Protective effects of curcumin against amiodarone-induced pulmonary fibrosis in rats.
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ABSTRACT:
SUBMITTER: Punithavathi D
PROVIDER: S-EPMC1573957 | biostudies-other | 2003 Aug
REPOSITORIES: biostudies-other
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Project description:Inhalation of crystalline silica particles leads to pulmonary fibrosis, eventually resulting in respiratory failure and death. There are few effective drugs that can delay the progression of this disease; thus, patients with silicosis are usually only offered supportive care. Dioscin, a steroidal saponin, exhibits many biological activities and health benefits including its protective effects against hepatic fibrosis. However, the effect of dioscin on silicosis is unknown.We employed experimental mouse mode of silicosis. Different doses of dioscin were gavaged to the animals 1 day after crystalline silica instillation to see the effect of dioscin on crystalline silica induced pulmonary fibrosis. Also, we used RAW264.7 and NIH-3T3 cell lines to explore dioscin effects on macrophages and fibroblasts. Dioscin was also oral treatment but 10 days after crystalline silica instillation to see its effect on established pulmonary fibrosis.Dioscin treatment reduced pro-inflammation and pro-fibrotic cytokine secretion by modulating innate and adaptive immune responses. It also reduced the recruitment of fibrocytes, protected epithelial cells from crystalline silica injury, inhibited transforming growth factor beta/Smad3 signaling and fibroblast activation. Together, these effects delayed the progression of crystalline silica-induced pulmonary fibrosis. The mechanism by which dioscin treatment alleviated CS-induced inflammation appeared to be via the reduction of macrophage, B lymphocyte, and T lymphocte infiltration into lung. Dioscin inhibits macrophages and fibroblasts from secreting pro-inflammatory cytokines and may also function as a modulator of T helper cells responses, concurrent with attenuated phosphorylation of the apoptosis signal-regulating kinase 1-p38/c-Jun N-terminal kinase pathway. Also, dioscin could block the phosphorylation of Smad3 in fibroblast. Oral treatment of dioscin could also effectively postpone the progression of established silicosis.Oral treatment dioscin delays crystalline silica-induced pulmonary fibrosis and exerts pulmonary protective effects in mice. Dioscin may be a novel and potent candidate for protection against crystalline silica-induced pulmonary fibrosis.
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Project description:BackgroundIncreased expression of nitric oxide synthase (NOS) and an increase in plasma nitrite plus nitrate (NOx) have been reported in patients with pulmonary fibrosis, suggesting that nitric oxide (NO) plays an important role in its development. However, the roles of the entire NO and NOS system in the pathogenesis of pulmonary fibrosis still remain to be fully elucidated. The aim of the present study is to clarify the roles of NO and the NOS system in pulmonary fibrosis by using the mice lacking all three NOS isoforms.MethodsWild-type, single NOS knockout and triple NOS knockout (n/i/eNOS-/-) mice were administered bleomycin (BLM) intraperitoneally at a dose of 8.0 mg/kg/day for 10 consecutive days. Two weeks after the end of the procedure, the fibrotic and inflammatory changes of the lung were evaluated. In addition, we evaluated the effects of long-term treatment with isosorbide dinitrate, a NO donor, on the n/i/eNOS-/- mice with BLM-induced pulmonary fibrosis.ResultsThe histopathological findings, collagen content and the total cell number in bronchoalveolar lavage fluid were the most severe/highest in the n/i/eNOS-/- mice. Long-term treatment with the supplemental NO donor in n/i/eNOS-/- mice significantly prevented the progression of the histopathological findings and the increase of the collagen content in the lungs.ConclusionsThese results provide the first direct evidence that a lack of all three NOS isoforms led to a deterioration of pulmonary fibrosis in a BLM-treated murine model. We speculate that the entire endogenous NO and NOS system plays an important protective role in the pathogenesis of pulmonary fibrosis.
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Project description:Amiodarone (AD) is an iodinated benzofuran derivative, especially known for its antiarrhythmic properties. It exerts serious side-effects even in patients receiving low doses. AD is well-known to induce apoptosis of type II alveolar epithelial cells (AECII), a mechanism that has been suggested to play an important role in AD-induced lung fibrosis. The precise molecular mechanisms underlying this disease are, however, still unclear. Because of its amphiphilic nature, AD becomes enriched in the lysosomal compartments, affecting the general functions of these organelles. Hence, in this study, we aimed to assess the role of autophagy, a lysosome-dependent homeostasis mechanism, in driving AECII apoptosis in response to AD. In vitro, AD-treated MLE12 and primary AECII cells showed increased proSP-C and LC3B positive vacuolar structures and underwent LC3B-dependent apoptosis. In addition, AD-induced autophagosome-lysosome fusion and increased autophagy flux were observed. In vivo, in C57BL/6 mice, LC3B was localised at the limiting membrane of lamellar bodies, which were closely connected to the autophagosomal structures in AECIIs. Our data suggest that AD causes activation of macroautophagy in AECIIs and extensive autophagy-dependent apoptosis of alveolar epithelial cells. Targeting the autophagy pathway may therefore represent an attractive treatment modality in AD-induced 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.
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Project description:Idiopathic pulmonary fibrosis (IPF) involves alveolar epithelial injury and abnormal collagen production caused by activated fibroblasts; transforming growth factor (TGF)-?1 is implicated in this activation. In this study, we screened for chemicals capable of inhibiting TGF-?1-induced collagen production in cultured fibroblasts from medicines already in clinical use. We selected felodipine based on its extent of collagen production inhibition, clinical safety profile, and other pharmacological activity. Felodipine is a dihydropyridine Ca2+ channel blocker that has been used clinically to treat patients with high blood pressure. Felodipine suppressed collagen production within LL29 cells in the presence of TGF-?1, but not in its absence. Intratracheal administration of felodipine prevented bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction. Felodipine also improved pulmonary fibrosis, as well as lung and respiratory function when administered after fibrosis development. Furthermore, administration of felodipine suppressed a bleomycin-induced increase in activated fibroblasts in the lung. We also found other dihydropyridine Ca2+ channel blockers (nifedipine and benidipine) inhibited collagen production in vitro and partially prevented bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction in vivo. We propose that these Ca2+ channel blockers may be therapeutically beneficial for IPF patients.
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Project description:Idiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 Th2 T cells, but its signaling receptor IL-31RA is primarily expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31RA deficiency in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including extracellular matrix and epithelial cell-associated gene networks. Furthermore, the lungs of human IPF showed an elevated expression of IL-31 when compared to healthy subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. Thus, therapeutic targeting the IL-31-IL-31RA axis may prevent collagen deposition, improve lung function, and have therapeutic potential in pulmonary fibrosis.
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Project description:Rhodiola rosea L. (RRL) possesses a wide range of pharmacological properties, including lung-protective activity, and has been utilized in folk medicine for several 100 years. However, the lung-protective mechanism remains unclear. This study investigated the possible lung-protective activity mechanism of RRL in a pulmonary fibrosis (PF) rat model. Lung fibrotic injury was induced in Sprague-Dawley rats by single intratracheal instillation of saline containing bleomycin (BLM; 5 mg/kg). The rats were administered 125, 250, or 500 mg/kg of a 95% ethanol extract of RRL for 28 days. The animals were killed to detect changes in body weight, serum levels of glutathione (GSH) and total superoxide dismutase (T-SOD), as well as lung tissue hydroxyproline (HYP) content. Tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), and interleukin 6 (IL-6) levels were measured in bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assay. Hematoxylin and eosin, Masson's trichrome, and immunohistochemical staining were performed to observe the histopathological changes in lung tissues. Additionally, target-related proteins were measured by Western blotting. RRL alleviated the loss of body weight induced by instilling BLM in PF rats, particularly at the 500 mg/kg per day dose. RRL reduced HYP (p < 0.01) and increased GSH and T-SOD contents. BALF levels of TNF-α, TGF-β1, and IL-6 decreased significantly in the RRL-treated groups. Expression levels of matrix metalloproteinase-9 (MMP-9) and α-smooth muscle actin decreased significantly in a dose-dependent manner in response to RRL. Moreover, the levels of TGF-β1 and tissue inhibitor of metalloproteinase-1 in lung tissues also decreased in the RRL-treated groups. RRL alleviated BLM-induced PF in rats. Our results reveal that the protective effects of RRL against fibrotic lung injury in rats are correlated with its anti-inflammatory, antioxidative, and anti-fibrotic properties. MMP-9 may play important roles in BLM-induced PF.
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Project description:Gastric ulcers are among the most broadly perceived illnesses affecting individuals. Alcohol consumption is the main cause of gastric ulceration. This study assessed the protective effects of Salvadora persica (SP) extract against ethanol-induced gastric ulcer and elucidated the conceivable underlying mechanisms involved. For this purpose, 40 rats were allotted into 4 equal groups (control, ethanol- (EtOH-) treated, and SP-treated "SP200 and SP400" groups). The control and EtOH-treated groups were given phosphate buffer saline (PBS), and both the SP200 and SP400 groups were given SP extract dissolved in PBS at doses of 200 and 400?mg/kg b.w., respectively. All treatments were given orally for 7 constitutive days. On the 8th day, all rats were fasted for 24?h followed by oral gavage of PBS in the control group and chilled absolute ethanol solution (5?ml/kg b.w.) in the EtOH- and SP-treated groups to induce gastric lesions. One hour later, the rats were sacrificed and the stomachs were harvested. Gross and microscopic examinations of the EtOH-treated group showed severe gastric hemorrhagic necrosis, submucosal edema, destruction of epithelial cells, and reduced glycoprotein content at the mucus surface. These pathological lesions were defeated by SP extract treatment. Administration of SP extract modulated the oxidative stress and augmented the antioxidant defenses. The elevated ethanol-expressed tumor necrosis factor-? (TNF-?) and interleukin-1? (IL-1?) genes, as well as bcl-2-like protein 4 (Bax) and inducible nitric oxide synthase (iNOS), were diminished in the SP-treated group. Curiously, SP extract upregulated endothelial nitric oxide synthase (eNOS) and transforming growth factor-?1 (TGF-?1) gene expression comparable to that of the EtOH-treated rats. Aggregately, SP exerted antiulcer activities in ethanol-induced gastric ulcer rat models via modulation of oxidant/antioxidant status, mitigation of proinflammatory cytokines, and apoptosis, as well as remodeling of both NOS isoforms.
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