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0.005 % hypochlorite reduces serine protease in cultured human keratinocytes: Evidences supporting bleach bath improves atopic dermatitis

  • Author Footnotes
    1 These authors contributed equally to this work.
    Shu-Mei Huang
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Yang-Yi Chen
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Yin-Chun Chen
    Affiliations
    Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Ching-Shuang Wu
    Affiliations
    Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan

    Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
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  • Cheng-Che E. Lan
    Correspondence
    Correspondence to: Department of Dermatology, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd, Kaohsiung 807, Taiwan.
    Affiliations
    Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Author Footnotes
    1 These authors contributed equally to this work.
      Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease. Current treatment strategy for AD includes alleviating inflammation, normalizing microbiome, and restoring barrier function. Because epidermal density of Staphylococcus aureus (SA) was reported to positively correlate with the disease severity of AD [
      • Totte J.E.
      • van der Feltz W.T.
      • Hennekam M.
      • van Belkum A.
      • van Zuuren E.J.
      • Pasmans S.G.
      Prevalence and odds of Staphylococcus aureus carriage in atopic dermatitis: a systematic review and meta-analysis.
      ], bleach bath (with 0.005 % hypochlorite (HOCl) solution) was originally considered as a beneficial anti-septic therapy for AD patients with skin lesions heavily colonized SA [
      • Barnes T.M.
      • Greive K.A.
      Use of bleach baths for the treatment of infected atopic eczema.
      ]. Two randomized, placebo-controlled trials evaluating the efficacy of twice-weekly 10-min bleach bath showed that this proposed protocol significantly decreases AD severity as compared to water bath [
      • Huang J.T.
      • Abrams M.
      • Tlougan B.
      • Rademaker A.
      • Paller A.S.
      Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity.
      ,
      • Wong S.M.
      • Ng T.G.
      • Baba R.
      Efficacy and safety of sodium hypochlorite (bleach) baths in patients with moderate to severe atopic dermatitis in Malaysia.
      ]. However, Wong et al. demonstrated no significant difference in SA density between bleach bath-treated group and control group although bleach bath showed significant reduction in AD severity [
      • Wong S.M.
      • Ng T.G.
      • Baba R.
      Efficacy and safety of sodium hypochlorite (bleach) baths in patients with moderate to severe atopic dermatitis in Malaysia.
      ]. Recent observation documented that HOCl-induced antimicrobial and anti-biofilm effects against SA require higher concentration (at least 0.01 % in vitro, and 0.04 % ex vivo) than currently used in bleach bath protocol [
      • Eriksson S.
      • van der Plas M.J.A.
      • Morgelin M.
      • Sonesson A.
      Antibacterial and antibiofilm effects of sodium hypochlorite against Staphylococcus aureus isolates derived from patients with atopic dermatitis.
      ]. Topical HOCl has been shown to have anti-inflammatory effects on epidermal keratinocytes. Leung et al. first demonstrated that 0.005 % HOCl solution ameliorates epidermal inflammation by inhibiting nuclear factor-kappa B (NF-κB) signaling in mice with acute radiation dermatitis [
      • Leung T.H.
      • Zhang L.F.
      • Wang J.
      • Ning S.
      • Knox S.J.
      • Kim S.K.
      Topical hypochlorite ameliorates NF-kappaB-mediated skin diseases in mice.
      ]. As aforementioned, impaired epidermal barrier function also plays an important role in the pathogenesis of AD. Aberrant activity of epidermal serine proteases (SPs) is found to associate with the barrier dysfunction in atopic skin [
      • Jurakic Toncic R.
      • Marinovic B.
      The role of impaired epidermal barrier function in atopic dermatitis.
      ]. Although during bleach bath treatment HOCl comes in direct with skin, the impact of HOCl on SPs in atopic skin have not been carefully investigated. Therefore, this study aimed to determine the direct effects of 0.005 % HOCl on the expression and activity of SP, a molecule that is involved in pathogenesis of AD, in cultured human keratinocytes. Among the SP involved in epidermal changes of AD, kallikrein-related peptidase (KLK)-5 and KLK7 contribute significantly to development acute skin damage [
      • Komatsu N.
      • Saijoh K.
      • Kuk C.
      • Liu A.C.
      • Khan S.
      • Shirasaki F.
      • et al.
      Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients.
      ,
      • Ovaere P.
      • Lippens S.
      • Vandenabeele P.
      • Declercq W.
      The emerging roles of serine protease cascades in the epidermis.
      ]. The effect of 0.005 % HOCl on KLK5 and KLK7 and SP inhibitor (SPINK5 and SLPI) gene expressions in keratinocytes were determined. To mimic the AD microenvironment, IL-1β was used. Addition of IL-1β is particularly relevant for this study as Bernard et al. demonstrated that exogenous IL-1β closely reproduces an AD-like phenotype in reconstructed human epidermis [
      • Bernard M.
      • Carrasco C.
      • Laoubi L.
      • Guiraud B.
      • Rozieres A.
      • Goujon C.
      • et al.
      IL-1beta induces thymic stromal lymphopoietin and an atopic dermatitis-like phenotype in reconstructed healthy human epidermis.
      ].
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