes of acute inflammation...
The excavation of he surface of a tissue. They are chronic but experience acute episodes, acute and chronic can be concurrent
Arthritis: acute or chronic?
A chronic disease which may have acute episodes. Display redness, pain, swelling
Serous inflammation: describe
ex: burn. A transudate: thin, cell-free fluid, can see droplets of fluid have been exuded onto the surface of inflamed tissue
what are two examples of serous inflammation?
When depositions of Fibrin, a pink meshwork histologically, overlie the surface of inflamed tissue. Amorphous, eosinophilic mass, congestion of small blood vessels with the accumulation of red blood cells
When the epicardium becomes covered with a shaggy layer of Fibrin. Occurs in patients with a high BUN. Fibrinogen is converted to fibrin and deposited on the surface of the epicardium
2 clinical signs of Fibrinous pericarditis?
1. High Blood urea nitrogen (BUN)
2. friction "rub" heard upon auscultation
turbid, viscous, yellow pus, containing white blood cells and debris (whitish to yellow color)
Acute vs. Subacute vs. Chronic Inflammation:
Acute- 0-48 hours duration
Subacute- 2 days to ten days
Chronic- Greater than 2 weeks
Principle cells of acute Inflammation?
Cells of Subacute Inflammation? 6
Cells of chronic inflammation? 5
Granuloma cells (epithelioid and giant cells)
What are the predominant inflammatory cells of parasitic infections and allergic reactions?
Other 4 cell types involved in inflammation?
What is the function of Fibroblasts in inflammation?
as the tissue is healing, they help with the repair process; repair, scarring
How are mast cells involved with inflammation?
they produce the chemical mediators that generate the cardinal signs of inflammation
Molecular systems in two categories?
6 molecular systems that are plasma-derived:
Acute phase proteins
What are the plasma-derived components of the immune system?
What are the plasma-derived components of the complement system?
C3, C5 fragments
What are the plasma-derived components of the kinin system?
What are the plasma-derived components of the Clotting system?
What are the plasma-derived components of the fibrinolytic system?
What are the plasma-derived components of the Acute Phase Protein system?
What is Ceruloplasmin?
An acute phase protein that is an antioxidant that prevents inflammation from becoming excessive
2- Vasodilation: arteriolar, results in increased capillary blood flow- follows any transient
changes in vascular flow and caliber...limited by precapillary sphincters in normal vessel, but in inflammation, sphincters relax to allow more fluid here
Transudation vs. Exudation
Transudation vs. Exudation
Normal= when hydrostatic pressure equals colloid osmotic pressure
Transudation= An increased hydrostatic pressure and a decreased colloid osmotic pressure, but still intact membranes, leads to FLUID leakage, non-cellular
Exudation= Vasodilation and stasis of the vessels along with increased intracellular space in the membrane (both caused by inflammation), leads to FLUID and PROTEIN leakage in the extravascular space
What is normal hydrostatic pressure?
32 mmHg at the arterial end of a capillary bed,
and 12 mmHg at the venous end
What is mean colloid osmotic pressure?
25mmHg, which equals the mean arterial pressure
at the levels of capillaries and POSTCAPILLARY VENULES,
happens as a result of endothelial cells contracting, signaled by histamine, NO, and other signals. This is a transient event, happening within minutes and not lasting very long
name 3 other mechanisms that can cause vascular leakage other than endothelial cell contraction:
1. Direct injury
2. Leukocyte injury
3. New blood vessel leakage
Direct endothelial injury in vascular leakage:
can happen in any type of vessel, caused by burns, toxins
Rapid, but long-lived (hours to days)
Leukocyte-induced injury as a mechanism of vascular leakage:
occurs in venules, pulmonary capillaries; later stages of inflammation; long lived (hours)
**Chemical mediators can cause damage to endothelium as well, causing leakage
**Major point: in many senses inflammation s a good thing if it is contained; but if it is over a large area for a long period of time it can cause damage because inflammatory cells create chemicals that are deleterious to normal tissues
New Blood vessel leakage as a mechanism for vascular leakage:
"Addition mechanism" of capillary leakage, where new capillaries that migrate into that area will be initially leaky due to poorly developed basement membranes
Stasis of circulation with leakage results in an increase of what 2 things?
