10
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: not found
      • Article: not found

      Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          <p class="first" id="d15524657e213">Mucous membrane pemphigoid (MMP) is a systemic mucosal scarring disease, commonly causing blindness, for which there is no antifibrotic therapy. Aldehyde dehydrogenase family 1 (ALDH1) is upregulated in both ocular MMP (OMMP) conjunctiva and cultured fibroblasts. Application of the ALDH metabolite, retinoic acid (RA), to normal human conjunctival fibroblasts in vitro induced a diseased phenotype. Conversely, application of ALDH inhibitors, including disulfiram, to OMMP fibroblasts in vitro restored their functionality to that of normal controls. ALDH1 is also upregulated in the mucosa of the mouse model of scarring allergic eye disease (AED), used here as a surrogate for OMMP, in which topical application of disulfiram decreased fibrosis in vivo. These data suggest that progressive scarring in OMMP results from ALDH/RA fibroblast autoregulation, that the ALDH1 subfamily has a central role in immune-mediated ocular mucosal scarring, and that ALDH inhibition with disulfiram is a potential and readily translatable antifibrotic therapy. </p><p class="first" id="d15524657e216">Diseased conjunctival mucous membrane pemphigoid fibroblasts maintain fibrosis by aldehyde dehydrogenase autoregulation, which may be inhibited by disulfiram. </p>

          Related collections

          Most cited references41

          • Record: found
          • Abstract: not found
          • Article: not found

          Fibrosis--a common pathway to organ injury and failure.

            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application.

            Aldehyde dehydrogenases (ALDHs) belong to a superfamily of enzymes that play a key role in the metabolism of aldehydes of both endogenous and exogenous derivation. The human ALDH superfamily comprises 19 isozymes that possess important physiological and toxicological functions. The ALDH1A subfamily plays a pivotal role in embryogenesis and development by mediating retinoic acid signaling. ALDH2, as a key enzyme that oxidizes acetaldehyde, is crucial for alcohol metabolism. ALDH1A1 and ALDH3A1 are lens and corneal crystallins, which are essential elements of the cellular defense mechanism against ultraviolet radiation-induced damage in ocular tissues. Many ALDH isozymes are important in oxidizing reactive aldehydes derived from lipid peroxidation and thereby help maintain cellular homeostasis. Increased expression and activity of ALDH isozymes have been reported in various human cancers and are associated with cancer relapse. As a direct consequence of their significant physiological and toxicological roles, inhibitors of the ALDH enzymes have been developed to treat human diseases. This review summarizes known ALDH inhibitors, their mechanisms of action, isozyme selectivity, potency, and clinical uses. The purpose of this review is to 1) establish the current status of pharmacological inhibition of the ALDHs, 2) provide a rationale for the continued development of ALDH isozyme-selective inhibitors, and 3) identify the challenges and potential therapeutic rewards associated with the creation of such agents.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Vitamin A, infection, and immune function.

              In populations where vitamin A availability from food is low, infectious diseases can precipitate vitamin A deficiency by decreasing intake, decreasing absorption, and increasing excretion. Infectious diseases that induce the acute-phase response also impair the assessment of vitamin A status by transiently depressing serum retinol concentrations. Vitamin A deficiency impairs innate immunity by impeding normal regeneration of mucosal barriers damaged by infection, and by diminishing the function of neutrophils, macrophages, and natural killer cells. Vitamin A is also required for adaptive immunity and plays a role in the development of T both-helper (Th) cells and B-cells. In particular, vitamin A deficiency diminishes antibody-mediated responses directed by Th2 cells, although some aspects of Th1-mediated immunity are also diminished. These changes in mucosal epithelial regeneration and immune function presumably account for the increased mortality seen in vitamin A-deficient infants, young children, and pregnant women in many areas of the world today.
                Bookmark

                Author and article information

                Journal
                JCI Insight
                American Society for Clinical Investigation
                2379-3708
                August 4 2016
                August 4 2016
                : 1
                : 12
                Article
                10.1172/jci.insight.87001
                5033866
                27699226
                0da192d0-e59e-4016-b5fb-921458c17fb5
                © 2016
                History

                Comments

                Comment on this article