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Carstens E, Akiyama T, editors. Itch: Mechanisms and Treatment. Boca Raton (FL): CRC Press/Taylor & Francis; 2014.

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Itch: Mechanisms and Treatment.

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Chapter 15Lipid Mediators and Itch

and .

15.1. INTRODUCTION

Lipid mediators have a variety of biological and pathophysiological functions in the skin. Especially well known are the metabolites of arachidonic acid that, when liberated from membrane phospholipids by phospholiplase A2, are involved in inflammation and pain. In the 1970s, prostaglandin (PG) E2, one such arachidonic acid metabolite, was reported to elicit itch, probably via histamine release, and to enhance experimentally evoked itch in humans (Hägermark and Strandberg 1977; Fjellner and Hägermark 1979). For a long time after that, only a few reports describing the roles of lipid mediators in pruritus have been published. One reason for such little progress in understanding the lipid itch mediators could be the lack of a reliable method for the behavioral evaluation of itch in animal experiments (Woodward et al. 1985). In 1995, pruritogenic substances, but not algogenic, were shown to elicit hind-paw scratching in mice, raising the possibility that scratching can be used as an index of itch response in rodents (Kuraishi et al. 1995). Animal experiments have revealed the involvement and roles of several lipid mediators for itch. In this chapter, the roles of lipid mediators in human and animal itch are explained.

15.2. ARACHIDONIC ACID METABOLITES

15.2.1. Prostanoids

PGs such as PGE2, PGI2, PGF2α, and PGD2 are synthesized from PGH2, a metabolite of arachidonic acid produced by a reaction catalyzed by cyclooxygenase-1 and -2 (Williams and DuBois 1996). In human subjects, an intradermal injection of PGE2 (2.8–71 µM) elicits mild itching, whereas that of PGE2 (~14 µM) enhances histamine- and serotonin-induced itching (Hägermark and Strandberg 1977; Fjellner and Hägermark 1979). Pruritus in polyerythemia vera is alleviated by aspirin, and it is thought to be mediated by the enhancement of serotonin-induced itching by PGE2 (Fjellner and Hägermark 1979). In animals, on the other hand, an intradermal injection of PGE2 (60 nM to 6 mM) does not induce scratching in mice (Andoh and Kuraishi 1998), but a topical application of PGE2 (~280 µM) inhibits spontaneous scratching in NC mice with chronic dermatitis (Arai et al. 2004). In contrast to an application to the skin, an application of PGE2 (1.4 and 14 mM) to the ocular surface induces hind-paw scratching in guinea pigs (Woodward et al. 1995, 1996). There are four PGE2 receptor subtypes, EP1 to EP4 (Sugimoto and Narumiya 2007). Although a limited role of the EP1 receptor subtype has been shown in allergy-induced ocular scratching, the roles of EP receptor subtypes in pruritus remains unclear.

As noted above, an application of PGI2 (1.4 and 14 mM) to the ocular surface elicits hind-paw scratching in guinea pigs (Woodward et al. 1996); in contrast, a topical application of PGI2 (~0.28 mM) to the lesional skin suppresses spontaneous scratching in NC mice with chronic dermatitis (Arai et al. 2004).

When travoprost, a synthetic prostaglandin F2α analogue, is instilled into the eyes of patients with open-angle glaucoma or ocular hypertension, the most frequent related adverse event observed is pruritus (Goldberg et al. 2001). However, an application of PGF2α (1.4 and 14 mM) to the ocular surface does not elicit ocular scratching in guinea pigs (Woodward et al. 1995, 1996).

The application of PGD2 (14–140 mM) or BW245C, a potent PGD2 agonist, to the ocular surface elicits itch in human subjects (Nakajima et al. 1991). Similarly, an application of PGD2 (~280 mM) to the ocular surface of guinea pigs induces hind-paw scratching (Hashimoto et al. 2003). In contrast, topical applications to the skin of PGD2 (2.8–280 µM) and TS-022, a DP1 receptor agonist suppress both spontaneous scratching in mice with chronic dermatitis (Arai et al. 2004, 2007) and scratching induced by compound 48/80 injection or allergy (Hashimoto et al. 2005).

Thromboxane A2 (TXA2) is synthesized from PGH2 by thromboxane synthase (Needleman et al. 1976), and it is altered spontaneously to inactive TXB2. Thromboxane synthase is present in epidermal keratinocytes (Andoh et al. 2007), inflammatory cells such as eosinophils (Mita et al. 1999), mast cells (Mita et al. 1999), macrophages (Tone et al. 1994), and platelets (Yokoyama et al. 1991). The serum concentration of TXB2 is increased in humans with some pruritic diseases (Marks et al. 1984; Mysliwiec et al. 1985; Grekas et al. 1989; Veale et al. 1994). However, it is unknown whether TXA2 administered to human skin is pruritogenic. An intradermal injection of 9,11-dideoxy-9a,11a-methanoepoxy prostaglandin F2α (U-46619), a stable analogue of TXA2, elicits hind-paw scratching through its action on the TP prostanoid receptor (Andoh et al. 2007). In the skin, TP receptors are expressed in epidermal keratinocytes and primary afferents (Andoh et al. 2007). TXA2 may produce itch signaling through its action on primary afferents and enhance itching through its action on epidermal keratinocytes, which produce many itch mediators, including TXA2 itself.

