leukotrienes

1. LeukotrienesLeukotrienes
Prepared By:Prepared By:
Pireh Yusra RajputPireh Yusra Rajput
Mphil Scholar, 2015Mphil Scholar, 2015
University Of KarachiUniversity Of Karachi

2.  The human body responds to a variety ofThe human body responds to a variety of
noxious stimuli as trauma, infection or allergicnoxious stimuli as trauma, infection or allergic
reactions with the release of preformed, storedreactions with the release of preformed, stored
mediators such as epinephrine, normediators such as epinephrine, nor
epinephrine , histamine, serotonin prostanoids &epinephrine , histamine, serotonin prostanoids &
LeukotrienesLeukotrienes etc.etc.

3. LeukotrienesLeukotrienes
 Lekotrienes are a family of eicosanoids, collection ofLekotrienes are a family of eicosanoids, collection of
oxygen derivative of 20 essential fatty acids.oxygen derivative of 20 essential fatty acids.
 They are inflammatory mediators mainly produced inThey are inflammatory mediators mainly produced in
leukocytes, mast cells, macrophages and other tissuesleukocytes, mast cells, macrophages and other tissues
by the oxidation of arachidonic acid by the enzymeby the oxidation of arachidonic acid by the enzyme
arachidonate 5 lipoxygenase.arachidonate 5 lipoxygenase.
 The name leukotriene derives from the original discoveryThe name leukotriene derives from the original discovery
of these substances from WBC ( polymorph nuclearof these substances from WBC ( polymorph nuclear
leucocytes) .leucocytes) .

4.  Leukotrienes together with prostaglandins andLeukotrienes together with prostaglandins and
other related compounds are derived from 20other related compounds are derived from 20
carbon (eicosa) fatty acids that contains doublecarbon (eicosa) fatty acids that contains double
bonds. Hence this group is called Eicosanoids.bonds. Hence this group is called Eicosanoids.
 They are produced in response to immunologicalThey are produced in response to immunological
and non immunological stimuli.and non immunological stimuli.
 The name leukotriene introduced by SwedishThe name leukotriene introduced by Swedish
biochemist Bengt samuelesson in 1979 comesbiochemist Bengt samuelesson in 1979 comes
from the word “Leukocytes and triene indicatingfrom the word “Leukocytes and triene indicating
compounds having 3 conjugated double bonds.compounds having 3 conjugated double bonds.

5.  Leukotrienes are produced along with histamineLeukotrienes are produced along with histamine
but unlike histamine they are four folds morebut unlike histamine they are four folds more
potent & have longer duration that’s why calledpotent & have longer duration that’s why called
as Slow Reacting Substances ( SRS) .as Slow Reacting Substances ( SRS) .
 Like hormones produced in low concentrationLike hormones produced in low concentration
and rapid metabolic turn over. Unlike hormones,and rapid metabolic turn over. Unlike hormones,
they are not produced in a central organ butthey are not produced in a central organ but
locally produced.locally produced.

8. Control &Control &
RegulationRegulation
 1)1) Membrane Phospholipids:Membrane Phospholipids:
The control & regulation od leukotriene is dependent onThe control & regulation od leukotriene is dependent on
factors like availability and amount of integral fatty acids.factors like availability and amount of integral fatty acids.
Alpha linoleic acid, which is present in the plasmaAlpha linoleic acid, which is present in the plasma
membrane. Without this lipid there is no product b/c it ismembrane. Without this lipid there is no product b/c it is
the precursor of arachidonic acid.the precursor of arachidonic acid.
One of these fatty acids are broken down to arachidonicOne of these fatty acids are broken down to arachidonic
acid by lipoxygenase pathway to start leukotrieneacid by lipoxygenase pathway to start leukotriene
production.production.

