Portal de Periódicos da CAPES

Histamine H1 and H2 Receptor Antagonists Accelerate Skin Barrier Repair and Prevent Epidermal Hyperplasia Induced by Barrier Disruption in a Dry Environment

2001; Elsevier BV; Volume: 116; Issue: 2 Linguagem: Inglês

10.1046/j.1523-1747.2001.01238.x

1523-1747

Yutaka Ashida, Mitsuhiro Denda, Tetsuji Hirao,

Dermatology and Skin Diseases

Keratinocytes have histamine H1 and H2 receptors, but their functions are poorly understood. To clarify the role of histamine receptors in the epidermis, we examined the effects of histamine receptor antagonists and agonists applied epicutaneously on the recovery of skin barrier function disrupted by tape stripping in hairless mice. Histamine H2 receptor antagonists famotidine and cimetidine accelerated the recovery of skin barrier function, but histamine and histamine H2 receptor agonist dimaprit delayed the barrier repair. Application of compound 48/80, a histamine releaser, also delayed the recovery. Imidazole, an analog of histamine, had no effect. The histamine H1 receptor antagonists diphenhydramine and tripelennamine accelerated the recovery. Histamine H3 receptor agonist Nα-methylhistamine and antagonist thioperamide had no effect. In addition, topical application of famotidine or diphenhydramine prevented epidermal hyperplasia in mice with skin barrier disrupted by acetone treatment in a dry environment (humidity <10%) for 4 d. In conclusion, both the histamine H1 and H2 receptors in the epidermis are involved in skin barrier function and the cutaneous condition of epidermal hyperplasia. Keratinocytes have histamine H1 and H2 receptors, but their functions are poorly understood. To clarify the role of histamine receptors in the epidermis, we examined the effects of histamine receptor antagonists and agonists applied epicutaneously on the recovery of skin barrier function disrupted by tape stripping in hairless mice. Histamine H2 receptor antagonists famotidine and cimetidine accelerated the recovery of skin barrier function, but histamine and histamine H2 receptor agonist dimaprit delayed the barrier repair. Application of compound 48/80, a histamine releaser, also delayed the recovery. Imidazole, an analog of histamine, had no effect. The histamine H1 receptor antagonists diphenhydramine and tripelennamine accelerated the recovery. Histamine H3 receptor agonist Nα-methylhistamine and antagonist thioperamide had no effect. In addition, topical application of famotidine or diphenhydramine prevented epidermal hyperplasia in mice with skin barrier disrupted by acetone treatment in a dry environment (humidity <10%) for 4 d. In conclusion, both the histamine H1 and H2 receptors in the epidermis are involved in skin barrier function and the cutaneous condition of epidermal hyperplasia. transepidermal water loss Histamine is well known as a chemical mediator that plays important roles in allergic inflammatory and immune reactions (Falus and Meretey, 1992Falus A. Meretey K. Histamine: an early messenger in inflammatory and immune reactions.Immunol Today. 1992; 13: 154-156Abstract Full Text PDF PubMed Scopus (2) Google Scholar). In skin, it is synthesized and stored in mast cells in the dermis but is also generated in keratinocytes (Malaviya et al., 1996Malaviya R. Morrison A.R. Pentland A.P. Histamine in human epidermal cells is induced by ultraviolet light injury.J Invest Dermatol. 1996; 106: 785-789Crossref PubMed Scopus (64) Google Scholar). Histamine in the epidermis is derived from the keratinocyte itself and from mast cells in the dermis, but the role of histamine in the epidermis is still largely unknown. Histamine has three types of receptors. In skin, both the histamine H1 receptor and histamine H2 receptor exist (Greaves and Davies, 1982Greaves M.W. Davies M.G. Histamine receptors in human skin: indirect evidence.Br J Dermatol. 1982; 107: 101-105Crossref PubMed Scopus (38) Google Scholar). The histamine H1 receptor is considered to contribute to itch, and histamine H1 receptor antagonists are clinically used for pruritus in patients with atopic dermatitis (Zuberbier and Henz, 1999Zuberbier T. Henz B.M. Use of cetirizine in dermatologic disorders.Ann Allergy Asthma Immunol. 