July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Cathepsin S Inhibitor Reduces Lacrimal Gland Inflammation and Increases Tear Flow In a Mouse Model of Sjögren’s Syndrome
Author Affiliations & Notes
  • Wannita Klinngam
    Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, California, United States
  • Srikanth Reddy Janga
    Department of Ophthalmology, Roski Eye Institute and Keck School of Medicine, University of Southern California, Los Angeles, California, United States
  • Maria C. Edman
    Department of Ophthalmology, Roski Eye Institute and Keck School of Medicine, University of Southern California, Los Angeles, California, United States
  • Mihir Shah
    Department of Ophthalmology, Roski Eye Institute and Keck School of Medicine, University of Southern California, Los Angeles, California, United States
  • Frances Yarber
    Department of Ophthalmology, Roski Eye Institute and Keck School of Medicine, University of Southern California, Los Angeles, California, United States
  • Hao Guo
    Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, California, United States
  • Benjamin Cooperman
    Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, California, United States
  • Dandan Wang
    Department of Anatomic and Clinical Pathology, Los Angeles County + University of Southern California Medical Center, Los Angeles, California, United States
  • Sarah Hamm-Alvarez
    Department of Ophthalmology, Roski Eye Institute and Keck School of Medicine, University of Southern California, Los Angeles, California, United States
    Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, California, United States
  • Footnotes
    Commercial Relationships   Wannita Klinngam, None; Srikanth Janga, None; Maria Edman, None; Mihir Shah, None; Frances Yarber, None; Hao Guo, None; Benjamin Cooperman, None; Dandan Wang, None; Sarah Hamm-Alvarez, None
  • Footnotes
    Support  EY011386
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2672. doi:
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      Wannita Klinngam, Srikanth Reddy Janga, Maria C. Edman, Mihir Shah, Frances Yarber, Hao Guo, Benjamin Cooperman, Dandan Wang, Sarah Hamm-Alvarez; Cathepsin S Inhibitor Reduces Lacrimal Gland Inflammation and Increases Tear Flow In a Mouse Model of Sjögren’s Syndrome. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2672.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The activity of Cathepsin S (CTSS), a protease implicated in autoimmunity, is increased in tears and lacrimal gland (LG) of the male NOD mouse, a model of autoimmune-mediated dry eye associated with Sjögren’s Syndrome (SS), and also increased in SS patient tears. We hypothesized that inhibition of CTSS can treat the symptoms of autoimmune dacryoadenitis specifically by reducing LG inflammation and increasing aqueous tear production. In this study, we test this hypothesis using the CTSS inhibitor, Z-FL-COCHO (Z-FL), in male NOD mice.

Methods : Z-FL was dissolved in 10%DMSO+40%PEG300+50% PBS (vehicle) and its concentration was validated by HPLC. 14 wk male NOD mice received IP injections of 4 mg/kg, 1 mg/kg of Z-FL or vehicle every other day for 2 wk. At the end of the study, tear secretion was stimulated by application of topical carbachol to LGs, and LGs were evaluated by RT-qPCR and histology. CTSS activity was measured in tears, LG, and spleen. Liver, spleen, and kidneys were assessed for toxicity.

Results : In the 4 mg/kg Z-FL group, CTSS activity was decreased by 2.1-fold in tears (p=0.0337), 1.9-fold in LG (p=0.0062), and 3.2-fold in spleen (p=0.0026) vs vehicle. When compared to the 1 mg/kg Z-FL group, CTSS activity in the 4 mg/kg group was decreased by 2.7-fold in tears (p=0.0043) and 1.9-fold in spleen (p=0.023). In the 1 mg/kg Z-FL group, only spleen CTSS activity was significantly decreased (1.7-fold, p=0.0339) vs vehicle. The total area of the LG occupied by lymphocytic infiltration from the 4 mg/kg Z-FL group was reduced by 1.8-fold vs the vehicle group (p=0.042) and by 1.8 fold vs the 1 mg/kg Z-FL group (p = 0.0216). The stimulated tear volume in the 4 mg/kg Z-FL group was increased by 1.3-fold (p=0.0094) and by 1.4-fold (p=0.0078) relative to vehicle and 1 mg/kg Z-FL groups, respectively. 4 mg/kg Z-FL reduced MHC-II gene expression relative to vehicle (1.4-fold, p=0.0463) and 1 mg/kg Z-FL treated mice (1.6-fold, p=0.0248). There was no significant difference in liver, spleen, and kidney weights between treatment groups, and no histological signs of toxicity were detected in any groups.

Conclusions : IP injection of Z-FL can reduce autoimmune-mediated LG inflammation while improving stimulated tear secretion. Therefore, CTSS could be a potential drug target for treatment of SS-associated dry eye.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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