9.  2) Metabolism :2) Metabolism :
The limited amounts of leukotrienes that areThe limited amounts of leukotrienes that are
available in the body at the same time allows foravailable in the body at the same time allows for
a rather larger degree of control.a rather larger degree of control.
 They are metabolized extremely which allowsThey are metabolized extremely which allows
the body to increase or decrease their amountsthe body to increase or decrease their amounts
very quickly.very quickly.
 Their half life is less than 5 minutes.Their half life is less than 5 minutes.

10.  3) Enzymatic Control:3) Enzymatic Control:
 Enzymes are integral in the process ofEnzymes are integral in the process of
leukotrienes synthesis.leukotrienes synthesis.
 The amount and presence of specific enzymesThe amount and presence of specific enzymes
not only controls the initial production but thenot only controls the initial production but the
differentiation reactions as well.differentiation reactions as well.

11. BiosynthesisBiosynthesis

13.  The arachidonic acid is oxygenated by 4The arachidonic acid is oxygenated by 4
separate routesseparate routes
1)1) Lipoxygenase pathwayLipoxygenase pathway
2)2) Isoprostone pathwayIsoprostone pathway
3)3) Cycloxygenase pathwayCycloxygenase pathway
4)4) 450 epoxygenase pathway450 epoxygenase pathway

15. The first step in the synthesis of leukotrienes areThe first step in the synthesis of leukotrienes are
catalyzed by the calcium and ATP dependentcatalyzed by the calcium and ATP dependent
enzyme 5 Lipoxygenase from LOX enzymes.enzyme 5 Lipoxygenase from LOX enzymes.
Which metabolize arachidonic acid intoWhich metabolize arachidonic acid into
hydroperoxysatetrioic acid (HPETE’S).hydroperoxysatetrioic acid (HPETE’S).
The most active leukotrienes are those producedThe most active leukotrienes are those produced
by 5 LOX present in leukocytes ( neutrophils,by 5 LOX present in leukocytes ( neutrophils,
basophils, esinophils and monocytes) and inbasophils, esinophils and monocytes) and in
other inflammatory cells as mast cells andother inflammatory cells as mast cells and
dendritic cells.dendritic cells.

16. SynthesisSynthesis
 Stimulation of leukotriene producing cells elevatesStimulation of leukotriene producing cells elevates
intracellular calcium and arachidonic acid is released byintracellular calcium and arachidonic acid is released by
Phospholipases.Phospholipases.
 Arachidonic acid is converted to 5HPETE as 5LOX isArachidonic acid is converted to 5HPETE as 5LOX is
Translocates to the nuclear membrane. A nuclear membraneTranslocates to the nuclear membrane. A nuclear membrane
protein FLAP ( lipoxygenase activating protein) is neededprotein FLAP ( lipoxygenase activating protein) is needed
along with oxygen to convert A.A intoalong with oxygen to convert A.A into
hydroxyperoxyeicosatetrionic acid. 5LOx used FLAP in thishydroxyperoxyeicosatetrionic acid. 5LOx used FLAP in this
conversion by the help of enzyme arachidonate 5LOXconversion by the help of enzyme arachidonate 5LOX
(ALOX5).(ALOX5).

17.  ALOX5 also catalyze the conversion of 5HPETE intoALOX5 also catalyze the conversion of 5HPETE into
5HETE ( 5hydroxy eicosatetrionic acid).5HETE ( 5hydroxy eicosatetrionic acid).
 5LOX again acts on HETE & convert it into LTA45LOX again acts on HETE & convert it into LTA4
which is an unstable epoxide.which is an unstable epoxide.
 LTA4 is intermediate compound and either convertsLTA4 is intermediate compound and either converts
into dihydroxyleukotrienes LTB4 or conjugates withinto dihydroxyleukotrienes LTB4 or conjugates with
glutathione to yield LTC4 cysteinyl leukotrienes.glutathione to yield LTC4 cysteinyl leukotrienes.
 In cells equipped with LTA hydrolase as neutrophilsIn cells equipped with LTA hydrolase as neutrophils
and monocytes, LTA4 converted into LTB4 which isand monocytes, LTA4 converted into LTB4 which is
a powerful chemo attractants for neutrophils.a powerful chemo attractants for neutrophils.