1999; 83: 476-480Abstract Full Text PDF PubMed Scopus (22) Google Scholar). Keratinocytes have histamine H2 receptors, but their function is not clearly understood (Fitzsimons et al., 1998Fitzsimons C. Duran H. Labombarda F. Molinari B. Rivera E. Histamine receptor signalling in epidermal tumor cell lines with H-ras gene alterations.Inflamm Res. 1998; 47: S50-S51Crossref PubMed Google Scholar). The Ca2+ concentration affects the quantity of histamine H2 receptors on keratinocytes as well as the differentiation of keratinocytes (Fitzsimons et al., 1999Fitzsimons C. Duran H. Engel N. Molinari B. Rivera E. Changes in H2 receptor expression and coupling during Ca2+-induced differentiation in mouse epidermal keratinocytes.Inflamm Res. 1999; 48: S73-S74Crossref PubMed Google Scholar). The histamine H2 receptor also accelerates cell proliferation (Wang et al., 1997Wang L.-D. Hoeltzel M. Butler K. Hare B. Todisco A. Wang M. Del Valle J. Activation of the human histamine H2 receptor is linked to cell proliferation and c-fos gene transcription.Am J Physiol. 1997; 273: C2037-C2045PubMed Google Scholar) and affects the immune system (Nielsen and Hammer, 1992Nielsen H.J. Hammer J.H. Possible role of histamine in pathogenesis of autoimmune diseases: implications for immunotherapy with histamine-2 receptor antagonists.Med Hypotheses. 1992; 39: 349-355Abstract Full Text PDF PubMed Scopus (22) Google Scholar). Attempts to assess the clinical efficacy of histamine H2 receptor antagonists on psoriasis have not been successful (Nielsen, 1996Nielsen H.J. Histamine-2 receptor antagonists as immunomodulators: new therapeutic views?.Ann Med. 1996; 28: 107-113Crossref PubMed Scopus (25) Google Scholar). The existence and the role of the histamine H3 receptor in skin are still unclear in humans (Kavanagh et al., 1998Kavanagh G.M. Sabroe R.A. Greaves M.W. Archer C.B. The intradermal effects of the H3 receptor agonist Rα methylhistamine in human skin.Br J Dermatol. 1998; 138: 622-626Crossref PubMed Scopus (17) Google Scholar). In rats, however, the histamine H3 receptor is involved in the autoregulation of histamine release on mast cells (Ohkubo et al., 1994Ohkubo T. Shibata M. Inoue M. Kaya H. Takahashi H. Autoregulation of histamine release via the histamine H3 receptor on mast cells in the rat skin.Arch Int Pharmacodyn Ther. 1994; 328: 307-314PubMed Google Scholar), and the regulation of substance P release is also mediated via prejunctional histamine H3 receptors located on peripheral endings of sensory nerves (Ohkubo et al., 1995Ohkubo T. Shibata M. Inoue M. Kaya H. Takahashi H. Regulation of substance P release mediated via prejunctional histamine H3 receptors.Eur J Pharmacol. 1995; 273: 83-88https://doi.org/10.1016/0014-2999(94)00668-wCrossref PubMed Scopus (0) Google Scholar). It is well known that seasonal changes affect the condition of normal skin and inflammatory dermatoses. The low humidity during winter makes the skin condition worse (Wilkinson and Rycroft, 1992Wilkinson J.D. Rycroft R.J. Contact dermatitis.in: Burton J.L. Ebling F.J.G. Champion Relative Humidity Textbook of Dermatology. 5th edn. Blackwell Scientific Publications, Oxford1992: 614-615Google Scholar;Sauer and Hall, 1996Sauer G.C. Hall J.C. Seasonal skin diseases.in: Sauer G.C. Hall J.C. Manual of Skin Diseases. Lippincott-Raven, Philadelphia1996: 23-28Google Scholar), and it sometimes causes itch. Low humidity also stimulates epidermal DNA synthesis (Sato et al., 1998Sato J. Denda M. Ashida Y. Koyama J. Loss of water from the stratum corneum induces epidermal DNA synthesis in hairless mice.Arch Dermatol Res. 1998; 290: 634-637https://doi.org/10.1007/s004030050364Crossref PubMed Scopus (34) Google Scholar), and amplifies the hyperproliferative response to disruption of skin barrier function (Denda et al., 1998Denda M. Sato J. Tsuchiya T. Elias P.M. Feingold K.R. Low humidity stimulates epidermal DNA synthesis and amplifies the hyperproliferative response to barrier disruption: Implication for seasonal exacerbations of inflammatory dermatoses.J Invest Dermatol. 1998; 111: 873-878https://doi.org/10.1046/j.1523-1747.1998.00364.xCrossref PubMed Scopus (225) Google Scholar). The skin barrier function is the epidermal permeability barrier mechanism at the level of the stratum corneum, which allows life in a terrestrial dry environment. Acute barrier disruption by tape stripping elicits a homeostatic repair response in the epidermis. Substances that accelerate the recovery of the disrupted skin barrier have been reported to be effective against epidermal hyperplasia (Denda et al., 1997Denda M. Kitamura K. Elias P.M. Feingold K.R. trans-4-(Aminomethyl) cyclohexane carboxylic acid (t-AMCHA), an anti-fibrinolytic agent, accelerates barrier recovery and prevents the epidermal hyperplasia induced by epidermal injury in hairless mice and humans.J Invest Dermatol. 