Inflammatory mediators Flashcards
Summary of what happens in tissue injury
Inflammatory mediators can be of what two types?
Cell-derived
–Cytokines
–Vasoactive Amines
–Arachidonic acid metabolites
Plasma-derived
–Complement proteins/products
–Kinins
Cytokines
What are they? they act in short or long range?
Which cytokine allows immediate communication between leukocytes in acute inflammation?
What are some cytokines used in chronic inflammation?
•Proteins produced by many cell types
- Act at short range
1. Mediate WBC recruitment and migration
i) In acute inflammation: - TNF (tumor necrosis factor)
- IL-1 (mediate communications between[inter] leukocytes)
- Chemokines (chemical-attractant cytokines)
ii) In chronic inflammation:
•IL-2, IL-4, IL-5, IL-17, IFN-γ
iii) .Hematopoiesis: GM-CSF, IL-7
iv) .Limit, terminate response: TGF-β and IL-10
Vasoactive Amines
What is their function?
What are the two main types?
- Stored as pre-formed molecules in cells
- Mediate
–->Vasodilation
–->Increased vascular permeability
•Two main vasoactive amines: Histamine, serotonin
Vasoactive amines:
Histamine
Where are they mostly stored?
What is their mechanism of action?
•Mostly stored in mast cells
•Released in response to
oPhysical injury; trauma, cold, heat, etc
oBinding of Abs (hypersensitivity reactions)
oComplement products; C3a, C5a
oOther: neuropeptides (subs P), IL-1, IL-8
Mechanisms of action
o Dilation of arterioles
o Increased permeability of venules
• Binds to H1 receptors on endothelial cells
oAntagonistic medications (steroids, anti-histamines) exploit this binding
Vasoactive amine:
Serotonin
Where is it stored?
Primary function is as a_________ in gastrointestinal tract.
Secondary functions is as _________ of blood vessels.
•Stored in platelets and neuroendocrine cells of gastrointestinal tract (GIT)
–Primarily acts as neurotransmitter in GIT
–Secondarily acts as vasoconstrictor
Arachidonic acid metabolites
Where is AA present at?
What enzyme releases AA from it place of storage/location?
Cyclooxygenases generate__________
Lipooxygenases generate____________
The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid (AA) present in membrane phospholipids, and stimulate vascular and cellular reactions in acute inflammation.
AA does not occur free in the cell but is normally esterified in membrane phospholipids.
Mechanical, chemical, and physical stimuli or other mediators (e.g., C5a) release AA from membrane phospholipids through the action of cellular phospholipases, mainly phospholipase A2.
Activation of phospholipase A2 :
- increase in cytoplasmic Ca 2+
- activation of various kinases in response to external stimuli
- AA-derived mediators (eicosanoids), are synthesized by two major classes of enzymes:
- Cyclooxygenases (which generate prostaglandins)
- lipoxygenases (which produce leukotrienes and lipoxins)
- Eicosanoids bind to G protein-coupled receptors on many cell types and mediate virtually every step of inflammation
Arachidonic acid metabolites:
Cyclooxygenase pathway
a) _____1_______ made by mast cells (more widely distributed); vasodilation and increased permeability of postcapillary venules –> edema formation; hyperanalgesic and makes the skin hypersensitive to painful stimuli; cytokine-induced fever during infections
b) ____________ major prostaglandin made by mast cells; chemoattractant for neutrophils
c) ________ stimulates the contraction of uterine and bronchial smooth muscle and small arterioles
d) ________ (prostacyclin); prostacyclin synthase is responsible for the formation of PGI 2 and its stable end product PGF 1a ; vasodilator and a potent inhibitor of platelet aggregation; potentiates the permeability-increasing and chemotactic effects of other mediators
- __________ (thromboxane A2); contained in platelets, potent platelet-aggregating agent and vasoconstrictor; unstable and rapidly converted to its inactive form_______.
A thromboxane-prostacyclin imbalance has been implicated as an early event in thrombus formation in coronary and cerebral blood vessels.
Prostaglandins are also involved in the pathogenesis of pain and fever in inflammation.
1-PGE2
2-PGD2
3- PGF2a
4-PGI2
5- TXA2; TXB2
Arachidonic acid metabolites:
Prostaglandins
When in COX1 produced and what is its function?