18.  In cells that express LTC4 synthase as mast cellsIn cells that express LTC4 synthase as mast cells
and eisinophil cells. LTA4 is conjugated withand eisinophil cells. LTA4 is conjugated with
glutathione to form LTC4 which undergoesglutathione to form LTC4 which undergoes
sequential degradation of glutathione by peptidasesequential degradation of glutathione by peptidase
to yield LTD4 & LTE4.to yield LTD4 & LTE4.

19. Mechanism Of leukotrienesMechanism Of leukotrienes
Effects:Effects:
 There are specialized cell receptors present inThere are specialized cell receptors present in
the cell membrane of cells.the cell membrane of cells.
 Defense system cells, WBC’S bind to them toDefense system cells, WBC’S bind to them to
trigger off a series of activities giving rise to celltrigger off a series of activities giving rise to cell
movement and regulation.movement and regulation.
 There are 2 types of leukotrienes receptorsThere are 2 types of leukotrienes receptors
1) BLT Receptors 2) CL Receptors1) BLT Receptors 2) CL Receptors

20.  Leukotrienes B4 Receptors ( BLT) :Leukotrienes B4 Receptors ( BLT) :
Includes:Includes:
1)1) BLTR1 2) BLTR2BLTR1 2) BLTR2
Signaling pathway :Signaling pathway :
They are G Protein coupled receptors associated with Gq.They are G Protein coupled receptors associated with Gq.
Upon binding of cells with receptors, activated Gq protein.Upon binding of cells with receptors, activated Gq protein.
Gq stimulates the membrane bound phospholipase CGq stimulates the membrane bound phospholipase C
( class of enzymes cleaves phospholipids) which then( class of enzymes cleaves phospholipids) which then
cleaves PIP2 into two second messengers IP3 & DAG.cleaves PIP2 into two second messengers IP3 & DAG.
DAG remains bound to the membrane and IP3 is releasedDAG remains bound to the membrane and IP3 is released

21. As a soluble structure into cytosol. IP3 binds to IP3As a soluble structure into cytosol. IP3 binds to IP3
receptors within cells particularly Calcium channels inreceptors within cells particularly Calcium channels in
endoplasmic reticulum and cause increase Ca andendoplasmic reticulum and cause increase Ca and
release mediators.release mediators.
Location Of BLT Receptors:Location Of BLT Receptors:
Spleen, blood leukocytes, ovary, pancreas, heart, prostateSpleen, blood leukocytes, ovary, pancreas, heart, prostate
gland, testes, kidneys, colon, muscles, placenta.gland, testes, kidneys, colon, muscles, placenta.
BLTBLT1, have limited expression mainly circulating blood1, have limited expression mainly circulating blood
leukocytes & lymphocytes.leukocytes & lymphocytes.

22.  Functions:Functions:
Primarily acts as potent chemo attractant.Primarily acts as potent chemo attractant.
Involved primarily in conditions in which inflammation isInvolved primarily in conditions in which inflammation is
dependent on neutrophils in inflammatory condition asdependent on neutrophils in inflammatory condition as
cystic fibrosis, inflammatory bowl disease and psoriasis.cystic fibrosis, inflammatory bowl disease and psoriasis.
 Most important endogenously synthesized chemotacticMost important endogenously synthesized chemotactic
factor for granulocytes.factor for granulocytes.
 Cause adhesion of the granulocytes to the vascularCause adhesion of the granulocytes to the vascular
endothelium by activating receptors on the surface ofendothelium by activating receptors on the surface of
granulocytes.granulocytes.

