Eicosanoids in Skin Wound Healing

Abstract

Wound healing is an important process in the human body to protect against external threats. A dysregulation at any stage of the wound healing process may result in the development of various intractable ulcers or excessive scar formation. Numerous factors such as growth factors, cytokines, and chemokines are involved in this process and play vital roles in tissue repair. Moreover, recent studies have demonstrated that lipid mediators derived from membrane fatty acids are also involved in the process of wound healing. Among these lipid mediators, we focus on eicosanoids such as prostaglandins, thromboxane, leukotrienes, and specialized pro-resolving mediators, which are produced during wound healing processes and play versatile roles in the process. This review article highlights the roles of eicosanoids on skin wound healing, especially focusing on the biosynthetic pathways and biological functions, i.e., inflammation, proliferation, migration, angiogenesis, remodeling, and scarring.

Keywords: eicosanoids; inflammation; lipid mediators; specialized pro-resolving mediators; wound healing.

Figure 1

Biosynthetic pathways and receptors of eicosanoids. Upon stimulation, an omega-6 PUFA arachidonic acid (AA) is liberated from the phospholipids of the cell membrane by the action of phospholipase A₂ (PLA₂), and AA is metabolized into various bioactive lipid mediators. Prostanoids, leukotrienes (LTs), hydroxyeicosatetraenoic acid (HETEs), and epoxyeicosatrienoic acid (EETs) are formed from AA via cyclooxygenase (COX) (green), a lipoxygenase (LOX) (purple), and cytochrome P450 (CYP) (red) pathways, respectively. Specific eicosanoid receptors and peroxisome proliferator-activated receptors (PPARs) that are potentially activated by eicosanoids are shown in boxes. sEH: soluble epoxide hydrolase; TxAS: thromboxane A synthase; PGIS: prostacyclin synthase; PGFS: prostaglandin F synthase; cPGES: cytosolic prostaglandin E synthase; mPGES: membrane-associated prostaglandin E synthase; H-PGDS: hematopoietic-type prostaglandin D synthase; L-PGDS: lipocalin-type prostaglandin D synthase; LTA₄H: LTA₄ hydrolase; LTC₄S: LTC₄ synthase; HpETE: hydroperoxyeicosatetraenoic acid.

Figure 2

Biosynthetic pathways of specialized pro-resolving mediators (SPMs).In addition to AA, LOX pathway (purple) and CYP pathway (red) can metabolize the omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into various SPMs, which act as endogenous immunoresolvents upon stimulation. Lipoxins (LxA₄ and LxB₄) are formed from AA, E-series of resolvins (RvE1, RvE2, and RvE3) are formed from EPA, and D-series of resolvins (RvD1, RvD2, RvD3, RvD4, RvD5, and RvD6), protectins (PD1 and PDX), and maresins (MaR1 and MaR2) are formed from DHA. HpEPE: hydroperoxyeicosapentaenoic acid; HpDHA: hydroperoxydocosahexaenoic acid.

Figure 3

Summary of biological functions of eicosanoids and SPMs in full-thickness wound healing. The process of skin wound healing consists of three consecutive and overlapping steps, including hemostasis/inflammatory, proliferative, and remodeling phases. In this process, a wide variety of eicosanoids and SPMs are produced from skin-resident cells and infiltrated cells by the wound stimuli and play multiple roles. The metabolites formed by the COX, LOX, and CYP pathways are shown as green, purple, and red boxes, respectively. PG: prostaglandin; Tx: thromboxane; LT; leukotriene; 12-HHT: 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid; EET: epoxyeicosatrienoic acid; LX: lipoxin; Rv: resolvin; PD1: protectin D1; SPM: specialized pro-resolving mediator; CysLT: cysteinyl leukotriene.