stilbenes and Pulmonary-Fibrosis

Polydatin (PD) is a polyphenolic compound found naturally in many fruits such as grapes. It has anti-oxidant and anti-inflammatory activities that are of paramount importance for its pharmacological actions. This study aimed to explore possible protective effects of PD against methotrexate (MTX)-induced pulmonary fibrosis in rats. A single oral dose of MTX (14 mg/kg) per week for 2 weeks caused a significant decrease in glutathione (GSH) content with a marked increase in transforming growth factor-beta (TGF-β), alpha-smooth muscle actin (α-SMA), pulmonary content of malondialdehyde (MDA), interleukin-1β (IL-1β), Hydroxyproline, tumor necrosis factor-alpha (TNF-α), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as compared with the control group. Contrarily, daily administration of PD (25, 50, and 100 mg/kg, p.o.) for 14 days concomitantly with MTX ameliorated MTX-induced pulmonary fibrosis as indicated by mitigation of the previously mentioned biochemical parameters and histopathological changes in a dose-dependent manner. In conclusion, the protective effect of PD against pulmonary fibrosis induced by MTX in rats might be attributed to its anti-oxidant, anti-inflammatory as well as anti-fibrotic effects.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Glucosides; Glutathione; Methotrexate; Oxidative Stress; Pulmonary Fibrosis; Rats; Stilbenes

Pulmonary fibrosis (PF) is characterized by oxidative injury and excessive collagen synthesis in lung fibroblasts, causing impaired pulmonary function and chronic lung injury. Piceatannol, a dietary polyphenol, possesses vital pharmacological effects in metabolic disorders, cancers, cardiovascular disease and infectious disease; however, its role in PF is still not completely elucidated. Mice (8 to 10 weeks old) were administered bleomycin (BLM) intratracheally (2 U/kg) to establish an in vivo PF model. Murine primary lung fibroblasts were isolated and stimulated with TGF-β (10 ng/mL) for 48 h to induce its activation. Meanwhile, mice or primary lung fibroblasts were treated with different doses of piceatannol to observe its protective roles. Pulmonary function and arterial blood gas were detected to assess pulmonary physiological status. Collagen deposition and the mRNA levels of profibrotic genes were determined by H&E staining and RT-PCR. Meanwhile, the protein and mRNA markers, as well as end-product of oxidative stress were detected in vivo and in vitro. The results showed that pulmonary function was significantly impaired in BLM-induced mice, accompanied by elevated oxidative stress and excessive collagen synthesis. Piceatannol significantly improved pulmonary function and decreased oxidative injury as well as collagen synthesis in mice with PF. Mechanically, piceatannol treatment significantly inhibited the activation of JAK2/STAT3 signaling pathway in BLM-induced mice and TGF-β-induced lung fibroblasts. Additional findings also demonstrated that coumermycin A1 (C-A1), an agonist of JAK2, could abolish the effects of piceatannol on TGF-β-induced lung fibroblasts and reactivated the phosphorylation STAT3. Taken together, our study demonstrated that piceatannol could protect against oxidative injury and collagen synthesis during PF in a JAK2/STAT3 signaling pathway-dependent manner.

Topics: Animals; Bleomycin; Collagen; Fibroblasts; Janus Kinase 2; Lung; Mice; Mice, Inbred C57BL; Oxidative Stress; Pulmonary Fibrosis; RNA, Messenger; Signal Transduction; Stilbenes; Transforming Growth Factor beta

