EICOSANOIDS IN SKIN

INFLAMMATION

Dr.Chandan PatilI MVSc V 1661/16Vety Pharmacology & ToxicologyDUVASU Mathura

INTRODUCTION• Eicosanoids are major group of lipid –derieved

autacoids.• Primarily derieved from Arachidonic acid• Contribute to number of physiological and

pathological processes I,e homeoststic processes and inflammatory responces.

• Eiconoid group includes Prostaglandins,Thromboxanes,Leukotriens etc,

Cutaneous Eicosanoids Biosynthesis

Cycloxygenase derieved mediators

• PGE2 is the main Cutaneous Eicosanoid produced by epidermal keratinocytes & dermal fibroblasts.

• PGE2 involved in Keratinocyte proliferation differentiation & modulation of dermal fibroblasts and facilitate in wound healing.

• PGE2 has direct effect on melanocyte mediated post inflamatory pigmentary response.

Cycloxygenase derieved mediators cont…

• Cutaneous PGD2 are produced by Langerhans cells and Dermal mast cells

• Cutaneous PGD2 is a potent anti-proliferative and anti-inflammatory PG

• PGD2 is precussor to the anti-inflammatory cyclopentanone prostaglandins:PGJ2 that are formed through non enzymatic hydrolysis.

Lipoxygenase derieved mediators• Skin express 5-,8-,12-,15-LOX activity to produce

Hydroxyeicosatetraenoic acid(HETE) from fatty acid derivatives of AA, Linoleic acid etc.

• 12HETE is potent pro-inflammatory chemotactic mediator produced by epidermal keratinocytes & dermal fibroblasts.

• 12 HETE binding sites are expressed by keratinocytes and langerhans cells suggesting active involvement in cutaneous wound healing and inflammatory diseases.

Mechanism Of action• All Prostanoid receptors are G-Protein

Coupled receptors.• These prostanoids utilise IP3/DAG/CAMP

transducer mechanism to act on their receptors

Eicosanoids in cutaneous inflammatory diseases

Atopic Dermatitis

Psoropsis Sunburn

Psoriasis• Chronic inflammatory & proliferative skin

disease with genetic and environmental etiologies characterised by abnormalities in skin lipids and increased production of inflammatory mediators

• Studies shown there is increased PLA2 activity & high concentration of 12-HETE which is a potent chemotactic eicosanoid highly prevalent in psoriatic skin.

Psoriasis cont…• On repeated injection of 15-HETE synthesised

by 15-LOX on the Psoriactic plaques resulted in regression and complete resolution of psoriasis

• So there has been interest in developing specific 12-LOX & PLA2 inhibitors as theraupetic agents to treat psoriasis

Atopic Dermatitis• Characterised by increased PLA2 activity with

COX derieved prostanoids mediators.• PGD2 is the principle prostanoid involved

because of active role of langerhans cells and mast cells.

• Invitro studies with GLA and DHA suggested PUFA can alter eicosanoids produced by immune cells which helps in treating atopic dermatitis

Sunburn Responce

• Characterised by increased COX and LOX mediated eicosanoid production

• UVR induced oxidative stress stimulates activity of PLA2 in human and animal skin

Effect of PUFA in Cutaneous inflammation

• Long chain n-3PUFA effect eicosanoid production through their ability to offer alternative substrates to lipid metabolizing enzymes.

• Fish derieved omega-3 fatty acid EPA(eicosapentaenoic acid) on action by COX produce PGE3 which is less inflammaory & 12 lox product such as 12-HEPE is less potent chemoattractant than their Arachidonic acid counterpart

• EPA also inhibit s COX2 expression in many cell types .

References• Eicosanoids in skin inflammation review article by Anna Nicolaou from

www.elsevier.com/plefa• REDUCING INFLAMMATION WITH DIET AND SUPPLEMENTS:The Story of

Eicosanoid Inhibition general review by Subhuti Dharmananda, Ph.D., Director, Institute for Traditional Medicine, Portland, Oregon