Chronic intermittent hypoxia worsens bleomycin-induced lung fibrosis in rats.
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ABSTRACT:
SUBMITTER: Braun RK
PROVIDER: S-EPMC5659967 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
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Chronic intermittent hypoxia worsens bleomycin-induced lung fibrosis in rats.
Braun Rudolf K RK Broytman Oleg O Braun Felix M FM Brinkman Jacqueline A JA Clithero Andrew A Modi Dhruvangkumar D Pegelow David F DF Eldridge Marlowe M Teodorescu Mihaela M
Respiratory physiology & neurobiology 20170427
Obstructive sleep apnea (OSA) has been linked to increased mortality in pulmonary fibrosis. Its key feature, chronic intermittent hypoxia (CIH), can lead to oxidative stress and inflammation, known to lead to fibrotic pathology in other organs. We tested the effects of CIH in an animal model of bleomycin-induced lung fibrosis. Sprague Dawley rats were instilled intratracheally with bleomycin (Blm) or saline (Sal), and exposed to CIH or normal air (Norm) for 9 or 30 days. Pulmonary function was t ...[more]
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Project description:PurposeChronic intermittent hypoxia (CIH) causes lung injury but the mechanism is unclear. Ferroptosis is a novel form of programmed cell death. In this research, we attempted to explore the role of ferroptosis in CIH-induced lung injury both in vitro and in vivo.MethodsSprague-Dawley rats were randomly separated into control group, CIH group and CIH + ferrostatin-1 group (CIH + Fer-1). Rats in the CIH group and CIH + Fer-1 group were exposed to intermittent hypoxia for 12 weeks. Human bronchial epithelial cell line (BEAS-2B) was cultivated for 24 h in either conventional culture medium or under CIH conditions. Fer-1 was applied to observe its treatment effects. Histological changes were evaluated by Hematoxylin-eosin (HE) staining and masson staining. The expression levels of Acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), interleukin-6 (IL-6) and tumour necrosis factor α (TNFα) were detected via qRT-PCR or Western blot. Cell counting kit-8 (CCK-8) was used to assess cell viability. The apoptotic rate and reactive oxygen species (ROS) was calculated by flow cytometry.ResultsHistology showed that CIH treatment induced lung injury and pulmonary fibrosis in lung tissue. After Fer-1 treatment, the pathological changes caused by CIH alleviated. The mRNA and protein levels of GPX4 decreased significantly in lung tissues of CIH-treated rats and BEAS-2B, (p < 0.05). The mRNA and protein levels of ACSL4 increased significantly in lung tissues of CIH-treated rats and BEAS-2B, (p < 0.05). The mRNA levels of IL-6 and TNFα in BEAS-2B increased after CIH treatment, (p < 0.05). Cell viability decreased, apoptosis rate and ROS increased in CIH-treated BEAS-2B, (p < 0.05). Cotreatment with Fer-1 reversed CIH-induced apoptosis, cell viability, ROS accumulation, mRNA and protein levels of GPX4, ACSL4, IL-6 and TNFα both in vitro and in vivo (p < 0.05).ConclusionsFerroptosis occurred in CIH-induced lung injury, both in vitro and in vivo. The ferroptosis inhibitor Fer-1 alleviated cell injury and ferroptosis in CIH-treated BEAS-2B and lung tissues of rats.