Early pulmonary fibrosis after acute lung injury leads to poor prognosis and high mortality. Pterostilbene (Pts), a bioactive component in blueberries, possesses anti-inflammatory, antioxidative and antifibrotic properties. However, the effects of Pts on lipopolysaccharide (LPS)-induced pulmonary fibrosis are still unknown. In our study, the Pts group showed lower lung injury and fibrosis scores, and lower levels of hydroxyproline and protein (collagen I and transforming growth factor-β) than the scores and levels in mice treated with LPS. MMP-1 was the degrading enzyme of collagen I and LPS caused the inhibition of MMP-1, disturbing the degradation of collagen. Additionally, Pts remarkably reversed the LPS-induced inhibition of interleukin-10 and the release of tumor necrosis factor-α, interleukin-6 and interleukin-1β. In terms of cellular pathways, Pts treatment ameliorated LPS-activated nuclear factor kappa B (NF-κB) and NOD-like receptor NLRP3 signaling. Besides, LPS-induced low levels of A20 could be activated by Pts. In addition, Pts treatment reversed the high levels of Caspase-3, poly ADP-ribose polymerase (PARP) and Bcl2-associated X protein (Bax) expression and the low levels of B cell lymphoma/lewkmia-2 (Bcl2) that had been induced by LPS. Moreover, oxidative stress is also involved in the pathogenesis of fibrosis. Our findings indicate that LPS injection triggered the production of myeloperoxidase (MPO) and malondialdehyde (MDA) and the depletion of superoxide dismutase (SOD) and glutathione (GSH), and that these effects were notably reversed by treatment with Pts. In addition, Pts induced the dissociation of Kelch-like epichlorohydrin-associated protein-1 (Keap-1) and NF-E2 related factor-2 (Nrf2) and the activation of downstream genes (heme oxygenase-1, NAD(P)H:quinine oxidoreductase, glutamate-cysteine ligase catalytic subunit and glutamate-cysteine ligase modifier). In conclusion, oxidative stress, apoptosis and inflammation are involved in early pulmonary fibrosis and Pts exerts a protective effect by activating Keap-1/Nrf2, inhibiting caspase-dependent A20/NF-κB and NLRP3 signaling pathways.

Topics: Animals; Antioxidants; Apoptosis; Blueberry Plants; Disease Models, Animal; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred Strains; Oxidative Stress; Phytotherapy; Pulmonary Fibrosis; Rabbits; Random Allocation; Stilbenes

Mycoplasma pneumoniae (MP) can infect both the upper and lower respiratory tracts. Polydatin (PD), a traditional Chinese medicine, is known to have anti-inflammation and antifibrosis properties. However, the protective effects of PD against MP pneumonia (MPP) remain unclear. So, the aim of this study was to describe the therapeutic effects and underlying mechanisms of PD against MPP. BALB/c mice were assigned to three groups: a normal control group, MP infection group, or PD-treated MP infection group. BEAS-2B cells transfected with or without NACHT domain-, leucine-rich repeat-, and pyd-containing protein 3 (NLRP3) were used to confirm the protective mechanisms of PD. Immunohistochemical analysis, Western blot analysis, enzyme-linked immunosorbent assay, and flow cytometry were used in this study. The results showed that PD treatment suppressed MP-induced lung injury in mice by suppressing the expression of inflammatory factors and inhibiting the development of pulmonary fibrosis. Meanwhile, PD treatment inhibited activation of the NLRP3 inflammasome and nuclear factor κB (NF-κB) pathway. Overexpression of NLRP3 reversed the protective effect of PD against MP-induced injury of BEAS-2B cells. Taken together, these results indicate that PD treatment suppressed the inflammatory response and the development of pulmonary fibrosis by inhibiting the NLRP3 inflammasome and NF-κB pathway after MP infection.

Topics: Animals; Cell Line; Drugs, Chinese Herbal; Epithelial Cells; Glucosides; Humans; Inflammasomes; Lung; Mice, Inbred BALB C; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pneumonia; Pneumonia, Mycoplasma; Protective Agents; Pulmonary Fibrosis; Signal Transduction; Stilbenes