1997; 109: 84-90Crossref PubMed Scopus (91) Google Scholar). In this study, we examined whether histamine H1 and H2 receptor antagonists accelerate the recovery of disrupted skin barrier function and are effective against epidermal hyperplasia. Hairless mice, 7–10 wk old (HR-1, Hoshino, Japan) were used. Before the experiment, animals were caged separately for at least 4 d. These cages were maintained in a room kept at 22°C-26°C with a relative humidity of 40%-70%. All experiments were approved by the Animal Research Committee of the Shiseido Research Center in accordance with the National Research Council (NRC) Guide (National Research Council, 1996National Research Council. Guide for the Care and Use of Laboratory Animals.Washington, DC. 7th edn. National Academic Press, 1996Google Scholar). Famotidine, cimetidine, diphenhydramine hydrochloride, tripelennamine hydrochloride, histamine dihydrochloride, imidazole, compound 48/80, and polyethylene glycol (MW 300) were purchased from Sigma (St. Louis, MO). Nα-methylhistamine dihydrochloride, thioperamide maleate, and dimaprit dihydrochloride were purchased from RBI (Natick, MA). The test compound was dissolved or suspended in the control vehicle, which was a mixture of polyethylene glycol:ethanol:distilled water 1:3:1 in order to increase the solubility of the compounds, which have different polarities. These test samples were used at a concentration of 5%, which was determined in a preliminary study, except for histamine, which was used at 0.1%, its pharmacologic concentration for histamine-induced itch. The pH was measured with a pH test paper (Toyo Roshi, Tokyo). The pH of each test sample was adjusted below 6.0 with HCl, because recovery of skin barrier function is impeded at a neutral pH (Mauro et al., 1998aMauro T. Grayson S. Gao W.N. et al.Barrier recovery is impeded at neutral pH, independent of ionic effects: implications for extracellular lipid processing.Arch Drmatol Res. 1998; 290: 215-222Crossref PubMed Scopus (234) Google Scholar). Barrier disruption was achieved by repeated applications of cellophane tape (Scotch Crystal Clear Tape, 3M, St. Paul, MN) on mouse flank skin. The procedure was terminated when transepidermal water loss (TEWL) levels reached 8.5 ± 1.5 mg per cm2 per h. Normal TEWL is less than 0.3 mg per cm2 per h. TEWL was measured by using an electrolytic water analyzer (Meeco, Warrington, PA). We disrupted the skin on both flanks of mice. Immediately after barrier disruption 100 μl of test sample was applied on one side, and medium was applied on the other side as a control. TEWL was measured before barrier disruption, immediately after barrier disruption, and at 3 h, 6 h, and 9 h after barrier disruption. The time points of the measurement were determined in a preliminary examination to be appropriate for the detection of the effect of the test compound. The barrier recovery results are expressed as percentage recovery because of variations from day to day in the extent of barrier disruption. In each animal the percentage recovery was calculated using the following formula: [1 – (TEWL at indicated time – baseline TEWL)/(TEWL immediately after treatment – baseline TEWL)] × 100%. All data were compared with data from simultaneously studied controls. To avoid scratching during the observation, we fixed the hind legs of the animal with flexible tape. Animals were kept separately in 7.2 l cages in which the relative humidity was maintained at less than 10% with dry air. The temperature was the same in all cages (22°C-26°C), and fresh air was circulated 100 times per hour. Animals were kept out of the direct stream of air. The animal's behavior was not restricted during the experiments. The weight gain and food intake of animals kept in a dry condition was not different from that of those kept in a normal condition during the course of the study. The level of NH3 was always below 1 ppm. We applied 100 μl of test sample per 6 cm2 of flank skin of mouse, and applied medium on the other side as a control. We kept the aminals in a dry condition for 48 h before barrier disruption. The test sample was applied