Hideki Miyake1, Tomoko Oda2, Osamu Katsuta2, Masaharu Seno3, Masatsugu Nakamura2. 1. Research and Development Division Santen Pharmaceutical Co., Ltd., Osaka, Japan 2Department of Medical Bioengineering, Division of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan. 2. Research and Development Division Santen Pharmaceutical Co., Ltd., Osaka, Japan. 3. Department of Medical Bioengineering, Division of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan.
Abstract
PURPOSE: A novel meibomian gland dysfunction (MGD) model was developed to facilitate understanding of the pathophysiology of MGD and to evaluate treatment with azithromycin ophthalmic solution (azithromycin). MGD was induced in HR-1 hairless mice by feeding them a special diet with limited lipid content (HR-AD). METHODS: Male HR-1 hairless mice were fed an HR-AD diet for 16 weeks. Development of MGD was assessed by histopathology at 4-week intervals. The lid margin was observed by slit-lamp examination. After cessation of the HR-AD diet, the mice were fed a normal diet to restore normal eye conditions. Expression of cytokeratin 6 was determined by immunostaining. We evaluated the effects of topically applied azithromycin on the plugged orifice in this model. RESULTS: After mice were fed the HR-AD diet, histopathology analysis showed hyperkeratinization of the ductal epithelium in the meibomian gland. Ductal hyperkeratinization resulted in the loss of acini, followed by atrophy of the gland. Slit-lamp examination revealed a markedly plugged orifice, telangiectasia, and a toothpaste-like meibum compared with that of a normal eyelid. Cessation of feeding with HR-AD ameliorated both the MGD signs and the expression of cytokeratin 6, restoring the tissue to a histologically normal state. Azithromycin treatment significantly decreased the number of plugged orifices and ameliorated atrophy, as revealed by histopathologic analysis. CONCLUSIONS: We developed a novel model that mimics human MGD signs in HR-1 hairless mice fed an HR-AD diet. Azithromycin treatment led to therapeutic improvement in this model. This MGD model could be useful for the evaluation of drug candidates for MGD.
PURPOSE: A novel meibomian gland dysfunction (MGD) model was developed to facilitate understanding of the pathophysiology of MGD and to evaluate treatment with azithromycin ophthalmic solution (azithromycin). MGD was induced in HR-1 hairlessmice by feeding them a special diet with limited lipid content (HR-AD). METHODS: Male HR-1 hairlessmice were fed an HR-AD diet for 16 weeks. Development of MGD was assessed by histopathology at 4-week intervals. The lid margin was observed by slit-lamp examination. After cessation of the HR-AD diet, the mice were fed a normal diet to restore normal eye conditions. Expression of cytokeratin 6 was determined by immunostaining. We evaluated the effects of topically applied azithromycin on the plugged orifice in this model. RESULTS: After mice were fed the HR-AD diet, histopathology analysis showed hyperkeratinization of the ductal epithelium in the meibomian gland. Ductal hyperkeratinization resulted in the loss of acini, followed by atrophy of the gland. Slit-lamp examination revealed a markedly plugged orifice, telangiectasia, and a toothpaste-like meibum compared with that of a normal eyelid. Cessation of feeding with HR-AD ameliorated both the MGD signs and the expression of cytokeratin 6, restoring the tissue to a histologically normal state. Azithromycin treatment significantly decreased the number of plugged orifices and ameliorated atrophy, as revealed by histopathologic analysis. CONCLUSIONS: We developed a novel model that mimics human MGD signs in HR-1 hairlessmice fed an HR-AD diet. Azithromycin treatment led to therapeutic improvement in this model. This MGD model could be useful for the evaluation of drug candidates for MGD.
Authors: Dongfang Yu; Yogesh Saini; Gang Chen; Andrew J Ghio; Hong Dang; Kimberlie A Burns; Yang Wang; Richard M Davis; Scott H Randell; Charles R Esther; Friedrich Paulsen; Richard C Boucher Journal: Am J Pathol Date: 2017-10-26 Impact factor: 4.307
Authors: Nancy J Reyes; Chen Yu; Rose Mathew; Carolina M Kunnen; Joan Kalnitsky; Rachel L Redfern; Andrea Leonardi; Victor L Perez; Amanda S MacLeod; Preeya K Gupta; Daniel R Saban Journal: Sci Transl Med Date: 2018-07-25 Impact factor: 17.956