15.2.2. Leukotrienes

Leukotrienes (LTs) such as LTB4 and cysteinyl LTs (LTC4, LTD4, and LTE4), are synthesized from arachidonic acid by arachidonate 5-lipoxygenase activated with 5-lipoxygenase-activating protein (FLAP) through 5-hydroperoxyeicosatetraenoic acid (5-HPETE), and then LTA4. LTB4, and LTC4, especially, are derived from LTA4 via the actions of LTA4 hydrolase and LTC4 synthase, respectively (Murphy and Gijón 2007). Furthermore, LTC4 is rapidly metabolized to LTD4 and then to LTE4 via γ-glutamyl transpeptidase and a membrane-bound dipeptidase, respectively (Murphy and Gijón 2007). LTB4 acts as both a high-affinity BLT1 and a low-affinity BLT2 receptor (Yokomizo et al. 2001a; Toda et al. 2002). Cysteinyl LTs act both on CysLT1 and CysLT2 (Evans 2002).

Zileuton, a 5-lipoxygenase inhibitor, reduces pruritus in Sjögren-Larsson syndrome (Willemsen et al. 2001) and decreases the tendency to produce it in atopic dermatitis (Woodmansee and Simon 1999). Azelastine, an H1 histamine receptor antagonist with LTB4 blocking activity, reduces pruritus in hemodialysis patients (Kanai et al. 1995; Matsui et al. 1994). LTB4 is elevated in the lesional skin of patients with psoriasis or atopic dermatitis (Brain et al. 1984; Ruzicka et al. 1986) and in the urine of patients with Sjögren-Larsson syndrome (Willemsen et al. 2001). These findings, taken together, raise the possibility that LTB4 is involved in itching in the above mentioned pruritic diseases. An intradermal injection of LTB4 (3–30 µM) elicits itch in one of six human subjects (Camp et al. 1983). In mice, intradermal injections of LTB4 (0.06–20 µM) elicit hind-paw scratching; the dose-response curve is bell shaped with a peak effect at 0.6 µM (Andoh and Kuraishi 1998). LTB4 is involved in spontaneous hind-paw scratching in NC mice with chronic dermatitis (Andoh et al. 2011), in scratching evoked by an allergen challenge in passive cutaneous anaphylaxis (Tsuji et al. 2010), and in contact dermatitis (Tsukumo et al. 2010). It is also associated with hind-paw scratching evoked by intradermal injections of pruritogens such as substance P (Andoh et al. 2001), nociceptin (Andoh et al. 2004), and sphingosylphosphorylcholine (Andoh et al. 2009). As for the eye, subconjunctival injections of LTB4 (0.5 and 5 µM) elicit hind-paw scratching in mice. Furthermore, LTB4 is involved in the scratching evoked by allergen challenge in ragweed pollen allergy (Andoh et al. 2012). Applications of LTC4 (0.8 mM), LTD4 (0.10 and 1.0 mM), and LTE4 (0.11 and 1.1 mM) to the eye do not induce hind-paw scratching in guinea pigs (Woodward et al. 1995).

Intradermal injections of LTC4 and LTD4 (0.24–0.76 µM) do not elicit itch in human subjects, although they do produce an erythematous reaction (Camp et al. 1983). Intradermal injections of LTD4 (0.2–6 µM) do not elicit hind-paw scratching in mice (Andoh et al. 2001); moreover, neither the cysteinyl LT antagonist pranlukast nor the LTD4 antagonist MK-571 suppress hind-paw scratching induced by mosquito allergy in mice (Kuraishi et al. 2007). These accumulated findings suggest that cysteinyl LTs are not pruritogenic in the skin and eye.