from the onset of the experiment, because the dry condition itself without barrier disruption also induces epidermal proliferation and hyperplasia (Sato et al., 1998Sato J. Denda M. Ashida Y. Koyama J. Loss of water from the stratum corneum induces epidermal DNA synthesis in hairless mice.Arch Dermatol Res. 1998; 290: 634-637https://doi.org/10.1007/s004030050364Crossref PubMed Scopus (34) Google Scholar). Then, the area of the flank skin was treated with acetone-soaked cotton balls, as described previously (Denda et al., 1998Denda M. Sato J. Tsuchiya T. Elias P.M. Feingold K.R. Low humidity stimulates epidermal DNA synthesis and amplifies the hyperproliferative response to barrier disruption: Implication for seasonal exacerbations of inflammatory dermatoses.J Invest Dermatol. 1998; 111: 873-878https://doi.org/10.1046/j.1523-1747.1998.00364.xCrossref PubMed Scopus (225) Google Scholar). The procedure was terminated when TEWL reached 1.2–1.8 mg per cm2 per h. Immediately after barrier disruption 100 μl of a 5% test sample was applied again to the treated area, and the animals were kept in a dry condition for 48 h. At the end of the experiment, the animals were killed and the skin from the treated versus control flanks was removed. After fixation with 4% paraformaldehyde, full-thickness skin samples were embedded in paraffin, sectioned (4 μm), and processed for hematoxylin and eosin staining. On each section, 50 areas were selected at random; the thickness of the epidermis was measured with an optical meter, and the mean value was calculated. Measurements were carried out in an observer-blinded fashion. The results are represented as a proliferative percentage to intact skin. Data are presented as mean ±;SD. Statistical differences were determined by ANOVA and Fisher's protected least significant difference as post hoc test. We first evaluated the effects of the antagonists of the three types of histamine receptor on barrier recovery. As shown in Figure 1, the histamine H1 receptor antagonist diphenhydramine significantly accelerated barrier recovery after tape stripping (Figure 1a, 41% and 21% faster at 3 h and 6 h, respectively), and the H2 receptor antagonist famotidine also accelerated barrier repair significantly (Figure 1b, 78%, 26%, and 12% faster at 3 h, 6 h, and 9 h, respectively). On the other hand, the histamine H3 receptor antagonist thioperamide did not affect the barrier repair process (Figure 1c). Additionally, we confirmed that the other histamine H1 and H2 receptor antagonists had similar effects on the barrier recovery (Table 1). The histamine H1 receptor antagonist tripelennamine significantly accelerated barrier recovery after tape stripping (204% faster at 3 h), and the H2 receptor antagonist cimetidine also accelerated barrier repair significantly (12-fold and 119% faster at 3 h and 6 h, respectively).Table 1Effects of other histamine-related compounds on skin barrier recovery disrupted by tape stripping in micebData are presented as mean ± SD (n = 4.8). *p< 0.05, **p< 0.01, p values were calculated by ANOVA and Fisher's protected least significant difference (Fisher's PLSD) as post hoc test.Recovery %bData are presented as mean ± SD (n = 4.8). *p< 0.05, **p< 0.01, p values were calculated by ANOVA and Fisher's protected least significant difference (Fisher's PLSD) as post hoc test.3 h6 h9 hhistamine H1 receptor antagonist tripelennaminecontrol18.5 ± 20.346.5 ± 23.550.7 ± 28.7treatment56.3 ± 12.4**60.2 ± 14.366.0 ± 19.0histamine H2 receptor antagonist cimetidinecontrol2.39 ± 10.823.4 ± 17.231.1 ± 12.9treatment28.0 ± 17.2*51.3 ± 26.5*51.5 ± 12.3histamine H3 receptor agonist Nα-methylhistaminecontrol48.1 ± 6.976.4 ± 5.788.4 ± 1.9treatment43.5 ± 10.380.0 ± 1.787.5 ± 4.7histamine analog imidazolecontrol4.56 ± 15.139.7 ± 12.450.0 ± 14.4treatment9.28 ± 18.028.7 ± 11.741.9 ± 14.5aRecovery rate was measured as described in the Materials and Methods.b Data are presented as mean ± SD (n = 4.8). *p< 0.05, **p< 0.01, p values were calculated by ANOVA and Fisher's protected least significant difference (Fisher's PLSD) as post hoc test. Open table in a new tab aRecovery rate was measured as described in the Materials and Methods. We next evaluated the effects of the histamine receptor agonists, histamine releaser, and histamine analog. As shown in Figure 2, histamine itself delayed the barrier repair process significantly (Figure 2a, 