23.  It also damages and increases vascular permeabilityIt also damages and increases vascular permeability
byby
1)1) By release of lysosomal enzymes & production oxygenBy release of lysosomal enzymes & production oxygen
radicals.radicals.
2)2) Increase the synthesis of interleukin 1 ( group ofIncrease the synthesis of interleukin 1 ( group of
cytokines , produced by macrophages, monocytes ,cytokines , produced by macrophages, monocytes ,
dendritic cells etc increase the expression of adhesiondendritic cells etc increase the expression of adhesion
factors on endothelial cells to enable diapedesis &factors on endothelial cells to enable diapedesis &
affect the activity of hypothalamus leads to increase inaffect the activity of hypothalamus leads to increase in
temperature in inflammation.temperature in inflammation.

24.  Cysteinyl Leukotrienes:Cysteinyl Leukotrienes:
 They includeThey include
1)1) LTC4LTC4
2)2) LTD4LTD4
3)3) LTE4LTE4
Their signaling pathway is same like LTB receptors. GqTheir signaling pathway is same like LTB receptors. Gq
associated.associated.
Functions:Functions:
The cysteinyl leukotrienes receptors are involved in theThe cysteinyl leukotrienes receptors are involved in the
pathophysiology of bronchial asthma, rhinitis, atopicpathophysiology of bronchial asthma, rhinitis, atopic
dermitits, uriticaria, CVS disorders & tumors.dermitits, uriticaria, CVS disorders & tumors.

25.  Effects:Effects:
 Stimulate pro-inflammatory activities like constriction ofStimulate pro-inflammatory activities like constriction of
airway smooth muscles, increased vascular permeability,airway smooth muscles, increased vascular permeability,
edema, increase mucus secretion, decrease mucociliaryedema, increase mucus secretion, decrease mucociliary
clearance, vascular permeability, mucus hyper secretion,clearance, vascular permeability, mucus hyper secretion,
chemokine production by mast cells and endothelial cellchemokine production by mast cells and endothelial cell
adherence.adherence.
 CYSLTR1 is activated by LTD4.CYSLTR1 is activated by LTD4.
 CYSLTR2 is activated by LTC4, LTD4 & LTE4.CYSLTR2 is activated by LTC4, LTD4 & LTE4.

26. Role Of Leukotrienes InRole Of Leukotrienes In
InflammationInflammation
 Leukotrienes act as Inflammatory mediators in manyLeukotrienes act as Inflammatory mediators in many
inflammatory conditions as :inflammatory conditions as :
 -> Asthma, autoimmune diseases, celiac diseases,-> Asthma, autoimmune diseases, celiac diseases,
hypersensitivities, Rheumatoid arthritis, inflammatoryhypersensitivities, Rheumatoid arthritis, inflammatory
bowl disease, allergies, myopathies, cancers etc…bowl disease, allergies, myopathies, cancers etc…
 Leukotrienes are a part of body’s innate immune systemLeukotrienes are a part of body’s innate immune system
produced by leukocytes and their derivatives responsibleproduced by leukocytes and their derivatives responsible
for immune defense strategies.for immune defense strategies.

27. InflammationInflammation
 Inflammation is the protective response by the bodyInflammation is the protective response by the body
towards injury, injury due to necrotic cells, introduction oftowards injury, injury due to necrotic cells, introduction of
foreign entity or hypoxia.foreign entity or hypoxia.
 It is the body’s way of attempting to remove the primaryIt is the body’s way of attempting to remove the primary
cause of inflammation and any damage that may havecause of inflammation and any damage that may have
occurred as a result ( healing & repair) .occurred as a result ( healing & repair) .
Why is it crucial?Why is it crucial?
if inflammation did not occur, then the body would beif inflammation did not occur, then the body would be
unable to deal with wounds and infections letting themunable to deal with wounds and infections letting them
go unchecked and progressively destroy the tissue. Allgo unchecked and progressively destroy the tissue. All
injured organs would therefore be unable to regaininjured organs would therefore be unable to regain
function, eventually leading to mortality.function, eventually leading to mortality.