15.2.3. 12(S)-Hydroperoxyeicosa-5Z,8Z,10E,14Z-Tetraenoic Acid

12(S)-Hydroperoxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid (12(S)-HPETE) is synthesized from arachidonic acid by arachidonate 12-lipoxygenase. An intradermal injection of 12(S)-HPETE (0.3–10 µM) elicits hind-paw scratching mediated by BLT2, but not BLT1, receptors in mice (Kim et al. 2007, 2008b); 12(S)-HPETE acts not only on BLT2 (Yokomizo et al. 2001b) but also on the transient receptor potential vanilloid 1 (TRPV1) (Hwang et al. 2000). BLT2 receptors are expressed in mast cells (Lundeen et al. 2006) but not in sensory neurons (Andoh and Kuraishi 2005). The fact that TRPV1 antagonist does not inhibit 12(S)-HPETE-induced scratching (Kim et al. 2008a) suggests that, in primary afferents, TRPV1 does not play a key role in intradermal 12(S)-HPETE-induced scratching. However, 12(S)-HPETE-induced scratching is inhibited by 5-HT1 and 5-HT2 receptor antagonists, but not by an H1 histamine receptor antagonist (Kim et al. 2008a). The pruritogenic activity of serotonin is greater than that of histamine in mice (Akiyama et al. 2010; Maekawa et al. 2000). These pieces of evidence suggest that 12(S)-HPETE acts on BLT2 receptors in mast cells to release serotonin, which, in turn, induces scratching in mice. The involvement of 12(S)-HPETE in human itching is unknown.

15.3. PLATELET-ACTIVATING FACTOR

Platelet-activating factor (PAF) is synthesized in a two-step process catalyzed by the enzymes phospholipase A2 and lyso-PAF acetyltransferase (Prescott et al. 1990). An intradermal injection of PAF elicits itch in human subjects (Fjellner and Hägermark 1985). Repeated topical application of the PAF antagonist RO-24-0238 was reported to reduce pruritus in patients with atopic dermatitis during the first 2 weeks, but not after 3 and 4 weeks (Abeck et al. 1997). The plasma level of PAF is increased in pruritic diseases such as psoriasis (Izaki et al. 1996) and cold urticaria (Grandel et al. 1985). In animal experiments, the subcutaneous injection of PAF induces scratching in mice (Ishiguro et al. 2002), and the topical application and intraconjunctival injection of PAF induce hind-paw scratching in guinea pigs (Woodward et al. 1995; Kato et al. 2003). The intravenous injection of the PAF antagonist CV-3988 does not inhibit hind-paw scratching induced by mosquito allergy in mice (Kuraishi et al. 2007).

15.4. LYSOPHOSPHATIDIC ACID

There are several potential metabolic routes to lysophosphatidic acid (LPA, monoacyl-glycerol-3-phosphate). Although extracellular LPA can be produced from phosphatidic acid by phospholipase A1 and A2, the most important pathway is the conversion of lysophosphatidylcholine by lysophospholipase D, also known as autotaxin (ATX) (Pebay et al. 2007). An intradermal injection of LPA (4.6 mM) elicits hind-paw scratching in mice; the scratching is inhibited by ketotifen, an H1 histamine receptor antagonist, and Y-27632, an inhibitor of Rho-associated protein kinase (Hashimoto et al. 2004). The fact that serum ATX levels have been shown to increase in cholestasis patients with pruritus raises the possibility that LPA produced by ATX is involved in cholestatic pruritus (Kremer et al. 2010, 2012). Thus, it is suggested that LPA is involved in cholestatic pruritus. An increase in serum ATX levels is not observed in patients with other pruritic diseases as uremia, Hodgkin’s disease, and atopic dermatitis; therefore, it was suggested that LPA has a role in itching in these pruritic diseases (Kremer et al. 2012).

15.5. SPHINGOLIPIDS

Sphingolipids comprise a complex set of lipids, including sphingomyelin and ceramides, in which fatty acids are linked via amide bonds to sphingoid. Ceramides are produced from sphingomyelin by sphingomyelinase in the stratum corneum, and they play an essential role in structuring and maintaining the water permeability barrier of the skin (Figure 15.1). In atopic dermatitis patients, the activity of sphingomyelin deacylase—an enzyme that converts sphingomyelin into sphingosylphosphorylcholin (SPC) and free fatty acid—is elevated (Murata et al. 1996; Hara et al. 2000), leading to an increase in the SPC content and a decrease in the ceramide content of the stratum corneum of atopic dermatitis (Okamoto et al. 2003) (Figure 15.1). Similarly, the SPC content is elevated in the skin of mice with atopy-like chronic dermatitis (Andoh et al. 2011). However, the activity of sphingomyelin deacylase is not increased in contact dermatitis (Hara et al. 2000). Intradermal injection of SPC (0.6 and 2 mM) elicits hind-paw scratching in mice, an action possibly mediated by the direct action on primary afferents and LTB4 production in keratinocytes (Andoh et al. 2009). Rho-associated protein kinase involvement in the SPC action has also been previously reported (Kim et al. 2008c). An increase in sphingomyelin deacylase activity may result in skin dryness due to a decrease in ceramides, as well as itching due to SPC production in the skin. Thus, the suppression of sphingomyelin deacylase activity may relieve skin dryness and pruritus in atopic dermatitis.

FIGURE 15.1. Metabolism of sphingomyelin in healthy skin and atopic dermatitis.

FIGURE 15.1

Metabolism of sphingomyelin in healthy skin and atopic dermatitis. (Modified schema from Hara, J. et al., J Invest Dermatol, 115, 406–413, 2000.)

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Bookshelf ID: NBK200912PMID: 24830020
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