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Protective effects of hypercapnic acidosis on Ischemia-reperfusion-induced retinal injury.

ABSTRACT: Ischemia-reperfusion (I/R) injury is associated with numerous retinal diseases, such as diabetic retinopathy, acute glaucoma, and other vascular retinopathies. Hypercapnic acidosis (HCA) has a protective effect on lung, myocardial, and central nervous system ischemic injury models. However, no study has evaluated its protective effects in an experimental retinal I/R injury model. In this study, retinal I/R injury was induced in Sprague Dawley rats by elevating the intraocular pressure to 110 mmHg for 60 minutes. HCA was induced before and after the injury. After 24 hours, the terminal dUTP nick end labeling assay was performed. Moreover, the ratios of cleaved caspase-3/total caspase-3, phosphorylated I?B/I?B, and phosphorylated p38 were measured through Western blotting. After 7 days, the rats' aqueous humor was analyzed. In addition, electroretinography and retinal thickness measurement were performed in the rats. Moreover, the retinal neural cell line RGC-5 was exposed to 500 ?M H2O2 for 24 hours to induce a sustained oxidative stress in vitro. The effects of HCA were evaluated by comparing oxidative stress, MAPK signals, NF-?B signals, survival rates, and apoptosis rates in the RGC-5 cells before and after H2O2 exposure. We further investigated whether the potent I/R-protective heat shock protein (HSP) 32 contribute to protective effects of HCA. Our results indicated that HCA has protective effects against retinal I/R injury both in vivo and in vitro, at multiple levels, including antiapoptotic, anti-inflammatory, antioxidative, and functional retinal cell protection. Further research clarifying the role of HCA in retinal I/R injury prevention and treatment is warranted.

SUBMITTER: Lin LT

PROVIDER: S-EPMC6347245 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Protective effects of hypercapnic acidosis on Ischemia-reperfusion-induced retinal injury.

Lin Le-Tien LT Chen Jiann-Torng JT Tai Ming-Cheng MC Chen Yi-Hao YH Chen Ching-Long CL Pao Shu-I SI Hsu Cherng Ru CR Liang Chang-Min CM

PloS one 20190125 1

Ischemia-reperfusion (I/R) injury is associated with numerous retinal diseases, such as diabetic retinopathy, acute glaucoma, and other vascular retinopathies. Hypercapnic acidosis (HCA) has a protective effect on lung, myocardial, and central nervous system ischemic injury models. However, no study has evaluated its protective effects in an experimental retinal I/R injury model. In this study, retinal I/R injury was induced in Sprague Dawley rats by elevating the intraocular pressure to 110 mmH ...[more]

PMID: 30682118

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Project description:Hypercapnic acidosis (HCA) has protective effects in animal models of acute lung injury, but the mechanism underlying the effect of HCA is unclear. Heme oxygenase-1 (HO-1) is an antioxidant enzyme that protects tissue from inflammation injury. We investigated whether HO-1 contributes to the protective effects of HCA in ischemia-reperfusion (IR)-induced lung injury. Typical acute lung injury in rats was successfully induced by 40 min of ischemia and 90 min of reperfusion in an isolated perfused lung model. The rat lungs were randomly assigned to the control group, IR group or IR + HCA group with or without zinc protoporphyrin IX (ZnPP), an HO-1 activity inhibitor. At the end of the experiment, bronchoalveolar lavage fluid (BALF) and lung tissues were collected to evaluate the degree of lung injury. In in vitro experiments, HO-1 siRNA transfected A549 cells were exposed to a normoxic or hypoxia-reoxygenation (H/R) environment in the presence or absence of HCA. IR caused significant increases in the pulmonary arterial pressure, lung weight to body weight and wet/dry ratios, lung weight gain, capillary filtration coefficient, lung injury scores, neutrophil infiltration, and concentrations of protein and TNF-? in the BALF. IR also induced degradation of inhibitor of nuclear factor (NF)-?B-?, increased I?B kinase (IKK)-? phosphorylation and nuclear translocation of NF-?B, and up-regulated HO-1 expression and activity. Furthermore, IR decreased Bcl-2 protein expression and increased the number of active caspase-3 stained cells. HCA treatment enhanced HO-1 expression and activity, and accordingly reduced IKK-NF-?B signaling, inhibited apoptosis, and significantly attenuated IR-induced changes. Treatment with ZnPP partially blocked the protective effect of HCA. In addition, HO-1 siRNA significantly reversed HCA-mediated inhibition of NF-?B signaling in A549 cells subjected to H/R. In conclusion, the protective effect of HCA in IR lung injury in rats was mediated in part by the anti-inflammatory and anti-apoptotic action of HO-1.