Increased viscosity and Increased Hematocrit
**As fluid leaves, Hematocrit increases, increases the viscosity of blood, resulting in STASIS, a sludge of red blood cells that move very slowly, resulting in vascular congestion...fluid overwhelms lymphatics, too much to filter at once --> edema
4 steps of Leukocyte extravasation:
The lining up of leukocytes, mostly neutrophils, along the endothelial cell surface (EC)
Adhesion of the rolling leukocytes to the Endothelial Cell surface
Migration of cell across endothelial cell surface and basement membrane into the interstitial space
directed movement of cells along a chemical gradient toward site if injury
"rolling" on the surface mediated by selectins, found on the endothelial cells surface, in response to inflammatory stimuli, they will migrate out of the vessel into the tissue between endothelial cells, can be stimulated by the injured tissue itself
Once you start inflammation, it snowballs...cell that initially respond attract more cells that respond, another reason that inflammation is tightly regulated because it can get out of hand and cause problems
What is the appendage of the migrating leukocyte called?
what are Cell Adhesion Molecules (CAM)?
=membrane protein that promote leukocyte attachment and participate in the inflammatory response
3 categories of CAM (cell adhesion molecules):
2. Immunoglobulin family (VCAM and ICAM)
selectins allow for rolling, serving as molecular velcro for cell to bind but not too tightly
=serve as molecular duct tape allowing the string adherance of leukocytes to the endothelial cell surface and resist flow
Regulation of Adhesion Molecules: how is the expression of P-selectins regulated?
Stimulation from histamine and Thrombin causes the "redistribution" of P-selectin on the cell surface, from stores within the endothelial cells called weibel-palade bodies
How do cytokines regulate adhesion molecules? which ones?
Stimulation of the endothelial cells by the cytokines, TNF and IL-1, increase the expression of selectins and ligands for integrins. Intergins usually in low concentration, but can change with stimulation, tightly regulated
How do chemokines regulate Adhesion Molecules?
Chemokines increase the binding avidity of integrins (conformational change of the integrins on the leukocyte that binds)
How are the immunoglobulin family regulated?
VCAM and ICAM are not normally synthesized, but in response to some signals can be made de novo and released for cells to stick to the surface
Selectins: what are they? what 3 cells can they be found on? purpose?
expressed on surface of endothelial cell, platelets, and leukocytes
Serve as homing receptors that mediate the rolling and slowing down of leukocytes at sites of inflammation
P in P-selectin stands for what?
what is P-selectin stored in and in what cells? stimulated by?
P-selectin stored in weibel-palade bodies
In endothelial cells and platelet alpha-granules
Stimulated by cytokines: TNF or IL-1
What 2 things do P-selectins recognize on protein surfaces?
1. Sialylated Lewis-X type oligosaccharides
2. P-selectin glycoprotein ligand 1 (PSGL-1)
What are the three groups of selectins? cell?
1. P-selectins (platelets)
2. E-selectins (endothelial)
3. L-selectins (leukocytes)
E-selectins: synthesized by? Stimulated by? recognizes what on surface proteins?
Synthesized by endothelial cells which are Stimulated by cytokine TNF and IL-1
recognize sialylated Lewis-X oligosaccharides on surface proteins
What is L-selectin for? On what cells? recognizes what 3 receptors/adhesion molecules?
serves as a homing receptor to lymphocytes binding to high endothelial lymph node venules, also appears on surface of lymphocytes and neutrophils to localize them to cytokine-activated EC's
GlyCAM-1 (glycan-binding cell adhesion molecules)
MadCAM-1 (glycan-binding cell adhesion molecules)
CD numbers for the three selectins:
What are the three endothelial molecules of the Immunoglobulin family?
= assists in the localization of leukocyte to tissue injury
- expressed on the surface of cytokine-activated endothelium
- Binds to: beta 2 family of Integrins: LFA-1 and MAC-1, on the cell membranes of macrophages and neutrophils
What are the two Beta-2-family intergins?
LFA-1 and MAC-1
VCAM-1: bind to what receptor on what cells?
PECAM-1 also called?
PECAM-1 also called CD-31
= Binds in a homophilic manner and plays an important role in the diapedesis step of leukocyte emigration
*PECAM-1 different from ICAM and VCAM in that is is not specific for leukocytes, but rather endothelial cell to endothelial cell junctional complexes, allowing cells to cross that junctional barrier
Integrins: define, general
=Adhesion molecules composed of heterodimers of alpha and beta subunits, which regulate cell-matrix and cell-cell adhesion. Integrins are transmembrane proteins, and thus can intergrate external/surface stimuli to the cytoskeleton
What is the Beta-1 Integrin?
what does it stand for?
Binds to what?