28. Types OfTypes Of
InflammationInflammation
 Acute Inflammation:Acute Inflammation:
It is of short duration from a very few minutes to few days.It is of short duration from a very few minutes to few days.
Main characteristics:Main characteristics:
Exudation of fluid and plasma protein (edema) andExudation of fluid and plasma protein (edema) and
emigration of leukocytes (neutrophils)emigration of leukocytes (neutrophils)
 Chronic Inflammation:Chronic Inflammation:
it is of longer duration and is associated with presence ofit is of longer duration and is associated with presence of
lymphocytes & macrophages .lymphocytes & macrophages .

29. Components Of InflammationComponents Of Inflammation
COMPONENTS OF CONNECTIVE TISSUECOMPONENTS OF CONNECTIVE TISSUE
LAYER:LAYER:
1)1) Mast cellsMast cells
2)2) FibroblastFibroblast
3)3) MacrophagesMacrophages

30.  CELLULAR COMPONENTS OF INFLAMMATION:CELLULAR COMPONENTS OF INFLAMMATION:
 Leukocytes:Leukocytes:
 Leukocytes or WBC’s are the mobile units of the body’sLeukocytes or WBC’s are the mobile units of the body’s
protective system formed partially by bone marrowprotective system formed partially by bone marrow
( granulocytes and monocytes) & partially by lymph tissues( granulocytes and monocytes) & partially by lymph tissues
and released in blood.and released in blood.
 Major leukocytes involved in inflammation are:Major leukocytes involved in inflammation are:
1)1) NeutrophilsNeutrophils : highly mobile,: highly mobile,a granulocyte that is filled witha granulocyte that is filled with
microscopic granules, little sacs containing enzymes thatmicroscopic granules, little sacs containing enzymes that
digest microorganisms. Also known as polymorphonucleardigest microorganisms. Also known as polymorphonuclear
leukocyteleukocyte..
2)2) Esinophil :Esinophil : secrete chemicals and involve in allergicsecrete chemicals and involve in allergic
manifestations.manifestations.
3)3) Monocytes:Monocytes: transformed into macrophages, phagocytictransformed into macrophages, phagocytic
action.action.
4)4) Lymphocytes:Lymphocytes:
B lymphocytes:B lymphocytes: transformed into plasma cells & secretetransformed into plasma cells & secrete

31. antibodies.antibodies.
T lymphocytes:T lymphocytes: Responsible for cell mediated immunityResponsible for cell mediated immunity
involving direct destruction of virus invaded cellsinvolving direct destruction of virus invaded cells
Inflammatory PathwayInflammatory Pathway
““ Walling Off “ Of Inflammation:Walling Off “ Of Inflammation:
One of the result of inflammation is the wall off the area of injuryOne of the result of inflammation is the wall off the area of injury
from remaining tissues by blocking it by fibrinogen so that fluidfrom remaining tissues by blocking it by fibrinogen so that fluid
barely flows through inflamed area so as to decrease thebarely flows through inflamed area so as to decrease the
spread of antigen.spread of antigen.

32. InflammatoryInflammatory
PathwayPathway
 First Line Of Defense:First Line Of Defense:
Inflammation is initiated by resident immune cells already presentInflammation is initiated by resident immune cells already present
in the involved tissue.in the involved tissue.
Cells involve:Cells involve: Macrophages, dendritic cells, histocytes, kupfferMacrophages, dendritic cells, histocytes, kupffer
cells and mast cells, activated by products of inflammation.cells and mast cells, activated by products of inflammation.
Mediators Released:Mediators Released:
Leukotrienes, histamine, nitric oxide, TNF, interleukin,Leukotrienes, histamine, nitric oxide, TNF, interleukin,
prostaglandins, serotonin and bradykinin.prostaglandins, serotonin and bradykinin.
Effects:Effects: These mediators cause:These mediators cause:
Vasodilatation which increases blood flow ( temperature), increaseVasodilatation which increases blood flow ( temperature), increase
capillaries permeability results in accumulation of fuildcapillaries permeability results in accumulation of fuild
(edema) , smooth muscle contraction, induce pain and(edema) , smooth muscle contraction, induce pain and