28% slower at 9 h), and the histamine H2 receptor agonist dimaprit also delayed barrier recovery significantly (Figure 2b, 20% slower at 6 h). Furthermore, the histamine releaser compound 48/80 delayed the barrier repair process significantly (Figure 2c, 12% slower at 6 h). On the other hand, the histamine H3 receptor agonist Nα-methylhistamine and histamine analog imidazole did not affect the barrier repair process (Table 1). Scratching behavior was not observed during the experiments. Finally, we tested whether histamine H1 and H2 receptor antagonists also have an effect on skin disorders in vivo. To quantify the effect of histamine receptor antagonists, we measured the epidermal thickness after barrier disruption with acetone in animals kept in a dry condition. As shown in Figure 3, famotidine significantly inhibited epidermal hyperplasia compared with the control, dose-dependently. The inhibition of epidermal hyperplasia by 1% and 5% famotidine was 43% and 78%, respectively. Also, 5% diphenhydramine inhibited it significantly (83%). The results of this study suggest that both the histamine H1 and histamine H2 receptors contribute to the maintenance of skin barrier function. We also found that both types of histamine receptor antagonist inhibited epidermal hyperplasia with barrier disruption induced by acetone treatment in mice kept in a dry condition. Therefore, the histamine H1 and H2 receptors may contribute not only to skin barrier function but also to epidermal proliferation or inflammation.Moy et al., 2000Moy A.B. Winter M. Kamath A. et al.Histamine alters endothelial barrier function at cell-cell and cell-matrix sites.Am J Physiol Lung Cell Mol Physiol. 2000; 278: L888-L898PubMed Google Scholar reported that histamine altered vascular endothelial barrier function at cell-cell and cell-matrix sites, but the effects of histamine and histamine receptor antagonists on the epidermal barrier function were not reported. The mechanism of the efficacy of histamine H1 and H2 receptor antagonists on skin barrier function and skin condition also has not been elucidated. Macroscopically, mast cell degranulation increases in a dry condition after acetone treatment (Denda et al., 1998Denda M. Sato J. Tsuchiya T. Elias P.M. Feingold K.R. Low humidity stimulates epidermal DNA synthesis and amplifies the hyperproliferative response to barrier disruption: Implication for seasonal exacerbations of inflammatory dermatoses.J Invest Dermatol. 1998; 111: 873-878https://doi.org/10.1046/j.1523-1747.1998.00364.xCrossref PubMed Scopus (225) Google Scholar). Histamine synthesis is also induced by ultraviolet (UV) B in keratinocytes (Malaviya et al., 1996Malaviya R. Morrison A.R. Pentland A.P. Histamine in human epidermal cells is induced by ultraviolet light injury.J Invest Dermatol. 1996; 106: 785-789Crossref PubMed Scopus (64) Google Scholar). These findings imply that the histamine content in skin tissue increases during cutaneous inflammation. UV radiation enhances histamine sensitivity in keratinocytes, and prostaglandin synthesis in keratinocytes after UV radiation is mediated by histamine (Pentland et al., 1990Pentland A.P. Mahoney M. Jacobs S.C. Holtzman J. Enhanced prostaglandin synthesis after ultraviolet injury is mediated by endogenous histamine stimulation.J Clin Invest. 1990; 86: 566-574Crossref PubMed Scopus (101) Google Scholar). Histamine also enhances UVB-induced interleukin-6 (IL-6) production in keratinocytes (Shinoda et al., 1998Shinoda S. Kameyoshi Y. Hide M. Moriya E. Yamamoto S. Histamine enhances UVB-induced IL-6 production by human keratinocytes.Arch Dermatol Res. 1998; 290: 429-434https://doi.org/10.1007/s004030050331Crossref PubMed Scopus (29) Google Scholar). IL-6 is a proinflammatory cytokine, which may be responsible for mast cell differentiation and keratinocyte proliferation (Saito et al., 1996Saito H. Ebisawa M. Tachimoto H. et al.Selective growth of human mast cells induced by steel factor IL-6, and prostaglandin E2 from cord blood mononuclear cells.J Immunol. 1996; 157: 343-350PubMed Google Scholar). Histamine accelerates cell proliferation (Wang et al., 1997Wang L.-D. Hoeltzel M. Butler K. Hare B. Todisco A. Wang M. Del Valle J. Activation of the human histamine H2 receptor is linked to cell proliferation and c-fos gene transcription.Am J Physiol. 1997; 273: C2037-C2045PubMed Google Scholar) and IL-6 also accelerates it (Grossman et al., 1989Grossman R.M. Krueger J. Yourish D. et al.Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes.Proc Natl Acad Sci. 1989; 86: 6367-6371Crossref PubMed Scopus (745) Google Scholar). These reports suggest that histamine may regulate skin conditions. Although the results of many trials for oral application of histamine H2 receptor antagonists to psoriasis with epidermal hyperplasia were not consistent, this study showed that epicutaneous application of histamine H2 receptor antagonists may inhibit keratinocyte proliferation and accelerate barrier formation. Further study is needed to elucidate the function of histamine H2 receptor in the epidermis. We consider that itch may be one of the important factors that exacerbate the skin condition because scratching behavior results in disruption of skin barrier function. In our study, scratching was prevented during the barrier repair process. Thus, the effects of histamine H1 and H2 receptor antagonists were due to biochemical effects on the barrier homeostasis. Histamine H1 receptor antagonists are used for the treatment of pruritus in patients with atopic dermatitis (Zuberbier and Henz, 1999Zuberbier T. Henz B.M. Use of cetirizine in dermatologic disorders.Ann Allergy Asthma Immunol. 1999; 83: 476-480Abstract Full Text PDF PubMed Scopus (22) Google Scholar). In addition, the histamine H2 receptor antagonist inhibits the scratching behavior induced by histamine and compound 48/80 in mice (Inagaki et al., 1999Inagaki N. Nakamura N. Nagao M. Musoh K. Kawasaki H. Nagai H. Participation of H1 and H2 receptors in passive cutaneous anaphylaxis-induced scratching behavior in ICR mice.Eur J Pharmacol. 1999; 367: 361-371https://doi.org/10.1016/s0014-2999(98)00974-1Crossref PubMed Scopus (0) Google Scholar). Therefore, the histamine H2 receptor antagonist in combination with histamine H1 receptor antagonist may not only accelerate barrier repair but also inhibit scratching behavior, which breaks the skin barrier.Schmelz et al., 1997Schmelz M. Schmidt R. Bickel A. Handwerker H.O. Torebjork H.E. Specific C-receptors for itch in human skin.J Neurosci. 1997; 17: 8003-8008PubMed Google Scholar reported that the microneurographic pattern of the response to histamine of histamine-sensitive c-fiber, which was mechanically insensitive, matched the time course of the itch sensation in the cutaneous branch of the peroneal nerve in humans. This type of c-fiber, which has very large innervation territories in skin, probably represents the afferent units long searched for mediating itch sensations (Schmelz et al., 1997Schmelz M. Schmidt R. Bickel A. Handwerker H.O. Torebjork H.E. Specific C-receptors for itch in human skin.J Neurosci. 1997; 17: 8003-8008PubMed Google Scholar). Further study is necessary to elucidate the various roles of histamine and the mechanism in skin including histamine H3 receptors on mast cells and on peripheral endings of sensory nerves that may regulate substance P release (Ohkubo et al., 1995Ohkubo T. Shibata M. Inoue M. Kaya H. Takahashi H. Regulation of substance P release mediated via prejunctional histamine H3 receptors.Eur J Pharmacol. 1995; 273: 83-88https://doi.org/10.1016/0014-2999(94)00668-wCrossref PubMed Scopus (0) Google Scholar). In this study we demonstrated that epicutaneous application of histamine H1 and H2 receptor antagonists accelerated the recovery of skin barrier function disrupted by tape stripping, and it also inhibited the epidermal hyperplasia with barrier dysfunction induced by acetone treatment in mice kept in a dry condition. Histamine and histamine receptor antagonists have effects on proliferation, differentiation, cytokine production and its release, and ion channels. The effects of histamine receptor antagonists via histamine H1 or H2 receptor on them have been reported for various tissues. Histamine-induced DNA synthesis is inhibited by H1 receptor antagonists in carcinoma and melanoma cells that express histamine H1 receptor (Tilly et al., 1990Tilly B.C. Tertoolen L.G. Remorie R. Ladoux A. de Verlaan I. Laat S.W. Moolenaar W.H. Histamine as a growth factor and chemoattractant for human carcinoma and melanoma cells: action through Ca++-mobilizing H1 receptors.J Cell Biol. 1990; 110: 1211-1215Crossref PubMed Scopus (134) Google Scholar). Pyrilamine, a histamine H1 receptor antagonist, blocks histamine-mediated UVB-induced IL-6 production in human keratinocytes (Shinoda et al., 1998Shinoda S. Kameyoshi Y. Hide M. Moriya E. Yamamoto S. Histamine enhances UVB-induced IL-6 production by human keratinocytes.Arch Dermatol Res. 1998; 290: 429-434https://doi.org/10.1007/s004030050331Crossref PubMed Scopus (29) Google Scholar). Histamine H1 receptor antagonists block cardiac Na+, Ca2+, and K+ channels (Delpon et al., 1999Delpon E. Valenzuela C. Tamargo J. Blockade of cardiac potassium and other channels by antihistamines.Drug Safety. 