VLA-4 is the only Beta-1 integrin, which stands for very late activation molecules
-expressed ONLY on leukocytes
- bind to VCAM-1 on endothelium
expression regulated by?
what are they? 4
deficiency results in?
-Activation of phagocytes by chemotactic stimuli increases surface expression of these integrins
1. LFA-1: leukocytes function associated antigens
2. CR3 and CR4: complement receptor type 3 and 4
Function: Bind to ICAM-1 and assist in localization of phagocytes to injury sites and subsequent extravasation (allow cells to stick to walls of vessel)
- Deficiencies result in susceptibility to infection
2 steps of Phagocytosis of an organism:
1. Recognition and Attachment
Phagocytosis of organisms: Step 1- Recognition and Attachment:
what 4 receptors?
-enhanced by OPSONINS (antibody, complement C3b, and mannose-binding lectin)
1. Leukocytes C3b receptor
2. Leukocyte Fc receptor
3. Leukocytes Mannose receptor
4. Leukocyte Scavenger receptor
Explain the engulfment step (step 2) of Phagocytosis of an organism
=pseudopods surround object, forming a phagosome, which binds with lysosome to form a phagolysosome
**Phagocytosis: must recognize the material to be phagocytosed, mediate with opsonins, of which there are many types (complement C3b, antibody, mannose-binding lectin), they act as opsonins because they have receptors for all these molecules and can bind specifically to bacteria that have these opsonins attached. Followed by engulfment, which isolates to foreign material from the rest of the cytoplasm, fuse to form a phagolysosome for the digestion of the material with enzymes
Fc and C3b receptors bind to opsonins to recognize the material, then engulf via psuedopods and form phagolysosome for digestion
What are the 3 pathways (aerobic and anaerobic) for the metabolic killing of organisms?
2. Peroxide-Myeloperoxidase-Halide System
Oxygen-Dependent metabolic pathway for killing organisms:
Oxygen reduced to Superoxide, with enzyme *NADPH oxidase, and superoxide rapidly converts to H2O2
H2O2-Myeloperoxidase-Halide system of killing organisms:
*myeloperoxidase enzyme (from neutrophil granules) catalyzes the reaction of H2O2 and Cl- (a halide) to HOCl, hypochlorous acid, which is a powerful oxidant and antimicrobial (=bleach)
Oxygen-Dependent pathway for killing organisms: describe and 3 examples:
= leukocyte granule proteins and ezymes,
1. Acid Hydrolases
4 functional responses induced on leukocyte to ACTIVATE:
1. Production of arachidonic metabolites
2. degranulation and secretion of lysosomal enzymes and activation of the oxidative burst
3. Secretion of cytokines, some are chemokines which attract more leukocytes to site of injury
4. Modulation of leukocyte adhesion molecules
*CRP is measured in patient suspected of having an MI because it goes up rapidly due to inflammatory response caused by necrotic cells of the heart. Alpha-1 antitrypsin is an inhibitor of proteolytic enzymes
Cell Mediators: where do they originate?
Either from PLASMA (in precursor form that must be activated) or from CELLS (sequestered in granules or synthesized)
What do Mediators bind to?
Bind to specific receptors on target cells
How can mediators act as Amplification system?
Mediators can stimulate the release of other (or same) mediator from target cells: Amplification or response integration mechanisms
What is the general half-life of mediators?
Most are SHORT-Lived. Decay quickly, inactivated by enzymes are are inhibited
Are mediators harmful?
They have the potential to cause harmful effects, yes...
Which mediators have to be activated: cell-derived or plasma-derived?
What are the 3 interconnected systems of plasma proteins?
1. Complement System
2. Kinin System
3. Clotting System
What is the critical step of complement activation (and of inflammation)? what is formed?
the cleavage of C3
- cleaved into C3a and C3b
What are the 4 pathways for complement activation?
1. Classic Pathway
2. Alternate pathway
3. Lectin Pathway
4. Cleavage by Proteolytic Enzymes
Complement Activation: Classic Pathway?
= initiated by the binding of antigen-antibody complex to C1 on the surface of a foreign body
Complement Activation: Alternate Pathway?
C3 is directly activated (cleaved) by bacterial endotoxins, complex polysaccharides, aggregated globulins (i.e. IgA)
Complement Activation: Lectin Pathway?
C1 activation by binding of plasma mannose-binding lectin to carbohydrates on microbes
Complement Activation: Cleavage by proteolytic enzymes?