33. large no of granulocytes & monocytes.large no of granulocytes & monocytes.
Neutrophils Invasion Of The Inflamed Area-Neutrophils Invasion Of The Inflamed Area-
Second Line Of Defense:Second Line Of Defense:
Within first hour after inflammation begins large no of neutrophilsWithin first hour after inflammation begins large no of neutrophils
begin to invade area by the action prior released mediatorsbegin to invade area by the action prior released mediators
(LTB4) &(LTB4) &
Alter the inside surface of endothelium causing neutrophils toAlter the inside surface of endothelium causing neutrophils to
stick to the capillary walls of the inflamed area with the helpstick to the capillary walls of the inflamed area with the help
cell adhesion molecule (CAM). The process is calledcell adhesion molecule (CAM). The process is called
Margination.Margination.
Diapedesis:Diapedesis: The endothelial cells of capillaries & smallThe endothelial cells of capillaries & small
venules start to separate, allowing neutrophils to pass intovenules start to separate, allowing neutrophils to pass into
tissues & cause release enzymes that digest organism.tissues & cause release enzymes that digest organism.

34.  Monocytes-Macrophages Invasion Of TheMonocytes-Macrophages Invasion Of The
Inflamed Tissue- The Third line Of Defense :Inflamed Tissue- The Third line Of Defense :
 Along with the invasion of neutrophils, monocytes fromAlong with the invasion of neutrophils, monocytes from
blood also enter the inflamed tissue.blood also enter the inflamed tissue.
 Their no in the circulation is very low and synthesis fromTheir no in the circulation is very low and synthesis from
bone marrow too.bone marrow too.
 They take several days to become active, even afterThey take several days to become active, even after
invading the inflamed tissues, monocytes are stillinvading the inflamed tissues, monocytes are still
immature and require 8 hours to swell to becomeimmature and require 8 hours to swell to become
macrophages and develops abundant lysozymes whichmacrophages and develops abundant lysozymes which
damage bacterial cell walls by catalyzing damage bacterial cell walls by catalyzing hydrolysishydrolysis of of
1,4-beta-linkages between N-acetyl muramic acid and N-1,4-beta-linkages between N-acetyl muramic acid and N-
acetyl-D- glucosamine residues in a peptidoglycan.acetyl-D- glucosamine residues in a peptidoglycan.
 Destroying and engulfing bacteria & larger particles asDestroying and engulfing bacteria & larger particles as
neutrophils and necrotic tissues.neutrophils and necrotic tissues.

35. ResearchResearch
 Research by Chen ST & Hsu CY published in europeResearch by Chen ST & Hsu CY published in europe
pubmed central about “thromboxanes, prostacyclins &pubmed central about “thromboxanes, prostacyclins &
Leukotrienes in cerebral ischemia” which statesLeukotrienes in cerebral ischemia” which states
 The optimal doses of aspirin along with TXA2, PGI2 &The optimal doses of aspirin along with TXA2, PGI2 &
Leukotrienes inhibitors are under study as newLeukotrienes inhibitors are under study as new
approaches for treatment of cerebral ischemia.approaches for treatment of cerebral ischemia.

37. ReferencesReferences
 Textbook of medical physiology by C.Guyton, M.DTextbook of medical physiology by C.Guyton, M.D
 Basic and clinical pharmacology katzungBasic and clinical pharmacology katzung
 www.sciencedirect.comwww.sciencedirect.com
 www.ncbi.nlm.nih.govwww.ncbi.nlm.nih.gov
 www.bmj.com/content/319/7207/90.1www.bmj.com/content/319/7207/90.1
 www.atsjournals.orgwww.atsjournals.org
 www.treloarphysio.comwww.treloarphysio.com
 www.pathguy.com.pkwww.pathguy.com.pk
 www.pharmacology.ucsd.eduwww.pharmacology.ucsd.edu

38. THANK YOUTHANK YOU