CHEMICAL MEDIATORS
OF
INFLAMMATION IN RELATION OF
PHOSPHOLIPIDS & METABOLISM
LEARNING OBJECTIVES
At the end of the lecture, students should be able to:
• Enlist chemical mediators with inflammatory response.
• Discuss the mechanism of PGs & leukotriens introduction & response
in inflammation.
• Discuss the relation of TNF & nitric oxide with inflammation.
• Discuss the role of microbial reactive oxygen intermediates with
phagocytosis.
• Enumerate chemical mediatorsof inflammation &
bronchoconstriction.
Cardinal signs of (acute) inflammation
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Rubor = Redness
Tumor = Swelling
Calor = Heat
Dolor = Pain
Functio laesa = Loss of function
ACUTE INFLAMMATION
• Vascular events (earliest response)
• Cellular events
VASCULAR EVENTS
(ALTERATION IN THE MICROVASCULATURE)
• Haemodynamic changes
• Altered vascular permeability
Vascular changes
• Vasodilation
– increased permeability of vessels due to widened intercell. junctions and
contraction of endothelial cells (histamin, VEGF, bradykinin)
• Protein poor transudate (edema)
• Protein rich exsudate
• Leukocyte-dependent endothelial injury
– proteolysis – protein leakage
•  Platelet adhesion  thrombosis
Cellular events
• Leukocytes margination  rolling  adhesion  transmigration
• Emigration of:
– neutrophils (1-2 days)
– monocytes (2-3 days)
• Chemotaxis
– endogenous signaling molecules - lymphokines
– exogenous - toxins
• Phagocytosis - lysosomal enzymes, free radicals, oxidative burst
• Passive emigration of RBC - no active role in inflamm. -
hemorrhagic inflammation
REVIEW OF NORMAL CAPILLARY EXCHANGE
• NOT ALL CAPILLARIES ARE OPEN IN 1 BED
 Difference in concentration of substance in blood and
isf promote diffusion
 Plasma colloid osmotic pressure is more than the
osmotic pressure in isf, so it retains the fluid inside the
lumen
HAEMODYNAMIC CHANGES
• Persistent progressive vasodilation
-- rapid: histamine, serotonin;
-- slower: nitric oxide, kallikerin, pge2, pgi2, pgd2 (mast
cells)
• Opening of precapillary arteriole sphincters resulting into
opening of microvascular bed
• Venules relax as well
• Vessels are congested (hyperemia) and pooling of blood in
post capillary venules
HAEMODYNAMIC CHANGES
• Elevate local h.s pressure results in transudation of
fluid into extra
vascular
tissue
HAEMODYNAMIC CHANGES
• Slowing or stasis of microvasc ulation
• Results in inc conc. of red cells
• Raised blood viscosity
• Leukocyte margination along the vascular endothelium.
ALTERERED VASCULAR PERMEABILITY
• Leading to a marked outflow of fluid & its accumulation in
the interstitial tissue (oedema)
• Contraction of endothelial cells
• Retraction of endothelial cells
• Direct injury to endothelial cells
• Endothelial injury mediated by leukocytes
• Other mechanisms
CONTRACTION OF ENDOTHELIAL CELLS
– Caused by histamines, bradykinins and leukotrienes within few
seconds
– Lasts for 15 – 30 min
– Phosphorylation of contractile & cytoskeletal proteins (myosin)
– Widens intercellular gaps of venules temporary (not arterioles,
capillaries)
RETRACTION OF ENDOTHELIAL CELLS
– Caused by cytokine mediators tnf, il-1, ifn-γ
– Through structural reorganization of cytoskeleton of
endothelial cells
– Takes 2 – 4 hrs after injury
– Lasting 24 hrs or more
DIRECT INJURY TO ENDOTHELIAL CELLS
– May cause delayed damage as in mild to moderate
thermal or uv injury, or some bacterial toxins (late
appearing sunburn)
– Begins after a delay of 2-12 hrs & lasting for several
hrs- days
ENDOTHELIAL INJURY MEDIATED BY LEUKOCYTES
– Endothelial cell-adherent leukocytes may be
activated
– Release proteolytic enzymes & toxic oxygen species
– Damage the endothelium
– Making the vessel leaky (late response)
– Seen in pulmonary venules and capillaries.
OTHER MECHANISMS
– Certain mediators (vegf) may cause inc.No. Of
vesiculovacuolar organelle causing increased
transcytosis to the endothelial cell surface
– Newly formed capillaries during the repair are
excessively leaky until endothelial cells mature.
CELLULAR EVENTS
• EXTRAVASATION
• PHAGOCYTOSIS
EXTRAVASATION
– Margination
– Rolling and adhesion
– Transmigration
– Chemotaxis and activation
• They are then free to participate in:
– Phagocytosis and degranulation
– Leukocyte-induced tissue injury.
CELLULAR EVENTS
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MARGINATION
ROLLING
ADHESSION
EMIGRATION
CHEMOTAXIS
MARGINATION
• With increased vascular permeability, fluid leaves the
vessel causing leukocytes to settle-out of the central flow
column and “marginate” along the endothelial surface
ROLLING & ADHESION
• Tumbling slowly and adhere transiently (rolling)
• Coming to rest & adhere firmly(adh)
• Brought about by 4 types of distinct adhesssion molecules
selectins
mucin-like glycoproteins
integrins
immunoglobulin superfamily adhesion molecule (glycam-1,
psgl-1, esl-1, cd34)
SELECTINS
• Take part in rolling of pmns over endothelial surface
Consists of
• P- selectins (on endothelium & platelets)
• E- selectins (conf to endothelium)
• L- selectins (on most leukocytes)
INTEGRINS (GLYCOPROTEINS)
• Expressed on many cell types
• Made up of alpha & beta chains
• Consisting of beta-1 & beta-2 mol
• Beta-2 (lfa-1, mac-1) bind to icam-1
• Beta-1 (vla mol) bind vcam-1
• Bring about firm adhesion b/w leukocytes & endothelium
IMMUNOGLOBILIN SUPERFAMILY ADHESION
MOLECULE
• 2 endo adhesion mols (icam-1,vcam-i)
• Expressed on endothelial surface by the action of tnf & il-1
• Serve as ligands for integrins found on leukocytes
• Help in localizing leucocytes to the site of injury.
MUCIN-LIKE GLYCOPROTEINS
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Glycam-1, psgl-1, esl-1, cd34
Found in extra cellular matrix and on the cell surfaces
Serve as a ligand for other leukocyte adhesion molecules
Regulate the localization of sub population of leukocytes
ROLLING AND ADHESION
• Stick and release causing the leukocyte to roll along the
endothelium like a tumbleweed
• Stop as mutual adhesion reaches a peak (activated)
EMIGRATION
• Cross The Basement Membrane By Damaging It Locally
With Secreted Collegenases.
DIAPEDESIS
• Diapedesis gives haemorrhagic apearrance to
inflammatory exudate.
CHEMOTAXIS
• Transmigration of leucocytes to reach the interstitial
tissues ,
• The chemotactic factor –mediated
• Crossing several barriers (endothelium, basement
membrane, perivascular myofibroblasts and matrix)
REFERENCES
• Robbins and Cotran – Pathologic basis of disease.
Sugars
E-Selectin
P-Selectin
Neutrophils
Monocytes
Integrins
CAMS
ICAM-1,2
VCAM-1
L-Selectin
Platelets
P-Selectin
Endothelium