Plasmin and lysosomal enzymes in inflammatory exudate
Complement Fragments Important to Inflammation? 5
1. C3a, C4a, C5a
C3a, C4a, C5a complement fragments also called? function?
function is to stimulate histamine release from mast cells, leading to increased vascular permeability and vasodilation
C5a complement fragment function?
(although also an anaphylatoxin)
= directs the chemotaxis of Monocytes and granulocytes; increases the surface expression leukocyte CAM; and activates the lipoxygenase pathway in neutrophils and monocytes
C3b complement fragment function?
opsonization with recognition by receptors on neutrophils, macrophages, and eosinophils
C5-9 complement fragment function?
=membrane attack complex, that inserts into the lipid bilayer forming macropores that increase cell permeability and lead to cell lysis
**The activations and function of the complement system. Activation of complement by different pathways leads to cleavage of C3. The functions of the complement system are mediated by the breakdown products of C3 and other complement proteins, and by the membrane attack complex (MAC)
**classic activation is activation of C1 by binding of antibody or of mannose-binding lectins to surface of microbe, all lead to cleavage of C# to C3a and C3b
What is the function of C3a?
=targets leukocytes to the site of inflammation
what is the function of C3b?
=binds microorganism and targets them for phagocytosis
What is Hageman Factor?
= Factor XII of the intrinsic clotting system
Factor XII/Hageman factor activated by?
Activated by: direct contact with endotoxins, collagen, or basement membrane (clotting of any NEGATIVE surface)
Triggers: the KININ system and the CLOTTING cascade
How does Hageman Factor(Factor XII) activate the KININ system?
Hageman factor cleaves PREKALLIKREIN to KALLIKREIN.
What is the main function of Kallikrein?
***The main function of Kallikrein is to cleave high molecular weight KININOGEN, which forms the kinins, including BRADYKININ
What are 4 other functions of kallikrein?
Amplifies the activation of Hageman Factor
Converts plasminogen to PLASMIN
Is a chemoattractant for Neutrophils and converts C5 to C5a, which is an chemoattractant for leukocytes
INcreases CAM expression on endothelium
What is bradykinin (class)?
= a short-lived vasoactive peptide
4 functions of Bradykinin?
Increases vascular permeability
Dilated Blood Vessels
Contracts non-vascular smooth muscle
Causes pain (Bee venom is largely bradykinin)
What enzyme inactivates Bradykinin?
How does Thrombin act as the link to Inflammation?
Thromin (protease) cleaves circulating fibrinogen, to generate soluble FIBRIN
What does Thrombin bind to? On what cells?
Thrombin binds to PAR's= Protease-activated Receptors
These receptors on:
- Smooth Muscle Cells
After Thrombin binds to Protease-activated receptors on platelets, endothelium, and smooth muscle cells then do what 5 things?
Mobilize P-selectin to cell surface in endothelial cells
Produce chemokines, NO, and PAF(platelet activating factor)
Induce COX-2 and production of Prostaglandins (arachidonic acid molecules)
Induce changes in endothelial shape
what does Plasmin Lyse?
What 2 things activate Plasmin?
Formed from the cleavage of plasminogen to plasmin by:
2. Plasminogen Activator
Plasminogen Activator (which activates Plasmin) is released by what 2 cells?
3 roles of PLasmin in Inflammation?
1. Activates Hageman Factor
2. Cleaves C3 to C3a
3. Degrades fibrin to form fibrin split products, which increase vascular permeability in skin and lung
What activates Hageman Factor?
What do Fibrin Split Products do?
Increase vascular permeability in skin and lung
Need to know the interrelationships between these clotting systems
Are vasoactive amines cell-derived or platelet-derived?
cell Derived mediators
what are the 2 important vasoactive amines?
Where do the vasoactive amines (histamine and serotonin) bind? to what receptor?
What is the effect of Histamine and Serotonin (the vasoactive amines): 3
1. Cause Arteriolar Dilation
2. Increased Permeability of postcapillary Venules
3. Constricts Large Arteries
***increased permeability in the microcirculation allows for more fluid out of capillaries into areas of inflammation
How quickly are the effects of Serotonin and HIstamine (vasoactive amines)? HOw long do they last?
Immediate but transient (one hour) effects
Why are the effects of the vasoactive amines (histamine and serotonin) so fast?
Because there are prestored in granules that are released
what 3 cells store granules of the vasoactive amines HIstamine and Serotinin?
