Abstract
Human α1-antitrypsin (AAT) is an abundant acute phase glycoprotein expressing anti-protease and immunomodulatory activities, and is used as a biopharmaceutical to treat patients with inherited AAT deficiency. The pleiotropic properties of AAT provide a rationale for using this therapy outside of inherited AAT deficiency. Therapy with AAT is administrated intravenously, yet the alternative routes are being considered. To examine the putative transepidermal application of AAT we used epiCS®, the 3D human epidermis equivalents reconstructed from human primary epidermal keratinocytes. We topically applied various concentrations of AAT protein with a constant volume of 50 µl, prepared in Hank’s balance solution, HBSS, to epiCS cultured under bas\\al condition or when culture medium supplemented with 100 µg/ml of a combined bacterial lipopolysaccharide (LPS) and peptidoglycan (PGN) mixture. AAT freely diffused across epidermis layers in a concentration and time-dependent manner. Within 18 h topically provided 0.2 mg AAT penetrated well the stratum corneum and localizes within the keratinocytes. The treatments with AAT did not induce obvious morphological changes and damages in keratinocyte layers. As expected, LPS/PGN triggered a strong pro-inflammatory activation of epiCS. AAT exhibited a limited capacity to neutralize the effect of LPS/PGN, but more importantly, it lowered expression of IL-18 and IL-8, and preserved levels of filaggrin, a key protein for maintaining the epidermal barrier integrity. Our findings suggest that the transepidermal route for delivering AAT is worthwhile to explore further. If successful, this approach may offer an easy-to-use therapy with AAT for skin inflammatory diseases.
Highlights
Human alpha1-antitrypsin (AAT) encoded by SERPINA1 gene is an acute phase glycoprotein, a member of the serpin superfamily
Intravenous infusions of human plasma-purified AAT preparations are used for the treatment of lung diseases associated with severe inherited AAT deficiency
Inherited AAT deficiency can be associated with other inflammatory disorders, such as antiproteinase-3-associated vasculitis, panniculitis, psoriasis, chronic urticarial, etc. (Blanco et al, 2017; Torres-Duran et al, 2018)
Summary
Human alpha1-antitrypsin (AAT) encoded by SERPINA1 gene is an acute phase glycoprotein, a member of the serpin (serine protease inhibitor) superfamily. Plasma levels of AAT range between 1.3 and 2 g/L, whereas during acute inflammation or infection these levels increase four to five times of the normal range. This protein plays an important role in preventing the proteolysis amplification during acute inflammation and organ injury (Janciauskiene et al, 2011). Intravenous infusions of human plasma-purified AAT preparations are used for the treatment of lung diseases associated with severe inherited AAT deficiency (circulating levels of AAT about 10% of normal). Inherited AAT deficiency can be associated with other inflammatory disorders, such as antiproteinase-3-associated vasculitis, panniculitis, psoriasis, chronic urticarial, etc. Results from the single cases and small patient cohorts show that AAT therapy is very effective in AAT deficient patients with panniculitis (Sandhaus et al, 2016; Miravitlles et al, 2017)
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