To explore the molecular mechanism of Res in regulation of pulmonary fibrosis (PF).. Rats were injected with bleomycin (BLM) to establish a PF model and treated with resveratrol (Res) and/or miR-21 agomir. After 14 days, lung tissues were collected for Hematoxylin-eosin and Masson's staining, and real-time quantitative polymerase chain reaction and Western blot were performed to detect fibrosis-related protein expression and the activation of the TGF-β1/Smad pathway. In vitro, MRC-5 cells were pretreated with TGF-β1, Res, and/or miR-21 agomir. After 48 h, total soluble collagen was detected with a Sircol Soluble Collagen Assay. Subsequently, a miR-21 mimic was transfected into MRC-5 cells, and a luciferase reporter assay was employed to verify whether miR-21 targeted Smad7.. Res reversed the increased levels of miR-21 induced by BLM and alleviated serious PF symptoms, but agomiR-21 treatment effectively impaired the above manifestations. In vivo, miR-21 inhibited the decreases of TGF-β1 and p-Smad2/3 that were induced by Res. In vitro, miR-21 significantly disrupted the positive effect of Res on TGF-β-induced collagen deposition, as well as the levels of Fn, α-SMA, p-Smad2, and Smad7. In addition, Smad7 was found to be a direct target of miR-21-5p. TGF-β stimulation led to an enormous increase in p-c-Jun, c-Jun, and c-Fos, which were significantly reduced by Res. Finally, miR-21 sharply reduced the increased phosphorylation levels of ERK, JNK and p38 that were induced by Res.. Res inhibits BLM-induced PF by regulating miR-21 through MAPK/AP-1 pathways.

Topics: Animals; Antioxidants; Disease Models, Animal; Female; Gene Expression Regulation; Male; MAP Kinase Signaling System; MicroRNAs; Pulmonary Fibrosis; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Transcription Factor AP-1

Pulmonary fibrosis is a scaring process related to chronic lung injury of all causes. The treatment options for pulmonary fibrosis are very limited. Rhapontin has anti-inflammatory effect and anti-proliferative activity which is widely distributed in the medicinal plants of Rheum genus in China. However, the anti-fibrotic activities of rhapontin have not been previously investigated.. The effect of rhapontin on TGF-β1-mediated extracellular matrix (ECM) deposition in primary lung fibroblast (PLF) cells, on TGF-β1 secretion in LPS-stimulated human THP-1 derived macrophages in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis was investigated in vivo. Fibrotic mice were induced by intratracheal instillation of bleomycin, and then treated with rhapontin (25, 50, or 100mg/kg/day) or prednisone (6.5mg/kg/day, positive drug) for 2weeks.. In TGF-β1 stimulated PLFs, treatment with rhapontin resulted in a reduction of ECM with a decrease in Lox2 and p-Smad2/3. In LPS activated macrophages, treatment with rhapontin reduced TGF-β1 production. However, in vitro the attenuated ECM deposition and inflammatory response by rhapontin were closely associated with AMPK activation, and these suppression of rhapontin were significantly abolished by the AMPK inhibitor. Treatment with rhapontin for 2weeks resulted in an amelioration of the BLM-induced pulmonary fibrosis in rats with a lower Lox2, whereas a higher AMPK expression, with reductions of the pathological score, collagen deposition, TGF-β1, α-SMA, Lox2, and HIF-1α expressions in lung tissues at fibrotic stage at 100mg/kg.. In summary, rhapontin reversed ECM, as well as Lox2 proliferation in vitro and prevented pulmonary fibrosis in vivo by modulating AMPK activation and suppressing the TGF-β/Smad pathway.

Topics: Animals; Bleomycin; Extracellular Matrix; Fibroblasts; Humans; Lipopolysaccharides; Lung; Macrophages; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred C57BL; Models, Animal; Pulmonary Fibrosis; Rheum; Signal Transduction; Smad Proteins; Stilbenes; THP-1 Cells; Transforming Growth Factor beta1