When is COX2 produced?
•Generated by enzymes
COX-1:
- Produced in response to inflammatory stimuli and
- Constitutively expressed in most tissues
- Function: fluid and electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract
COX-2:
- Induced by inflammatory stimuli
- Low or absent in most normal tissues
Arachidonic acid metabolites:
Lipooxygenase pathway
Produces__________.
Which one attracts and activates neutrophils?
•Produces leukotrienes
–LTB4: Attracts and activates neutrophils (also C5a, IL-8, bacterial products).
–LTC4, LTD4, LTE4: contract smooth muscle
–>Mediate vasoconstriction
–>Mediate bronchospasm
–>Increases vascular permeability
Arachidonic acid metabolites:
Lipoxins
What do they inhibit?
- ->Inhibit PMN chemotaxis
- ->Inhibit WBC adhesion
Leukocytes (esp PMNs)
–Produce intermediates in lipoxin synthesis
–Intermediates converted to lipoxins by platelets interacting with WBCs
Complement products
Complement products:
Steps
C3 convertase is generated (C3 –> C3a & C3b)
C3b helps produce C5 convertase
C5 convertase (C5 –> C5a & C5b)
C5b complexes with C6-C9–> formation of MAC
MAC: produces hole in cell membrane –> lysis of organism
C3a + C5a – trigger mast cell degranulation
C5a – chemotactic for PMNs
C3b – opsonin (recognized by PMNs) for phagocytosis
MAC – lysis of microbe
Hageman Factor VII
What activates Hageman factor VII?
Once activated, what does Hageman factor VII activates?
Associated with what type of sepsis?
- Produced in liver
- Inactive proinflammatory protein
–Activated with collagen exposure (subendothelial or tissue)
•Activates:
–Coagulation and fibrinolytic systems
–Complement system
–Kinin system: cleaves HMWK to bradykinin
–>vasodilation, increased vascular permeability, & pain
- Role in DIC (disseminated intravascular coagulation)
- Associated with gram negative sepsis
Kinin system
What does bradykinin does?
Kinins are vasoactive peptides derived from plasma proteins, called kininogens, by the action of specific proteases called kallikreins.
The enzyme kallikrein cleaves a plasma glycoprotein precursor, high-molecular-weight kininogen, to produce bradykinin.
Bradykinin increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain when injected into the skin.
—effects are similar to those of histamine.
—action of bradykinin is short-lived, because it is quickly inactivated by an enzyme called kininase.
—implicated as a mediator in some forms of allergic reaction, such as anaphylaxis
Describe the relationship between complement, coagulation, and kallikrein/kinin systems?
Complex relationship between complement, coagulation and kallikrein/kinin systems.
The complement, coagulation and kallikrein/kinin systems are working in concert with each other to provide both positive and negative feedback for hemostasis and inflammation.
Positive feedback between coagulation and kininogen/kinin systems occurs through FXII ability to activate prekallikrein (PK) and reciprocal effect of PK on FXII activation.
FXIIa activates complement system through activation of C1 component of complement triggering classical pathway of activation.
A positive feedback also exists between Kallikrein/kinin and complement system. Inflammation promoted through activation of complement and bradykinin-generating arm of kallikrein/kinin system, in turn, facilitates coagulation through activation of extrinsic coagulation pathway.
Certain products of kallikrein/kinin system (e.g., tPA) supply important negative feedback to coagulation system by initiating fibrinolysis and leading to clot dissolution and restoration of hemostasis. Contact activation of complement, FXII and kallikrein pathways is responsible for clotting complications during extracorporeal circulation.
***FXII is a common element providing positive feedback between the three systems. Selective inhibition of FXIIa allows safe anticoagulation without bleeding.
HMW—high molecular weight; tPA, tissue plasminogen activator; TF, tissue factor (CD142); PS, phosphatidylserine; “a” following coagulation factor indicates activated form of the factor; C3 and C5 are complement components 3 and 5, respectively, “a” and “b” following complement components indicate split products of these components; membrane attack complex (MAC), also known as terminal complex.
Summary
Summary of mediator, source, and action:
Summary of cytokines, sources and actions;