Project description:Ischemic stroke is one of the most common causes of mortality worldwide and is a primary cause of disability and mortality in adults. There is an unmet need for drugs that can effectively treat ischemic stroke. Hence, the present study explored the neuroprotective effects of andrographolide (Andro) in a mouse model of bilateral common carotid artery occlusion, and systematically evaluated the potential mechanisms underlying its effects. The effects of Andro on mouse brain tissue following cerebral ischemia‑reperfusion injury (CIRI) were evaluated by histopathological (H&E and Nissl) and immunofluorescence [glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN)] staining. A traditional Chinese medicine‑based network pharmacology method was performed to establish and analyze compound‑target‑disease and function‑pathway networks in order to elucidate the possible mechanisms responsible for the protective role of Andrographis paniculata in CIRI. In addition, western blot analysis and RT‑qPCR was performed to evaluate the expression and activation of signaling proteins predicted to be involved in this mechanism. The amelioration of histopathological alterations was observed in mice pre‑treated with Andro. Immunofluorescence staining revealed that Andro decreased the expression of GFAP and increased the expression of NeuN, and significantly decreased the levels of pro‑inflammatory cytokines (IL‑1β, IL‑6 and TNF‑α). Network pharmacology analysis revealed that neuroinflammatory response and apoptosis were associated with the effects of Andrographis paniculata on CIRI. Western blot analysis revealed that the mice pre‑treated with Andro exhibited an upregulated protein expression of tropomyosin receptor kinase B (TrkB), p‑PI3K and p‑Akt, as well as a decrease in the expression of GFAP and an increase in the expression of NeuN. In addition, the data of RT‑qPCR indicated that the mice pre‑treated with Andro exhibited a significantly decreased expression of encoding IL‑1β mRNA, IL‑6 mRNA and TNF‑α mRNA in the brain compared to the untreated mice following CIRI. On the whole, the findings of the present study suggest that pre‑treatment with Andro exerts a protective effect against CIRI, which may be partly related to its potential to reduce neuroinflammatory response and apoptosis in patients with stroke.

Project description:Ischemia-reperfusion (I/R) events are involved in the development of various ocular pathologies, e.g., retinal artery or vein occlusion. We tested the hypothesis that resveratrol is protective against I/R injury in the murine retina. Intraocular pressure (IOP) was elevated in anaesthetized mice to 110 mm Hg for 45 min via a micropipette placed in the anterior chamber to induce ocular ischemia. In the fellow eye, which served as control, IOP was kept at a physiological level. One group received resveratrol (30 mg/kg/day p.o. once daily) starting one day before the I/R event, whereas the other group of mice received vehicle solution only. On day eight after the I/R event, mice were sacrificed and retinal wholemounts were prepared and immuno-stained using a Brn3a antibody to quantify retinal ganglion cells. Reactivity of retinal arterioles was measured in retinal vascular preparations using video microscopy. Reactive oxygen species (ROS) and nitrogen species (RNS) were quantified in ocular cryosections by dihydroethidium and anti-3-nitrotyrosine staining, respectively. Moreover, hypoxic, redox and nitric oxide synthase gene expression was quantified in retinal explants by PCR. I/R significantly diminished retinal ganglion cell number in vehicle-treated mice. Conversely, only a negligible reduction in retinal ganglion cell number was observed in resveratrol-treated mice following I/R. Endothelial function and autoregulation were markedly reduced, which was accompanied by increased ROS and RNS in retinal blood vessels of vehicle-exposed mice following I/R, whereas resveratrol preserved vascular endothelial function and autoregulation and blunted ROS and RNS formation. Moreover, resveratrol reduced I/R-induced mRNA expression for the prooxidant enzyme, nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2). Our data provide evidence that resveratrol protects from I/R-induced retinal ganglion cell loss and endothelial dysfunction in the murine retina by reducing nitro-oxidative stress possibly via suppression of NOX2 upregulation.

Project description:BackgroundRetinal function is ordered by interactions between transcriptional and posttranscriptional regulators at the molecular level. These regulators include transcription factors (TFs) and posttranscriptional factors such as microRNAs (miRs). Some studies propose that miRs predominantly target the TFs rather than other types of protein coding genes and such studies suggest a possible interconnection of these two regulators in co-regulatory networks.ResultsOur lab has generated mRNA and miRNA microarray expression data to investigate time-dependent changes in gene expression, following induction of ischemia-reperfusion (IR) injury in the rat retina. Data from different reperfusion time points following retinal IR-injury were analyzed. Paired expression data for miRNA-target gene (TG), TF-TG, miRNA-TF were used to identify regulatory loop motifs whose expressions were altered by the IR injury paradigm. These loops were subsequently integrated into larger regulatory networks and biological functions were assayed. Systematic analyses of the networks have provided new insights into retinal gene regulation in the early and late periods of IR. We found both overlapping and unique patterns of molecular expression at the two time points. These patterns can be defined by their characteristic molecular motifs as well as their associated biological processes. We highlighted the regulatory elements of miRs and TFs associated with biological processes in the early and late phases of ischemia-reperfusion injury.ConclusionsThe etiology of retinal ischemia-reperfusion injury is orchestrated by complex and still not well understood gene networks. This work represents the first large network analysis to integrate miRNA and mRNA expression profiles in context of retinal ischemia. It is likely that an appreciation of such regulatory networks will have prognostic potential. In addition, the computational framework described in this study can be used to construct miRNA-TF interactive systems networks for various diseases/disorders of the retina and other tissues.

Dataset Information

Protective effects of hypercapnic acidosis on Ischemia-reperfusion-induced retinal injury.

Publications

Protective effects of hypercapnic acidosis on Ischemia-reperfusion-induced retinal injury.

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