Oxidative stress leads to alveolar epithelial cell injury and fibroblast-myofibroblast differentiation (FMD), key events in the pathobiology of pulmonary fibrosis (PF). Sirtuin 3 (SIRT3) is a mitochondrial protein deacetylase regulator of antioxidant response and mitochondrial homeostasis. Here, we demonstrate reduced SIRT3 expression in the lungs of old mice compared to young mice, as well as in two murine models of PF. The analysis of the pattern of SIRT3 expression in the lungs of patients with PF revealed low SIRT3 staining within the fibrotic regions. We also demonstrated, using murine models of PF and human lung fibroblasts, that reduced SIRT3 expression in response to transforming growth factor beta 1 (TGFβ1) promotes acetylation (inactivation) of major oxidative stress response regulators, such as SOD2 and isocitrate dehydrogenase 2. Reduction of SIRT3 in human lung fibroblasts promoted FMD. By contrast, overexpression of SIRT3 attenuated TGFβ1-mediated FMD and significantly reduced the levels of SMAD family member 3 (SMAD3). Resveratrol induced SIRT3 expression and ameliorated acetylation changes induced by TGFβ1. We demonstrated that SIRT3-deficient mice are more susceptible to PF compared to control mice, and concomitantly exhibit enhanced SMAD3 expression. Collectively, these data define a SIRT3/TGFβ1 interaction during aging that may play a significant role in the pathobiology of PF.

Topics: Aging; Animals; Cell Differentiation; Disease Models, Animal; Down-Regulation; Fibroblasts; Humans; Isocitrate Dehydrogenase; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Pulmonary Fibrosis; Resveratrol; Sirtuin 3; Smad3 Protein; Stilbenes; Superoxide Dismutase; Transforming Growth Factor beta1

The aim of this study was to investigate the effect of resveratrol on the idiopathic bleomycin (BLM)-induced pulmonary fibrosis, which is increasingly recognized as an epithelial-to-mesenchymal transition (EMT)-associated disease.. We evaluated the effect of resveratrol on the BLM-induced fibrosis in a mouse model, via monitoring the pathological chance in mice lung, the mice body weight change and the mice death. And we also explored the regulation by BLM on (and) resveratrol on the expression and activity of Sirt 1 and on the expression of epithelial-to-mesenchymal transition (EMT)-associated markers in mice lung.. It was demonstrated that resveratrol ameliorated the BLM-induced fibrosis-like pathological change in mice lung, inhibited BLM-induced mice body weight loss and death. Moreover, resveratrol also inhibited the BLM-induced EMT-associated molecular events, such as reduced E-cadherin and elevated Collagen I and α-SMA. We also confirmed the amelioration by resveratrol on the BLM-mediated inhibition of Sirt 1 in expression and activity in mice lung.. Our study confirmed the inhibitory role of resveratrol in the BLM-induced pulmonary fibrosis in a mouse model. Resveratrol ameliorated the BLM-induced pathological change of fibrosis, mice body weight loss and death. And such amelioration might be associated with the activation of Sirt 1 in mice lung. The present study implied that resveratrol might be a promising agent for effective control the pulmonary fibrosis.

Topics: Animals; Bleomycin; Cadherins; Enzyme Activation; Epithelial-Mesenchymal Transition; Mice; Pulmonary Fibrosis; Resveratrol; Sirtuin 1; Stilbenes

This study was designed to examine whether resveratrol exerts the protective effects on LPS and cigarette smoke (LC)-induced COPD in a murine model. In lung histopathological studies, H&E, Masson's trichrome, and AB-PAS staining were performed. The cytokines (IL-6, IL-17, TGF-β, and TNF-α) and inflammatory cells in BALF were determined. The Beclin1 level in the lungs of mouse was analyzed. Compared with the LC-induced mouse, the level of inflammatory cytokines (IL-17, IL-6, TNF-α, and TGF-β) of the BALF in the resveratrol + cigarette smoke-treated mouse had obviously decreased. Histological examination of the lung tissue revealed that the resveratrol treatment attenuated the fibrotic response and mucus hypersecretion. In addition, resveratrol inhibited the expression of the Beclin1 protein in mouse lungs. The presented findings collectively suggest that resveratrol has a therapeutic effect on mouse LC-induced COPD, and its mechanism of action might be related to reducing the production of the Beclin1 protein.

