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ACIDO ARACHIDONICO

Acido arachidonico un acido grasso essenziale che contiene 4 doppi legami Esterificato in posizione 2 nei fosfolipidi di membrana

Eicosanoidi sono degli autacoidi, cio sostanze liberate dalle cellule e che agiscono attraverso recettori specifici nelle vicinanze della sede doi produzione

Piastrine

COOH

Arachidonic Acid

PGH synthase

5-, 12-, 15 Lipoxygenase

P450 epoxygenase

Free Radicals

Prostaglandins and Thromboxanes

Epoxyeicosatrienoic acids

Leukotrienes, Lipoxins And Hepoxilins

Isoeicosanoids (isoprostanes, etc.)

Lipoxin

Prostanoids
Leukotrienes

COOH

Arachidonic Acid

PGH synthase

5-, 12-, 15 Lipoxygenase

P450 epoxygenase

Free Radicals

Prostaglandins and Thromboxanes

Epoxyeicosatrienoic acids

Leukotrienes, Lipoxins And Hepoxilins

Isoeicosanoids (isoprostanes, etc.)

COOH
AA

COX
O HO COOH O OH
PGD
2

Cyclooxygenase

COOH
PGG
2

PGDsynthase

O OOH
Peroxidase

COX

PGIsynthase

COOH O HO
PGI 2

PGE-synthase

O O

COOH

O COOH HO HO COOH HO
PGF 2 PGE 2 OH

PGH 2 OH
TXA-synthase PGF-synthase

OH

O O
TXA 2 OH

COOH

OH

DP2

cAMP via Gi

COOH

Arachidonic Acid

PGH synthase

5-, 12-, 15 Lipoxygenase

P450 epoxygenase

Free Radicals

Prostaglandins and Thromboxanes

Epoxyeicosatrienoic acids

Leukotrienes, Lipoxins And Hepoxilins

Isoeicosanoids (isoprostanes, etc.)

COOH
AA
H OOH

5-LO
COOH

5-HPETE

5-LO
O COOH
LTA 4 -hydrolase

LTA4
-glutamyl-transferase

OH

COOH OH

LTC 4 -synthase

LTB 4

OH OH S CH 2 COOH S CH 2 COOH

LTD 4

CHCONHCH 2 COOH NH 2
Cysteinyl-glicine dipeptidase

LTC 4

CHCONHCH 2 COOH NHCOCH 2 CH 2 CHCOOH NH 2

OH S CH 2

COOH

LTE 4

CHCOOH NH 2

CLASSIFICATION OF LEUKOTRIENE RECEPTORS

BLT

Cys-LT

BLT1
Gq/11

BLT2
Gq/11

blocked by classical antagonists


Gq/11

Cys-LT1

blocked by BAY u 9773


Gq/11

Cys-LT2

Recettori CysLT
CysLT1 CysLT2

Gene localizzato sul braccio lungo del cromosoma X; 32% omologia con P2Y1R, PAF-R e 28% omologia con BLTR; Proteina glicosilata: 337 aa con PM= 38 kDa;

Gene localizzato cromosoma 13;

38% omologia con Cys-LT1 Proteina glicosilata: 346 aa con PM= 40 kDa;

Prolo farmacologico: LTD4 >> LTC4 > LTE4


sensibile agli antagonisti classici (zarlukast, montelukast, pranlukast) e BAY u9773;

Prolo farmacologico: LTD4 = LTC4 > LTE4


sensibile solo BAY u9773;

Distribuzione: leucociti periferici, milza;


polmone: cellule muscolari lisce peribronchiali e macrofagi alveolari.

Distribuzione: leucociti periferici, milza;


cuore; sistema nervoso centrale; Polmone: macrofagi alveolari.

COOH

Arachidonic Acid

PGH synthase

5-, 12-, 15 Lipoxygenase

P450 epoxygenase

Free Radicals

Prostaglandins and Thromboxanes

Epoxyeicosatrienoic acids

Leukotrienes, Lipoxins And Hepoxilins

Isoeicosanoids (isoprostanes, etc.)

mostly Gi

COOH

Arachidonic Acid

PGH synthase

5-, 12-, 15 Lipoxygenase

P450 epoxygenase

Free Radicals

Prostaglandins and Thromboxanes

Epoxyeicosatrienoic acids

Leukotrienes, Lipoxins And Hepoxilins

Isoeicosanoids (isoprostanes, etc.)

Hydroxy EPOXide InsuLIN

COOH

Arachidonic Acid

PGH synthase

5-, 12-, 15 Lipoxygenase

P450 epoxygenase

Free Radicals

Prostaglandins and Thromboxanes

Epoxyeicosatrienoic acids

Leukotrienes, Lipoxins And Hepoxilins

Isoeicosanoids (isoprostanes, etc.)

Epoxyeicosatrienoic acids

COOH

Arachidonic Acid

PGH synthase

5-, 12-, 15 Lipoxygenase

P450 epoxygenase

Free Radicals

Prostaglandins and Thromboxanes

Epoxyeicosatrienoic acids

Leukotrienes, Lipoxins And Hepoxilins

Isoeicosanoids (isoprostanes, etc.)

Patrono & FitzGerald, ATVB. 1997;17:2309

Transcellular metabolism of AA
LTC4-S

LTA4-H

COX-1

5-LO

COX-2

LTC4-S

Patrono & FitzGerald, ATVB. 1997;17:2309

LEUKOTRIENES Biological activities


LTB4
Leukotropic Degranulation Plasma exudation Chemotaxis & migration

LTC4, LTD4 & LTE4


Myotropic Cardiac depression Vasoconstriction Bronchoconstriction
Dahlen (1993)

Potenziali siti dazione dei leucotrieni nella fisiopatologia dellasma


aumentata secrezione di muco RIDOTTO TRASPORTO DI MUCO proteine cationiche (danno cellulare epiteliale)

epitelio vie aeree Aumentato rilascio di tachichinine

Fibre sensoriali C

VASI SANGUIGNI

Cisteinil Leucotrieni
Muscolo liscio

Edema

Cellule infiammatorie (es.mastociti eosinofili)

Contrazione e proliferazione

Hay et al. Trends Pharmacol Sci 16:304-309, 1995

(Lipocortina)

LTC4/D4/E4 antagonists
III/Launched

Discontinued, Preclinical, I, II

GINA GUIDELINES

Secrezione gastrica