| S-EPMC9793575 | biostudies-literature
Project description:BackgroundObstructive sleep apnoea (OSA) induced chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH). Our study investigate the mechanism underlying CIH-induced renal damage and whether the cannabinoid receptor 1 (CB1R) antagonist rimonabant (Ri) alleviates CIH-induced renal injury.MethodsMale Sprague-Dawley rats were randomly divided into five groups: one normal control (NC) group, two chronic intermittent hypoxia (CIH) groups, and two CIH + Ri groups. Rats in the NC groups were exposed to room air, while the CIH groups were exposed to a CIH environment for 4 weeks (4w CIH group) and 6 weeks (6w CIH group), respectively. Additionally, rats in the CIH + Ri groups were administered 1.5 mg/kg/day Ri for 4 weeks (4w CIH + Ri group) and 6 weeks (6w CIH + Ri group), respectively. Following this, the rats were euthanized and kidneys were excised for downstream analysis. In the renal tissues, the morphological alterations were examined via haematoxylin eosin (HE) staining and periodic acid schiff (PAS) staining, CB1R, Fis1, Mfn1, and p66Shc expression was assessed through western blot and immunohistochemistry, and the mitochondrial ultrastructural changes in kidney sections were assessed by electron microscopy.ResultsCB1R expression in the 4w and 6w CIH groups was significantly elevated, and further increased with prolonged hypoxia; however, Ri prevented the increase in CIH-induced CB1R expression. Fis1 and p66Shc expression in the CIH groups were increased, but Mfn1 expression decreased. Ri decreased Fis1 and p66Shc expression and increased Mfn1 expression. Renal damage in the 4w or 6w CIH + Ri group was evidently improved compared with that in the 4w or 6w CIH group. CB1R expression was positively correlated with Fis1 and p66Shc and negatively correlated with Mfn1. Meanwhile, electron microscopy showed that the percentage of fragmented mitochondria in the tubular cells in each group was consistent with the trend of CB1R expression.ConclusionCIH causes endocannabinoid disorders and induces abnormal mitochondrial dynamics, resulting in renal injury. Treatment with CB1R antagonists reduces CIH-induced renal damage by inhibiting dysregulated renal mitochondrial dynamics.
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Project description:Chronic LPS inhalation causes submucosal thickening and airway narrowing. To address the hypothesis that environmental airway disease is, in part, a fibroproliferative lung disease, we exposed C57BL/6 mice daily to LPS by inhalation for up to two months followed by one month of recovery. C57BL/6 mice exposed to daily inhaled LPS had significantly enhanced mRNA expression of TGF-beta1, TIMP-1, fibronectin-1, and pro-collagen types I, III, and IV and show prominent submucosal expression of the myofibroblast markers desmin and alpha-smooth muscle actin. To identify novel candidate genes that contribute to airway fibroproliferation, we performed microarray analysis on total lung RNA from mice exposed to LPS for one week. This analysis revealed a distinct subset of genes known to regulate ECM homeostasis. To further identify candidate genes specifically involved in generic fibroproliferation we interrogated this analysis with genes induced in C57BL/6 mouse lung by bleomycin. This analysis yielded a list of 212 genes in common. Prominent among which are genes know to be important in maintenance of bone homeostasis and which may play a central role in ECM homeostasis in the lung. These results suggest that there is a common subset of genes that regulate fibroproliferation in the lung independent of etiologic agent and site of injury. Keywords: mouse model of pulmonary fibrosis; timecourse
2008-03-01 | GSE8553 | GEO
Project description:Purpose:Atrial remodeling takes part in the pathogenesis of atrial fibrillation (AF). Aliskiren, as a direct renin inhibitor, has been shown to exert protective effects against arrhythmia. The aim of this study was to investigate the potential role of aliskiren in atrial remodeling in a chronic intermittent hypoxia (CIH) rat model. Methods:A total of 45 Sprague-Dawley rats were randomly assigned into three groups (n=15 per group): control group; CIH group; and CIH with aliskiren (CIH-A) group. CIH and CIH-A rats were subjected to CIH for 6 h per day for 4 weeks. Atrial fibrosis was evaluated using Masson's trichrome staining. Electrophysiological tests were conducted in the isolated perfused hearts to assess the atrial effective refractory period and inducibility of AF. Atrial ionic remodeling was measured using the whole-cell patch-clamp technique, and Western blotting and real-time quantitative polymerase chain reactionwere performed to evaluate changes in ion channels. Results:CIH induced obvious collagen deposition, and the abnormal fibrosis was significantly attenuated by aliskiren. The inducibility of AF was increased significantly in the CIH group compared with the control and CIH-A groups (23±24.5% vs 2.0±4.2% vs 5.0±7.0%, respectively; P<0.05). Compared with the control group, the densites of the calcium current (I CaL) and sodium current (I Na) were reduced significantly in the CIH group (I CaL: -3.16±0.61 pA/pF vs -7.13±1.98 pA/pF; I Na: -50.97±8.71 pA/pF vs -132.58±25.34 pA/pF, respectively; all P<0.05). Following intervention with aliskiren, the reductions in I CaL and I Na were significantly improved, and the ionic modeling changes assessed at the mRNA and protein levels were also significantly improved. Conclusion:CIH could alter atrial modeling and subsequently promote the occurrence and development of AF, which could be attenuated by treatment with aliskiren.
| S-EPMC7502603 | biostudies-literature
Project description:Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality, which have been attributed to intermittent hypoxia (IH). The effects of IH on lung structure and function are unknown. We used a mouse model of chronic IH, which mimics the O(2) profile in patients with OSA. We exposed adult C57BL/6J mice to 3 mo of IH with a fraction of inspired oxygen (F(I)(O(2))) nadir of 5% 60 times/h during the 12-h light phase. Control mice were exposed to room air. Lung volumes were measured by quasistatic pressure-volume (PV) curves under anesthesia and by water displacement postmortem. Lungs were processed for morphometry, and the mean airspace chord length (Lm) and alveolar surface area were determined. Lung tissue was stained for markers of proliferation (proliferating cell nuclear antigen), apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling), and type II alveolar epithelial cells (surfactant protein C). Gene microarrays were performed, and results were validated by real-time PCR. IH increased lung volumes by both PV curves (air vs. IH, 1.16 vs. 1.44 ml, P < 0.0001) and water displacement (P < 0.01) without changes in Lm, suggesting that IH increased the alveolar surface area. IH induced a 60% increase in cellular proliferation, but the number of proliferating type II alveolocytes tripled. There was no increase in apoptosis. IH upregulated pathways of cellular movement and cellular growth and development, including key developmental genes vascular endothelial growth factor A and platelet-derived growth factor B. We conclude that IH increases alveolar surface area by stimulating lung growth in adult mice.
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Project description:The balancing functions of pro/anti-inflammatory mediators of the complex innate responses have been investigated in a variety of experimental inflammatory settings. Annexin-A1 (AnxA1) is one mediator of endogenous anti-inflammation, affording regulation of leukocyte trafficking and activation in many contexts, yet its role in lung pathologies has been scarcely investigated, despite being highly expressed in lung cells. Here we have applied the bleomycin lung fibrosis model to AnxA1 null mice over a 21-day time-course, to monitor potential impact of this mediator on the control of the inflammatory and fibrotic phases.Analyses in wild-type mice revealed strict spatial and temporal regulation of the Anxa1 gene, e.g. up-regulation in epithelial cells and infiltrated granulocytes at day 7, followed by augmented protein levels in alveolar macrophages by day 21. Absence of AnxA1 caused increases in: i) the degree of inflammation at day 7; and ii) indexes of fibrosis (assessed by deposition of hydroxyproline in the lung) at day 7 and 21. These alterations in AnxA1 null mice were paralleled by augmented TGF-?1, IFN-? and TNF-? generation compared to wild-type mice. Finally, treatment of wild type animals with an AnxA1 peptido-mimetic, given prophylactically (from day 0 to 21) or therapeutically (from day 14 onward), ameliorated both signs of inflammation and fibrosis.Collectively these data reveal a pathophysiological relevance for endogenous AnxA1 in lung inflammation and, more importantly, fibrosis, and may open new insights for the pharmacological treatment of lung fibrosis.
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Project description:BackgroundJinlian Xiaodu Decoction (JXD) was reported to have anti-inflammatory and lung protection effects. This study aimed to explore the role and mechanism of JXD on bleomycin (BLM)-induced pulmonary fibrosis (PF).MethodsThe UHPLC-Q/TOF-MS system was applied to analyze JXD composition. The PF model was established by BLM intratracheal administration in Wistar rats. Subsequently, BLM-treated rats were intragastrically administered with dexamethasone (DXM, 1 g/kg/d) or JXD (3.5, 7 or 14 g/kg/d). Next, the lung coefficient was calculated; H&E, Masson, and TUNEL staining were used for lung morphological analysis and apoptosis assessment. Bronchoalveolar lavage fluid (BALF) biochemical analysis was conducted to count the inflammatory cell number. The expression of inflammatory factors mRNA in the lung tissue and BALF were measured by qRT-PCR. The content and activity of oxidative stress-related proteins were detected. The expression of PF-related, apoptosis-related, and TGF-β1 pathway-related protein were assessed by immunohistochemistry or Western blot.ResultsTwenty-six compounds were identified from JXD in both negative and positive ion modes. In BLM-induced rats, JXD reduced the lung coefficient and alleviated PF injury. JXD decreased inflammatory cell count and TNF-α, IL-1β, IL-6, and MCP-1 content. Meanwhile, JXD blunted BLM-induced oxidative stress and a high level of HYP. Furthermore, TUNEL analysis found that JXD inhibited cell apoptosis and increased Bcl-2/Bax ratio in BLM-induced lung. Moreover, JXD relieved the role of BLM on α-SMA, TGF-β1, collagen I, fibronectin, E-cadherin protein expression, and the phosphorylation of Smad2/3 in PF rat.ConclusionThis study revealed the protective effect and possible element of JXD on BLM-caused PF.
