Inhibition of endoplasmic reticulum stress by 4-phenylbutyrate alleviates retinal inflammation and the apoptosis of retinal ganglion cells after ocular alkali burn in mice

Huang, Yanqiao; Yuan, Miner; Duan, Fang; Yang, Yao; Lou, Bingsheng; Lin, Xiaofeng

doi:10.1007/s00011-022-01565-3

Cited by 4 publications

(8 citation statements)

References 54 publications

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“…Our previous study found that ER stress is involved in the retinal damage after an OAB. In addition, treatment with 4-PBA (a common ER stress inhibitor) inhibited the expression of ER stress-related molecules and inflammatory factors in the retinal tissue and reduced RGC apoptosis after an OAB [ 15 ]. The present study showed that TUDCA, another classical ER stress inhibitor, also decreased the protein levels of IRE1 (the mediator of ER stress-related inflammation) and CHOP (the mediator of ER stress-induced apoptosis) in OAB retinas.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous study, we found that endoplasmic reticulum (ER) stress participates in the retinal damage after an OAB. The inhibition of ER stress suppresses the retinal inflammation and reduces the RGC apoptosis in the OAB model [ 15 ]. Tauroursodeoxycholic acid (TUDCA), a chemical chaperone, has been demonstrated to be a common ER stress inhibitor by improving the ER-folding capacity and found to have anti-apoptosis and anti-inflammation effects [ 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Effect of Tauroursodeoxycholic Acid on Inflammation after Ocular Alkali Burn

Huang

Lin

Yang

et al. 2022

IJMS

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Inflammation is the main cause of corneal and retinal damage in an ocular alkali burn (OAB). The aim of this study was to investigate the effect of tauroursodeoxycholic acid (TUDCA) on ocular inflammation in a mouse model of an OAB. An OAB was induced in C57BL/6j mouse corneas by using 1 M NaOH. TUDCA (400 mg/kg) or PBS was injected intraperitoneally (IP) once a day for 3 days prior to establishing the OAB model. A single injection of Infliximab (6.25 mg/kg) was administered IP immediately after the OAB. The TUDCA suppressed the infiltration of the CD45-positive cells and decreased the mRNA and protein levels of the upregulated TNF-α and IL-1β in the cornea and retina of the OAB. Furthermore, the TUDCA treatment inhibited the retinal glial activation after an OAB. The TUDCA treatment not only ameliorated CNV and promoted corneal re-epithelization but also attenuated the RGC apoptosis and preserved the retinal structure after the OAB. Finally, the TUDCA reduced the expression of the endoplasmic reticulum (ER) stress molecules, IRE1, GRP78 and CHOP, in the retinal tissues of the OAB mice. The present study demonstrated that the TUDCA inhibits ocular inflammation and protects the cornea and retina from injury in an OAB mouse model. These results provide a potential therapeutic intervention for the treatment of an OAB.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Tauroursodeoxycholic Acid on Inflammation after Ocular Alkali Burn

Huang

Lin

Yang

et al. 2022

IJMS

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“…OAB is a detrimental event to the subjected eyes. It impacts both appearance and function, causing many fatal ocular complications [5][6][7][8]. The severe damage to the ocular surface is undoubtedly sight-threatening, resulting in corneal melting, exhaustion of limbal stem cells and eventually the decompensation of the ocular surface [4].…”

Section: Discussionmentioning

confidence: 99%

“…The severe damage to the ocular surface is undoubtedly sight-threatening, resulting in corneal melting, exhaustion of limbal stem cells and eventually the decompensation of the ocular surface [4]. Intraocular inflammation after OAB is another unignorable factor in several lethal disorders, including secondary glaucoma [1,2], complicated cataract, RGCs apoptosis [6][7][8], disfunction of the ciliary body, and even bulbi phthisis [39]. Thus, controlling intraocular inflammation is essential to restoring visual function in OAB patients.…”

Section: Discussionmentioning

confidence: 99%

“…Ocular alkali burn (OAB) is a common blinding disease in the working-age population, causing extensive damage to the ocular surface and anterior segment of the eye. Visual prognosis in severe cases of OAB is usually poor [1][2][3][4], because of numerous complications, including corneal opacity and perforation, corneal neovascularization, symblepharosis, glaucoma, cataract, and retinal ganglion cell damage [5][6][7][8]. It was believed decades ago that injuries to the ocular surface and intraocular tissue result from the direct impact of alkaline stimuli [9].…”

