title: Activation of HIF-1α (hypoxia inducible factor-1α) prevents dry eye-induced acinar cell death in the lacrimal gland.
abstract: The pathogenesis of immune-mediated lacrimal gland (LG) dysfunction in Sjögren's syndrome has been thoroughly studied. However, the majority of dry eye (DE) is not related to Sjögren type, and its pathophysiology remains unclear. The purpose of this study was to determine and investigate the protective mechanisms against DE stress in mice. DE induced prominent blood vessel loss without apoptosis or necrosis in the LG. Autophagic vacuoles, distressed mitochondria, and stressed endoplasmic reticulum were observed via electron microscopy. Immunoblotting confirmed the increase in autophagic markers. Glycolytic activities were enhanced with increasing levels of succinate and malate that, in turn, activated hypoxia-inducible factor (HIF)-1α. Interestingly, the areas of stable HIF-1α expression overlapped with COX-2 and MMP-9 upregulation in LGs of DE-induced mice. We generated HIF-1α conditional knockout (CKO) mice in which HIF-1α expression was lost in the LG. Surprisingly, normal LG polarities and morphologies were completely lost with DE induction, and tremendous acinar cell apoptosis was observed. Similar to Sjögren's syndrome, CD3(+) and CD11b(+) cells infiltrated HIF-1α CKO LGs. Our results show that DE induced the expression of HIF-1α that activated autophagy signals to prevent further acinar cell damage and to maintain normal LG function.
authors: Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.
authors: Y
authors: Y
authors: Seo
authors: Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.
authors: Y W
authors: YW
authors: Ji
authors: 1] Schephens Eye Research Institute, Harvard Medical School, Boston, MA, USA [2] Department of Ophthalmology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi-do, Korea.
authors: S M
authors: SM
authors: Lee
authors: Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.
authors: J
authors: J
authors: Shim
authors: Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.
authors: H
authors: H
authors: Noh
authors: Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.
authors: A
authors: A
authors: Yeo
authors: Clinical Trials Center, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea.
authors: C
authors: C
authors: Park
authors: Clinical Trials Center, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea.
authors: M S
authors: MS
authors: Park
authors: Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea.
authors: E J
authors: EJ
authors: Chang
authors: 1] Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea [2] Institute of Corneal Dystrophy Research, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea.
authors: H K
authors: HK
authors: Lee
mesh_terms: D000818:Animals; D001343:Autophagy; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D007765:Lacrimal Apparatus / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012859:Sjogren's Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse