Hyperbaric Oxygen Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice.
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ABSTRACT:
SUBMITTER: Yuan Y
PROVIDER: S-EPMC8211992 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although exertional dyspnea and worsening hypoxia are hallmark clinical features of idiopathic pulmonary fibrosis (IPF), no drug currently available could treat them. GBT1118 is a novel orally bioavailable small molecule that binds to hemoglobin and produces a concentration-dependent left shift of the oxygen-hemoglobin dissociation curve with subsequent increase in hemoglobin-oxygen affinity and arterial oxygen loading. To assess whether pharmacological modification of hemoglobin-oxygen affinity could ameliorate hypoxemia associated with lung fibrosis, we evaluated GBT1118 in a bleomycin-induced mouse model of hypoxemia and fibrosis. After pulmonary fibrosis and hypoxemia were induced, GBT1118 was administered for eight consecutive days. Hypoxemia was determined by monitoring arterial oxygen saturation, while the severity of pulmonary fibrosis was assessed by histopathological evaluation and determination of collagen and leukocyte levels in bronchoalveolar lavage fluid. We found that hemoglobin modification by GBT1118 had strong antihypoxemic therapeutic effects with improved arterial oxygen saturation to near normal level. Moreover, GBT1118 treatment significantly attenuated bleomycin-induced lung fibrosis, collagen accumulation, body weight loss, and leukocyte infiltration. This study is the first to suggest the beneficial effects of hemoglobin modification in fibrotic lungs and offers a promising and novel therapeutic strategy for the treatment of hypoxemia associated with chronic fibrotic lung disorders in human, including IPF.
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Project description:Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. Inflammation plays an integral role in the development of pulmonary fibrosis. Unresolved inflammatory responses can lead to substantial tissue injury, chronic inflammation, and fibrosis. The resolvins are a family of endogenous ω-3 fatty acid derived-lipid mediators of inflammation resolution. Resolvin D1 (RvD1) displays potent anti-inflammatory, pro-resolving activity, without causing immunosuppression. Its epimer, 17(R)-resolvin D1 (17(R)-RvD1), exhibits equivalent functionality to RvD1. In addition, 17(R)-RvD1 is resistant to rapid inactivation by eicosanoid oxidoreductases. In the present study, we tested the hypothesis that 17(R)-RvD1 can provide a therapeutic benefit in IPF by reducing inflammation and pulmonary fibrosis, while leaving the normal immune response intact. Mice were exposed to bleomycin (BLM) via micro-osmotic pump to induce pulmonary fibrosis, and were then treated with 17(R)-RvD1 or vehicle by intraperitoneal injection. Administration of 17(R)-RvD1 from the start of BLM treatment attenuated neutrophil alveolar infiltration, lung collagen content, and Interleukin-1β (IL-1β), transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), and type I collagen mRNA expression, along with subsequent reduction in histologically detectable fibrosis. The 17(R)-RvD1-induced infiltration of inflammatory cells was inhibited by an antagonist of lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2). The administration of 17(R)-RvD1 at the later fibrotic stage also improved the lung failure. These results suggest that 17(R)-RvD1 attenuates pulmonary fibrosis by promoting the resolution of neutrophilic inflammation and also provides pulmonary restoration. These data highlight the therapeutic potential of 17(R)-RvD1 in the management of this intractable disease.
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Project description:Protectin DX (10S,17S-dihydroxydocosa-4Z,7Z,11E,13Z,15E,19Z-hexaenoic acid) (PDX), generated from Ω-3 fatty docosahexaenoic acids, is believed to exert anti-inflammatory and proresolution bioactions. To date, few studies have been performed regarding its effect on pulmonary fibrosis. Herein we show that PDX exerts a potential therapeutic effect which is distinct from its anti-inflammation and pro-resolution activity on mice with pulmonary fibrosis. In the present study, we showed that bleomycin (BLM) increased inflammatory infiltration, collagen deposition, and lung dysfunction on day7 after challenged in mice. Posttreatment with PDX ameliorated BLM-induced inflammatory responses, extracellular matrix (ECM) deposition and the level of cytokines related to fibrosis as evaluated by histology analysis, transformation electron microscope (TEM), lung hydroxyproline content and cytokines test. Moreover, PDX improved lung respiratory function, remedied BLM-induced hypoxemia and prolonged life span. In addition, we found that PDX reversed epithelial-mesenchymal transition (EMT) phenotypic transformation in vivo and in vitro, reinforcing a potential mechanism of promoting fibrosis resolution. In summary, our findings showed that posttreatment with PDX could ameliorate BLM-induced pulmonary fibrosis and lung dysfunction in mice and PDX may be considered as a promising therapeutic approached to fibrotic lung diseases.