1. Mast Cells
9 things that stimulate the release of Vasoactive amines (serotonin and Histamine) from Mast cells:
Trauma, Cold, Heat, Platelet aggregation, the Anaphylatoxins (C3a, C4a, C5a), Neuropeptides (Substance P), Cytokines (IL-1 and IL-8), Histamine-releasing proteins (cationic) from Neutrophils and Platelets, and IgE binding to Mast cells
Arachidonic Acid Metabolites: cell or platelet derived?
What is arachidonic acid normally bound to? released by?
Arachidonic acid normally bound to the phospholipids of the cell membrane and is released by the action of CELLULAR PHOPHOLIPASES, by mechanical, chemical, and physical stimul.
What is 1 key activator of the release of arachidonic acid from the phospholipids of cell membranes?
2 key pathways of arachidonic Acid?
1. Cyclooxygenase Pathway
2. Lipoxygenase Pathway
How does Aspirin Work?
Aspirin and all NSAID inhibit the activity of *cyclooxygenase, blocking to production of the whole family of arachidonic acid metabolites (prostaglandins), which can reduce the symptoms of inflammation
How do glucocorticoids work?
Act indirectly by inhibiting *phopholipases
Synopsis of the cyclooxygenase pathway:
COX pathway converts arachidonic acid into prostaglandin intermediates that form several inflammation-related products
What are the 5 important prostaglandin intermediates formed by the COX pathway?
1. Thromboxane A2 (TXA2)
2. Prostacyclin (PGI2)
Function of Thromboxane A2 (TXA2)?
=Potent platelet aggregator and vasoconstrictor
Function of Prostacyclin (PGI2)?
= Vasodilator and inhibitor of platelet aggregation
what cell makes prostacyclin (PGI2)?
Function of PGE2?
=Sensitizes skin to painful stimuli and plays a role in cytokine-induced fever
Role of PGD2, PGF2a, and PGE2?
=Cause vasodilation and potentiate edema
Synopsis of Lipoxygenase Pathway:
Converts Arachidonic Acid into HPETE= hydroperoxyeicosatertraenoic) compounds which form the HETEs, the leukotrienes (proinflammatory) and lipoxins (antoinflammatory)
Leukotrienes and Lipoxins: which is pro- and which is anti-inflammatory?
What are the 4 leukotrienes produced by the Lipoxygenase Pathway?
3 Functions of Leukotriene B4?
Potent chemoattractant causing aggregation of neutrophils and adhesion to endothelial cells
Generation of ROS (in respiratory burst)
Release of Lysosomes
Functions of Leukotrienes C4, D4, and E4?
= cause intense vasoconstriction and bronshospasm, and increase vascular permeability
How do Lipoxins act as Anti-inflammtory agents?
Lipoxins are endogenous negative regulators of Leukotriene action; their principle actions are to inhibit leukocyte recruitment and the cellular activities of inflammation
Important Lipoxins to know? 2
Function of Lipoxins A4 and B4?
=Inhibit neutrophil chemotaxis and neutrophil adhesion to endothelial cells
describe the relationship between the amount of lipoxins and leukotrienes:
There is an inverse relationship between the amount of Leukotrienes and Lipoxins formed
Transcellular biosythetic mechanism for the production of Lipoxins: Know enzymes *5-Lipoxygenase and 12-Lipoxygenase
Summary figure of the formation of arachidonic acid metabolites and their role in inflammation
Chemical Name for PAF (platelet activating factor):
What 5 cells, when stimulated, produce PAF?
PAF (platelet activating factor) causes? (lots)
-Causes platelet aggregation and release of vasoactive platelet products (histamine and serotonin),
-causes vasoconstriction, bronchoconstriction, but at low concentrations causes vasodilation and venular permeability
-Stimulates leukocyte oxidative burst
- Increases leukocytes adhesion to endothelium
- Leukocyte chemotaxis
- Stimulates prostaglandin and leukotriene synthesis
Explain the different effects of various concentrations of PAF:
PAF causes vasoconstriction and brochoconstriction in high concentration, but in lower amounts causes vasodilation and venular permeability
what are cytokines?
= Polypeptides that function as "cellular hormones" or locally acting cell-to-cell mediators; and participate in intricate networks to achieve their effect
what are chemokines?
= Cytokines with strong chemotactic properties
What are the 2 key cytokines of inflammation?
IL-1 and TNF (inflammation cytokines), are produced mainly by?
=Mainly produced by activated MACROPHAGES
IL-1 and TNF (inflammatory cytokines) have 4 key effect processes:
"Acute Phase" Reactions
What are the effects of IL-1 and TNF (inflammatory cytokines) on "Acute Phase" reaction?