1999; 21: 11-18Crossref PubMed Scopus (34) Google Scholar). On the other hand, cimetidine, a histamine H2 receptor antagonist, reverses histamine-mediated increase in IL-1α-induced IL-1β synthesis in peripheral blood mononuclear cells (Vannier and Dinarello, 1993Vannier E. Dinarello C.A. Histamine enhances interleukin (IL) -1-induced IL-1 gene expression and protein synthesis via H2 receptors in peripheral blood mononuclear cells. Comparison with IL-1 receptor antagonist.J Clin Invest. 1993; 92: 281-287Crossref PubMed Scopus (84) Google Scholar). Histamine suppresses IL-12 and stimulates IL-10 production in peripheral monocytes, and cimetidine antagonizes these effects (Elenkov et al., 1998Elenkov I.J. Webster E. Papanicolaou D.A. Fleisher T.A. Chrousos G.P. Wilder R.L. Histamine potently suppresses human IL-12 and stimulates IL-10 production via H2 receptors.J Immunol. 1998; 161: 2586-2593PubMed Google Scholar). H2 receptor antagonists reverse histamine-induced increase of IL-4, IL-5, and interferon-γ production in T cells (Krouwels et al., 1998Krouwels F.H. Hol B.E.A. Lutter R. Bruinier B. Bast A. Jansen H.M. Out T.A. Histamine affects interleukin-4, interleukin-5, and interferon-γ production by human T cell clones from the airway and blood.Am J Respir Cell Mol Biol. 1998; 18: 721-730Crossref PubMed Scopus (52) Google Scholar). Cimetidine inhibits cell proliferation and c-fos gene transcription induced by histamine H2 receptor activation in human embryonic kidney cells stably transfected with human H2 receptor (Wang et al., 1997Wang L.-D. Hoeltzel M. Butler K. Hare B. Todisco A. Wang M. Del Valle J. Activation of the human histamine H2 receptor is linked to cell proliferation and c-fos gene transcription.Am J Physiol. 1997; 273: C2037-C2045PubMed Google Scholar). Histamine and the selective histamine H2 receptor agonist dimaprit reduced a specific K+ current in myenteric neurons from guinea pig small intestine, and cimetidine suppressed it (Starodub and Wood, 2000Starodub A.M. Wood J.D. Histamine suppresses A-type potassium current in myenteric neurons from guinea pig small intestine.J Pharmacol Exp Ther. 2000; 294: 555-561PubMed Google Scholar). But, the roles of each type of histamine receptor in the epidermis are unknown, and the mechanism of barrier repair acceleration of histamine H1 and H2 receptor antagonists is also still unknown. The production of various kinds of cytokines like IL-1α and tumor necrosis factor α in keratinocytes increases after skin barrier disruption (Wood et al., 1992Wood L.C. Jackson S.M. Elias P.M. Grunfeld C. Feingold K.R. Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice.J Clin Invest. 1992; 90: 482-487Crossref PubMed Scopus (412) Google Scholar;Nickoloff and Naidu, 1994Nickoloff B.J. Naidu Y. Perturbation of epidermal barrier function correlates with initiation of cytokine cascade in human skin.J Am Acad Dermatol. 1994; 30: 535-546Abstract Full Text PDF PubMed Scopus (429) Google Scholar) and not only the production of epidermal IL-1α but also its release increases after skin barrier disruption (Wood et al., 1996Wood L.C. Elias P.M. Calhoun C. Tsai J.C. Grunfeld C. Feingold K.R. Barrier disruption stimulates interleukin-1α expression and release from a pre-formed pool in murine epidermis.J Invest Dermatol. 1996; 106: 397-403Crossref PubMed Scopus (244) Google Scholar). Therefore, the histamine H1 and H2 receptors may regulate skin conditions via these cytokines. Also the quantity of histamine receptor on keratinocytes may change with the skin condition. In this study the effects of histamine H1 and H2 receptor antagonists appear so early that they may be involved in the secretion of lamellar bodies, which are related to the epidermal calcium and potassium gradient (Lee et al., 1992Lee S.H. Elias P.M. Proksch E. Menon G.K. Mao-Quiang M. Feingold K.R. Calcium and potassium are important regulators of barrier homeostasis in murine epidermis.J Clin Invest. 