Rapamycin Rescues Endoplasmic Reticulum Stress–Induced Dry Eye Syndrome in Mice

Abstract

mycin rescues endoplasmic reticulum stress-induced dry eye syndrome in mice. Invest Ophthalmol Vis Sci. 2019;60:1254-1264. https://doi.org/ 10.1167 PURPOSE. To investigate whether rapamycin protects tear production and the ocular surface during endoplasmic reticulum (ER) stress-induced dry eye syndrome in mice. METHODS.Tunicamycin was injected intraperitoneally in BALB/c mice without or with rapamycin (TM or RM5 group). Peritoneal injection of PBS performed in vehicle group. Group without injection served as control. Blinking rate, fluorescein staining score (FSS), and phenol red thread tear production test were measured at 4 days, 1 week, and 2 weeks after treatment. Levels of inflammatory and angiogenic cytokines were measured by ELISA. RESULTS.Blinking rate and FSS were elevated, and tear production was decreased in TM group compared with controls (P < 0.05 for all), which was ameliorated by rapamycin at 1 and 2 weeks. Levels of inflammatory and angiogenic cytokines in the cornea and lacrimal glands were higher in the TM group than controls, and lower in the RM5 group than the TM group at 1 and 2 weeks (P < 0.05 for all).CONCLUSION. Rapamycin protected tear production and the ocular surface against this dry eye syndrome by ameliorating ER stress-induced vascular damage and inflammation of lacrimal glands and the ocular surface.

High-Fat Nutritional Challenge Reshapes Circadian Signatures in Murine Extraorbital Lacrimal Glands

“…After dietary intervention, the lacrimal gland secretion response was measured at ZT0, ZT6, ZT12, and ZT18 at 12 weeks (NC-1 and HFD groups) and 14 weeks (NC-2 and HFD-NC groups), as described previously. 58 , 62 Briefly, pilocarpine hydrochloride was intraperitoneally injected (4.5 mg/kg in saline). After a rest time of 10 minutes, one end of a phenol red–soaked thread was lightly placed on the medial canthus for 20 seconds, and the length of red color on the thread was measured.…”

Role of Neutrophils on the Ocular Surface

“…Knockdown of autophagy-related 5 and autophagy-related 7 reduces the inflammatory function of neutrophils by inhibiting ROS production and degranulation [ 95 ]. In the inflammatory process, endoplasmic reticulum stress can provoke neutrophil autophagy, and autophagy can suppress endoplasmic reticulum stress [ 96 , 97 ]. Inhibition of autophagy through the knockdown of nucleotide oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) or inhibition of NLRP3 inflammasome promotes neutrophil recruitment and phagocytosis, thereby enhancing pathogen removal and improving the survival of septic mice [ 98 ].…”

“…Neutrophil infiltration and degranulation occur in patients with dry eye disease [ 172 , 173 ]. Our previous study revealed that systemic endoplasmic reticulum stress induced the neutrophil infiltration in lacrimal glands, which provoked ocular surface inflammation in the dry eye model [ 97 ]. It has been reported that neutrophil extracellular trap formation markers, such as neutrophil elastase, MPO, and citrullinated histone H3, exist on the ocular surface [ 174 ]; extracellular DNA production and clearance mechanisms are dysregulated in dry eye disease, which results in ocular surface inflammation [ 175 ].…”

Pharmacological Inhibition of Epidermal Growth Factor Receptor Prevents Intracranial Aneurysm Rupture by Reducing Endoplasmic Reticulum Stress

“…Details of experimental methods are available in Supplemental Materials. 5,7,8,19,[29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] Fisher exact test was used to analyze the incidences of aneurysm formation and subarachnoid hemorrhage. Log-rank (Mantel-Cox) test was used for the analysis of the survival rate.…”