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Project description:The progression of pulmonary fibrosis (PF) entails a complex network of interactions between multiple classes of molecules and cells, which are closely related to the vagus nerve. Stimulation of the vagus nerve increases fibrogenic cytokines in humans, therefore, activation of the nerve may promote PF. The hypothesis was tested by comparing the extent and severity of fibrosis in lungs with and without vagal innervation in unilaterally vagotomized mice. The results show that in vagotomized lungs, there were less collagen staining, less severe fibrotic foci (subpleural, peri-vascular and peri-bronchiolar lesions) and destruction of alveolar architecture; decreased collagen deposition (denervated vs intact: COL1α1, 19.1 ± 2.2 vs 22.0 ± 2.6 ng/mg protein; COL1α2, 4.5 ± 0.3 vs 5.7 ± 0.5 ng/mg protein; p < 0.01, n = 21) and protein levels of transforming growth factor beta and interleukin 4; and fewer myofibroblast infiltration (denervated vs intact: 1.2 ± 0.2 vs 3.2 ± 0.6 cells/visual field; p < 0.05, n = 6) and M2 macrophages [though the infiltration of macrophages was increased (denervated vs intact: 112 ± 8 vs 76 ± 9 cells/visual field; p < 0.01, n = 6), the percentage of M2 macrophages was decreased (denervated vs intact: 31 ± 4 vs 57 ± 9%; p < 0.05, n = 5)]. It indicated that the vagus nerve may influence PF by enhancing fibrogenic factors and fibrogenic cells.
| S-EPMC4542162 | biostudies-other
Project description:Ivermectin is a US Food and Drug Administration (FDA)-approved antiparasitic agent with antiviral and anti-inflammatory properties. Although recent studies reported the possible anti-inflammatory activity of ivermectin in respiratory injuries, its potential therapeutic effect on pulmonary fibrosis (PF) has not been investigated. This study aimed to explore the ability of ivermectin (0.6 mg/kg) to alleviate bleomycin-induced biochemical derangements and histological changes in an experimental PF rat model. This can provide the means to validate the clinical utility of ivermectin as a treatment option for idiopathic PF. The results showed that ivermectin mitigated the bleomycin-evoked pulmonary injury, as manifested by the reduced infiltration of inflammatory cells, as well as decreased the inflammation and fibrosis scores. Intriguingly, ivermectin decreased collagen fiber deposition and suppressed transforming growth factor-β1 (TGF-β1) and fibronectin protein expression, highlighting its anti-fibrotic activity. This study revealed for the first time that ivermectin can suppress the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, as manifested by the reduced gene expression of NLRP3 and the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), with a subsequent decline in the interleukin-1β (IL-1β) level. In addition, ivermectin inhibited the expression of intracellular nuclear factor-κB (NF-κB) and hypoxia‑inducible factor‑1α (HIF-1α) proteins along with lowering the oxidative stress and apoptotic markers. Altogether, this study revealed that ivermectin could ameliorate pulmonary inflammation and fibrosis induced by bleomycin. These beneficial effects were mediated, at least partly, via the downregulation of TGF-β1 and fibronectin, as well as the suppression of NLRP3 inflammasome through modulating the expression of HIF‑1α and NF-κB.
| S-EPMC10423969 | 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.
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Project description:Platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of pulmonary fibrosis. Nintedanib, a multi-kinase inhibitor that targets several tyrosine kinases, including PDGF receptor (PDGFR), was recently approved as an anti-fibrotic agent to reduce the deterioration of FVC in patients with idiopathic pulmonary fibrosis (IPF). However, the effects of PDGFR-? or -? on pulmonary fibrosis remain unclear. In an attempt to clarify their effects, we herein used blocking antibodies specific for PDGFR-? (APA5) and -? (APB5) in a bleomycin (BLM)-induced pulmonary fibrosis mouse model. The effects of these treatments on the growth of lung fibroblasts were examined using the 3H-thymidine incorporation assay in vitro. The anti-fibrotic effects of these antibodies were investigated with the Ashcroft score and collagen content of lungs treated with BLM. Their effects on inflammatory cells in the lungs were also analyzed using bronchoalveolar lavage fluid. We investigated damage to epithelial cells and the proliferation of fibroblasts in the lungs. APA5 and APB5 inhibited the phosphorylation of PDGFR-? and -? as well as the proliferation of lung fibroblasts induced by PDGF-AA and BB. The administration of APB5, but not APA5 effectively inhibited BLM-induced pulmonary fibrosis in mice. Apoptosis and the proliferation of epithelial cells and fibroblasts were significantly decreased by the treatment with APB5, but not by APA5. The late treatment with APB5 also ameliorated fibrosis in lungs treated with BLM. These results suggest that PDGFR-? and -? exert different effects on BLM-induced pulmonary fibrosis in mice. A specific approach using the blocking antibody for PDGFR-? may be useful for the treatment of pulmonary fibrosis.