1992; 89: 530-538Crossref PubMed Scopus (194) Google Scholar;Menon et al., 1994Menon G.K. Price L.F. Bommannan B. Elias P.M. Feingold K.R. Selective obliteration of the epidermal calcium gradient leads to enhanced lamellar body secretion.J Invest Dermatol. 1994; 102: 789-795Abstract Full Text PDF PubMed Google Scholar).Mauro et al., 1998bMauro T. Bench G. Sidderas-Haddad E. Feingold K. Elias P. Cullander C. Acute barrier perturbation abolishes the Ca2+ and K+ gradients in murine epidermis: quantitative measurement using PIXE.J Invest Dermatol. 1998; 111: 1198-1201https://doi.org/10.1046/j.1523-1747.1998.00421.xCrossref PubMed Scopus (156) Google Scholar showed an alteration of calcium and potassium localization immediately after barrier disruption. Topical application of calcium or potassium delayed the barrier recovery (Lee et al., 1992Lee S.H. Elias P.M. Proksch E. Menon G.K. Mao-Quiang M. Feingold K.R. Calcium and potassium are important regulators of barrier homeostasis in murine epidermis.J Clin Invest. 1992; 89: 530-538Crossref PubMed Scopus (194) Google Scholar). Keratinocyte K+ channels mediate Ca2+-induced differentiation (Mauro et al., 1997Mauro T. Dixon D.B. Komuves L. Hanley K. Pappone P.A. Keratinocyte K+ channels mediate Ca2+-induced differentiation.J Invest Dermatol. 1997; 108: 864-870Crossref PubMed Scopus (52) Google Scholar). These reports suggest that calcium and potassium concentration in the epidermis strongly relates to epidermal barrier homeostasis. On the other hand,Koizumi and Ohkawara, 1999Koizumi H. Ohkawara A. H2 histamine receptor-mediated increase in intracellular Ca2+ in cultured human keratinocytes.J Dermatol Sci. 1999; 21: 127-132https://doi.org/10.1016/s0923-1811(99)00027-4Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) demonstrated that histamine H2 receptor antagonist cimetidine specifically inhibited histamine-mediated increase in intracellular Ca2+ of cultured human keratinocytes significantly, although histamine H1 receptor antagonist diphenhydramine did not inhibit it significantly. Moreover, some potassium currents are regulated by histamine H2 receptor (Yazawa and Abiko, 1993Yazawa K. Abiko Y. Modulation by histamine of the delayed outward potassium current in guinea-pig ventricular myocytes.Br J Pharmacol. 1993; 109: 142-147Crossref PubMed Scopus (10) Google Scholar;Adeagbo and Oriowo, 1998Adeagbo A.S.O. Oriowo M.A. Histamine receptor subtypes mediating hyperpolarization in the isolated, perfused rat mesenteric pre-arteriolar bed.Eur J Pharmacol. 1998; 347: 237-244https://doi.org/10.1016/s0014-2999(98)00119-8Crossref PubMed Scopus (0) Google Scholar;Starodub and Wood, 2000Starodub A.M. Wood J.D. Histamine suppresses A-type potassium current in myenteric neurons from guinea pig small intestine.J Pharmacol Exp Ther. 2000; 294: 555-561PubMed Google Scholar).Fitzsimons et al., 1999Fitzsimons C. Duran H. Engel N. Molinari B. Rivera E. Changes in H2 receptor expression and coupling during Ca2+-induced differentiation in mouse epidermal keratinocytes.Inflamm Res. 1999; 48: S73-S74Crossref PubMed Google Scholar reported that the quantity of histamine H2 receptors changes with Ca2+ concentration in relation to differentiation in epidermal tumor cell lines. These reports also suggest that the differences in the function of histamine H1 and H2 receptors in the epidermis may depend on the regulation of calcium and potassium concentration in the epidermis. The roles of each histamine receptor in calcium and potassium concentration and ion transport including ion channels in the epidermis remain to be investigated. Furthermore,Lichey et al., 1994Lichey J. Zuberbier T. Luck W. Lau S. Wahn U. Influence of glycosphingolipids on the release of histamine and sulfidopepitide leukotrienes from human basophils.Int Arch Allergy Immunol. 1994; 103: 252-259Crossref PubMed Scopus (4) Google Scholar reported that histamine release is modulated by glycosphingolipids in basophils. But, the relationship between histamine receptors and lipid synthesis has not been clarified yet. A mechanistic study of the relationship between histamine receptors and the homeostatis of intercellular lipids in the stratum corneum should be carried out. In conclusion, both the histamine H1 and histamine H2 receptors in the epidermis are involved in skin barrier function and the skin condition of epidermal hyperplasia.