| First Author | Seo Y | Year | 2014 |
| Journal | Cell Death Dis | Volume | 5 |
| Pages | e1309 | PubMed ID | 24967971 |
| Mgi Jnum | J:263588 | Mgi Id | MGI:6188807 |
| Doi | 10.1038/cddis.2014.260 | Citation | Seo Y, et al. (2014) Activation of HIF-1alpha (hypoxia inducible factor-1alpha) prevents dry eye-induced acinar cell death in the lacrimal gland. Cell Death Dis 5:e1309 |
| abstractText | The pathogenesis of immune-mediated lacrimal gland (LG) dysfunction in Sjogren's syndrome has been thoroughly studied. However, the majority of dry eye (DE) is not related to Sjogren 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)-1alpha. Interestingly, the areas of stable HIF-1alpha expression overlapped with COX-2 and MMP-9 upregulation in LGs of DE-induced mice. We generated HIF-1alpha conditional knockout (CKO) mice in which HIF-1alpha 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 Sjogren's syndrome, CD3(+) and CD11b(+) cells infiltrated HIF-1alpha CKO LGs. Our results show that DE induced the expression of HIF-1alpha that activated autophagy signals to prevent further acinar cell damage and to maintain normal LG function. |