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Project description:Pulmonary fibrosis (PF) is a progressive interstitial lung disease with limited treatment options. The incidence and prevalence of PF is increasing with age, cell senescence has been proposed as a pathogenic driver, the clearance of senescent cells could improve lung function in PF. FOXO4-D-Retro-Inverso (FOXO4-DRI), a synthesis peptide, has been reported to selectively kill senescent cells in aged mice. However, it remains unknown if FOXO4-DRI could clear senescent cells in PF and reverse this disease. In this study, we explored the effect of FOXO4-DRI on bleomycin (BLM)-induced PF mouse model. We found that similar as the approved medication Pirfenidone, FOXO4-DRI decreased senescent cells, downregulated the expression of senescence-associated secretory phenotype (SASP) and attenuated BLM-induced morphological changes and collagen deposition. Furthermore, FOXO4-DRI could increase the percentage of type 2 alveolar epithelial cells (AEC2) and fibroblasts, and decrease the myofibroblasts in bleomycin (BLM)-induced PF mouse model. Compared with mouse and human lung fibroblast cell lines, FOXO4-DRI is inclined to kill TGF-β-induced myofibroblast in vitro. The inhibited effect of FOXO4-DRI on myofibroblast lead to a downregulation of extracellular matrix (ECM) receptor interaction pathway in BLM-induced PF. Above all, FOXO4-DRI ameliorates BLM-induced PF in mouse and may be served as a viable therapeutic option for PF.
| S-EPMC9170815 | biostudies-literature
Project description:BACKGROUND: Antiflammin-1 (AF-1), a derivative of uteroglobin (UG), is a synthetic nonapeptide with diverse biological functions. In the present study, we investigated whether AF-1 has a protective effect against bleomycin-induced pulmonary fibrosis. METHODS: C57BL/6 mice were injected with bleomycin intratracheally to create an animal model of bleomycin-induced pulmonary fibrosis. On Day 7 and Day 28, we examined the anti-inflammatory effect and antifibrotic effect, respectively, of AF-1 on the bleomycin-treated mice. The effects of AF-1 on the transforming growth factor-beta 1 (TGF-?1)-induced proliferation of murine lung fibroblasts (NIH3T3) were examined by a bromodeoxycytidine (BrdU) incorporation assay and cell cycle analysis. RESULTS: Severe lung inflammation and fibrosis were observed in the bleomycin-treated mice on Day 7 and Day 28, respectively. Administration of AF-1 significantly reduced the number of neutrophils in the bronchoalveolar lavage fluid (BALF) and the levels of tumor necrosis factor-alpha (TNF-?) and interleukin-1 beta (IL-1?) in the lung homogenates on Day 7. Histological examination revealed that AF-1 markedly reduced the number of infiltrating cells on Day 7 and attenuated the collagen deposition and destruction of lung architecture on Day 28. The hydroxyproline (HYP) content was significantly decreased in the AF-1-treated mice. In vitro, AF-1 inhibited the TGF-?1-induced proliferation of NIH3T3 cells, which was mediated by the UG receptor. CONCLUSIONS: AF-1 has anti-inflammatory and antifibrotic actions in bleomycin-induced lung injury. We propose that the antifibrotic effect of AF-1 might be related to its suppression of fibroblast growth in bleomycin-treated lungs and that AF-1 has potential as a new therapeutic tool for pulmonary fibrosis.
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Project description:Loss of microRNA-29 (miR-29) is known to be a mechanism of transforming growth factor-β (TGF-β)-mediated pulmonary fibrosis, but the therapeutic implication of miR-29 for pulmonary fibrosis remains unexplored. The present study investigated whether miR-29 had therapeutic potential for lung disease induced by bleomycin in mice. In addition, the signaling mechanisms that regulated miR-29 expression were investigated in vivo and in vitro. We found that miR-29 was a downstream target gene of Smad3 and negatively regulated by TGF-β/Smad signaling in fibrosis. This was evidenced by the findings that mice or pulmonary fibroblasts null for Smad3 were protected against bleomycin or TGF-β1-induced loss of miR-29 along with fibrosis in vivo and in vitro. Interestingly, overexpression of miR-29 could in turn negatively regulated TGF-β and connective tissue growth factor (CTGF) expression and Smad3 signaling. Therefore, Sleeping Beauty (SB)-mediated miR-29 gene transfer into normal and diseased lung tissues was capable of preventing and treating pulmonary fibrosis including inflammatory macrophage infiltration induced by bleomycin in mice. In conclusion, miR-29 is negatively regulated by TGF-β/Smad3 and has a therapeutic potential for pulmonary fibrosis. SB-mediated miR-29 gene therapy is a non-invasive therapeutic strategy for lung disease associated with fibrosis.
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