| S-EPMC9246571 | biostudies-literature
Project description:BackgroundRecent evidence has demonstrated the role of angiogenesis in the pathogenesis of pulmonary fibrosis. Endostatin, a proteolytic fragment of collagen XVIII, is a potent inhibitor of angiogenesis. The aim of our study was to assess whether endostatin has beneficial effects on bleomycin (BLM)-induced pulmonary fibrosis in rats.MethodsThe rats were randomly divided into five experimental groups: (A) saline only, (B) BLM only, (C) BLM plus early endostatin treatment, (D) BLM plus late endostatin treatment, and (F) BLM plus whole-course endostatin treatment. We investigated the microvascular density (MVD), inflammatory response and alveolar epithelial cell apoptosis in rat lungs in each group at different phases of disease development.ResultsEarly endostatin administration attenuated fibrotic changes in BLM-induced pulmonary fibrosis in rats. Endostatin treatment decreased MVD by inhibiting the expression of VEGF/VEGFR-2 (Flk-1) and the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). Endostatin treatment also decreased the number of inflammatory cells infiltrating the bronchoalveolar lavage fluid during the early inflammatory phase of BLM-induced pulmonary fibrosis. In addition, the levels of tumour necrosis factor-α (TNF-α) and transforming growth factor β1 (TGF-β1) were reduced by endostatin treatment. Furthermore, endostatin decreased alveolar type II cell apoptosis and had an epithelium-protective effect. These might be the mechanism underlying the preventive effect of endostatin on pulmonary fibrosis.ConclusionsOur findings suggest that endostatin treatment inhibits the increased MVD, inflammation and alveolar epithelial cell apoptosis, consequently ameliorating BLM-induced pulmonary fibrosis in rats.
| S-EPMC3668162 | biostudies-literature
Project description:Aims: This study aimed to characterize circular RNA (circRNA) profiles associated with atrial fibrosis-related atrial fibrillation (AF) and reveal critical circRNAs for AF. Methods: Sprague Dawley rats were randomly divided into control and atrial fibrosis-related AF groups (n = 15 in each group). The rats in the atrial fibrosis-related AF group were induced by chronic intermittent hypoxia (CIH), and then confirmed by electrocardiograms, echocardiography, hematoxylin-eosin staining, Masson staining, immunohistochemistry assays and western blotting. After that, the atrial tissues were sent for circRNA sequencing, and the differentially expressed circRNAs were identified and validated by quantitative real-time polymerase chain reaction (qRT-PCR). Finally, a series of cell experiments were performed to explore the roles of two crucial circRNAs in rat atrial fibroblasts. Results: A CIH-induced AF model was successfully established in the rats. After sequencing, five upregulated and 11 downregulated circRNAs were identified in the CIH-induced AF group. These dysregulated circRNAs were primarily associated with "carbohydrate metabolism" and "cardiovascular diseases". Two circRNAs (circRNA_0263 and circRNA_1507) were predicted to regulate target gene expression by interacting with corresponding miRNAs, including rno-miR-29b-5p, rno-miR-29b-3p, rno-miR-496-5p, rno-miR-136-5p, and novel123-mature. Additionally, circRNA_0263 knockdown and circRNA_1507 overexpression inhibited the cell viability of fibroblasts, and downregulated the expression of fibrosis-related proteins. Conclusion: A series of circRNAs were identified as dysregulated in an AF rat model, and circRNA_0263 and circRNA_1507 might be crucial for atrial fibrosis-related AF development by competing with several miRNAs.
| S-EPMC9908462 | biostudies-literature