Section: Introductionmentioning

confidence: 99%

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Th17 Activation and Th17/Treg Imbalance in Prolonged Anterior Intraocular Inflammation after Ocular Alkali Burn

Yuan

Qian

Huang

et al. 2022

IJMS

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Ocular alkali burn (OAB) is a sight-threatening disease with refractory ocular inflammation causing various blinding complications. Th17 lymphocytes account for the pathogeneses of the autoimmune disease and chronic inflammation, but their role in prolonged anterior intraocular inflammation after OAB is still unknown. A rat OAB model was established for this purpose. Anterior intraocular inflammation was observed in both the acute and late phases of OAB, and histological examination confirmed the presence of inflammatory cell infiltration and fibrin exudation in the anterior segment. Luminex xMAP technology and qPCR were used to evaluate the intraocular levels of cytokines. The levels of IL-1β, IL-6, and TNF-α were significantly elevated during the acute phase. The expression of IL-17A gradually increased from day 7 onwards and remained at a relatively high level. Immunofluorescence was performed to identify Th17 cells. CD4 and IL-17A double positive cells were detected in the anterior chamber from days 7 to 28. Flow cytometry showed that the frequency of Th17 cells increased in both lymph nodes and spleen, while the frequency of Treg cells remained unchanged, resulting in an elevated Th17/Treg ratio. The present study suggests that Th17 activation and Th17/Treg imbalance account for prolonged anterior intraocular inflammation after OAB.

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The prophylactic value of TNF-α inhibitors against retinal cell apoptosis and optic nerve axon loss after corneal surgery or trauma

Paschalis

Zhou

Sharma

et al. 2022

Preprint

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Background and Purpose: Late secondary glaucoma is an often severe complication after acute events like anterior segment surgery, trauma, infection, etc. TNF-α is a major mediator that is rapidly upregulated, diffusing also to the retina and causes apoptosis of the ganglion cells and degeneration of their optic nerve axons (mediating steps to glaucomatous damage). Anti-TNF-α antibodies are in animals very effective in protecting the ganglion cells and the optic nerve - and might therefore be useful prophylactically against secondary glaucoma in patients. Here we evaluate 1) toxicity and 2) efficacy of two TNF-α inhibitors (adalimumab and infliximab), in rabbits by subconjunctival administration. Methods: For drug toxicity, animals with normal, unburned corneas were injected with adalimumab (0.4, 4, or 40 mg), or infliximab (1, 10, or 100 mg). For drug efficacy, other animals were subjected to alkali burn before such injection, or steroids. The rabbits were evaluated clinically with slit lamp and photography, electroretinography, optical coherence tomography, and intraocular pressure manometry. Some eyes were stained ex vivo after 3 days for retinal ganglion cell apoptosis (TUNEL). In other experiments the optic nerves were evaluated with paraphenylenediamine staining after 50 or 90 days. Loss of retinal ganglion cells and optic nerve degeneration were quantified. Results: Subconjunctival administration of 0.4 mg or 4.0 mg adalimumab were well tolerated, whereas 40.0 mg was toxic to the retina. 1, 10, or 100 mg infliximab were also well tolerated. Analysis of the optic nerve axons after 50 days confirmed the safety of 4.0 mg adalimumab or of 100 mg infliximab. For efficacy, 4.0 mg adalimumab subconjunctivally in 0.08 mL provided practically full protection against ganglion cell apoptosis 3 days following alkali burn, and infliximab 100 mg only slightly less. At 90 days following a burn, the control optic nerve showed about 50% axon loss but only about 8% if protected with adalimumab. Conclusions: Subconjunctival injection of 4.0 mg adalimumab in rabbits shows no eye toxicity and provides excellent neuroprotection, short (3 days) and long-term (90 days). Our total accumulated data from several studies,z combined with the present paper, suggest that corneal injuries, including surgery, might benefit from routine administration of anti-TNF-α biologics to reduce inflammation and future secondary glaucoma.

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Inhibition of endoplasmic reticulum stress by 4-phenylbutyrate alleviates retinal inflammation and the apoptosis of retinal ganglion cells after ocular alkali burn in mice

Cited by 4 publications

References 54 publications

Effect of Tauroursodeoxycholic Acid on Inflammation after Ocular Alkali Burn

Effect of Tauroursodeoxycholic Acid on Inflammation after Ocular Alkali Burn

Th17 Activation and Th17/Treg Imbalance in Prolonged Anterior Intraocular Inflammation after Ocular Alkali Burn

The prophylactic value of TNF-α inhibitors against retinal cell apoptosis and optic nerve axon loss after corneal surgery or trauma

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