Produce fever, affect sleep and appetite, produce acute-phase proteins, cause neutrophilia, and hemodynamic effects in shock
What are the effects of IL-1 and TNF (inflammatory cytokines) on Endothelial cells?
Increase leukocyte adherence, stimulate PGI synthesis, increase procoagulant activity, and increase production of additional cytokines:
What are the effects of IL-1 and TNF (inflammatory cytokines) on Fibroblasts?
- Increase Proliferation
- Increase collagen synthesis
- increase PGE synthesis
- increase protease and collagenase production
What are the effects of IL-1 and TNF (inflammatory cytokines) on Leukocytes?
increased secretion of cytokines IL-1 and IL-6
Effects of TNF and IL-1 (inflammatory cytokines): main local and systemic effects
Chemokines: function in inflammation? how big? how classified?
= stimulate the recruitment of leukocytes in inflammation
-small proteins, 8-10 kD
- Classified according to the conserved cystein residue on the protein
What are the 4 classes of Chemokines?
1. alpha-chemokines/ "C-X-C"
2. beta-chemokines/ "C-C"
3. gamma-chemokines/ "C"
4. "CX3C" chemokines
C-X-C or alpha-chemokines (class): best example? acts primarily on?
Best Example is IL-8, acts primarily on neutrophils
C-C or beta-chemokines (Class): 3 examples? what do they attract? what do they NOT attract?
1. MCP-1, monocyte chemoattractant protein
2. MIP-1 alpha, macrophage inflammatory protein 1 alpha
3. Eotaxin, for eosiniphils
- This class of chemokine attracts Monocytes, Eosinophils, Basophils, and Lymphocyes, but NOT neutrophils
C or gamma-chemokines (class): example is? which attracts?
Lymphotactin, which attracts lymphocytes
CX3C chemokines (class): example? attracts what 2 cells?
Fractalkine is example
Attracts Monocytes and T-cells
Reactive Oxygen Metabolites (ROS) are produced and released extracellularly by what 2 cells?
ROS released extracellularly by macrophages and neutrophils causes what 3 types of damage?
1. Endothelial Cell Damage: increase in vascular permeability
2. Inactivation of anti-proteases: e.g. oxidation of methionyl residues on alpha 1 antitrypsin
3. Injury to other cells: tumor cells, erythrocytes, and parenchymal cells
Name 5 antioxidants that protect from free radical damage:
Are antioxidant pathways intra- or extracellular pathways?
NO is what technically?
= a soluble free radical gas
No produced by what 3?
2. Endothelial Cells
3. Some Neurons
How does NO work? (which 2nd messenger)
Acts in a paracrine fashion on target cells through cGMP (cyclic guanosine monophosphate)
3 functions of NO?
1. Strong vasodilation through smooth muscle cell relaxation
2. Reduces Platelet aggregation/adhesion and WBC recruitment (reduced inflammatory response)
3. No and derivitives are microbicidal
How does NO reduce the inflammatory response?
reduction of WBC recruitment
Functions of NO
5 typical enzyme components in Lysosomes of Leukocytes:
1. Acid Hydrolases, specif for degration of proteins, carbohydrates, lipids
4. Various neutral proteases
5. Plasminogen activator
what are the destructive effects of lysosomal enzymes?
the initial infiltration of leukocytes, if unchecked, can lead to further increases in vascular permeability and tissue damage
Most Likely Mediators in inflammation: Vasodilation?
Most Likely Mediators in inflammation: Vascular Permeability?
- Vasoactive Amines (serotonin and histamine)
- C3a and C5a (via Histamine)
- Leukotrienes C4, D4, and E4
- Substance P
Most Likely Mediators in inflammation: Chemotaxis and Leukocyte activation?
- Leukotriene B4
Most Likely Mediators in inflammation: Fever?
Most Likely Mediators in inflammation: Pain?
- Prostaglandins (E2 in particular)
Most Likely Mediators in inflammation: Tissue Damage?
- Oxygen Metabolites (ROS)
What are 3 inherited disorders of acute inflammation?
1. Chediak-Higashi Syndrome
2. Chronic Granulomatous Disease
3. Leukocyte adhesion deficiency, type I and type II
leukocyte migration, review
2 Neuropeptides we need to know? produced where?
1. Substance P
2. Neurokinin A
- members of a family of neuropeptides produced by the central and peripheral nervous system
4 Biological functions of Substance P:
Transmission of pain signals
Regulation of blood pressure
Stimulation of secretion by endocrine cells
Increasing vascular permeability
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