Topics: Animals; Beclin-1; Bronchoalveolar Lavage Fluid; Cytokines; Lipopolysaccharides; Lung; Mice; Mucus; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Resveratrol; Smoke; Stilbenes

Fibrotic changes seem to be responsible for the high mortality rate observed in patients with acute respiratory distress syndrome (ARDS). The present study aimed to determine whether resveratrol, a natural antioxidant polyphenol, had anti-fibrotic effects in the murine model of lipopolysaccharide (LPS)-induced pulmonary fibrosis.. Fibrosis was assessed by determination of collagen deposition, hydroxyproline and type I collagen levels in lung tissues. Development of epithelial-mesenchymal transition (EMT) was identified by the loss of E-cadherin accompanying by the acquisition of α-smooth muscle actin (α-SMA). Transforming growth factor (TGF)-β1 content, levels of phosphorylated Smad2/Smad3 and Smad4, malondialdehyde (MDA) content, total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, and catalase (CAT) activity in lung tissues were determined.. LPS increased collagen deposition, hydroxyproline and type I collagen contents, and meanwhile induced EMT process, stimulated TGF-β1 production and Smad activation in lung tissues on day 21 to day 28 after LPS administration. In addition, LPS treatment resulted in a rapid induction of oxidative stress as evidenced by increase of MDA and decreases of T-AOC, CAT and SOD activities as early as 7 days after LPS treatment, which was persistent for at least 4 weeks. In contrast, resveratrol treatment attenuated LPS-induced EMT and pulmonary fibrosis, meanwhile it suppressed LPS-induced oxidative stress, TGF-β1 production and activation of Smad signaling pathway.. Resveratrol may ameliorate LPS-induced EMT and pulmonary fibrosis through suppression of oxidative stress and TGF-β1/Smad signaling pathway. Application of antioxidants may represent a useful adjuvant pharmacologic approach to reduce ARDS-associated pulmonary fibrosis.

Topics: Animals; Catalase; Collagen Type I; Disease Models, Animal; Epithelial-Mesenchymal Transition; Lipopolysaccharides; Male; Malondialdehyde; Mice; Mice, Inbred ICR; Oxidative Stress; Pulmonary Fibrosis; Resveratrol; Signal Transduction; Stilbenes; Superoxide Dismutase; Transforming Growth Factor beta1

Polyphenols have been described to have a wide range of biological activities, and many reports, published during recent years, have highlighted the beneficial effects of phenolic compounds, illustrating their promising role as therapeutic tools in several acute and chronic disorders. The purpose of study was to evaluate, in an already-assessed model of lung injury caused by bleomycin (BLM) administration, the role of resveratrol and quercetin, as well as to explore the potential beneficial properties of a mango leaf extract, rich in mangiferin, and a grape leaf extract, rich in dihydroquercetin (DHQ), on the same model. Mice were subjected to intra-tracheal administration of BLM, and polyphenols were administered by oral route immediately after BLM instillation and daily for 7 d. Treatment with resveratrol, mangiferin, quercetin and DHQ inhibited oedema formation and body weight loss, as well as ameliorated polymorphonuclear infiltration into the lung tissue and reduced the number of inflammatory cells in bronchoalveolar lavage fluid. Moreover, polyphenols suppressed inducible nitric oxide synthase expression, and prevented oxidative and nitroxidative lung injury, as shown by the reduced nitrotyrosine and poly (ADP-ribose) polymerase levels. The degree of apoptosis, as evaluated by Bid and Bcl-2 balance, was also suppressed after polyphenol treatment. Finally, these natural products down-regulated cyclo-oxygenase-2, extracellular signal-regulated kinase phosphorylated expression and reduced NF-κBp65 translocation. Our findings confirmed the anti-inflammatory effects of resveratrol and quercetin in BLM-induced lung damage, and highlight, for the first time, the protective properties of exogenous administration of mangiferin and DHQ on experimental pulmonary fibrosis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apoptosis; Dietary Supplements; Disease Models, Animal; Lung; Male; Mangifera; Mice, Inbred ICR; Neutrophil Infiltration; Plant Extracts; Plant Leaves; Polyphenols; Pulmonary Fibrosis; Quercetin; Random Allocation; Respiratory Mucosa; Resveratrol; Stilbenes; Vitis; Xanthones

Resveratrol has a preventive potential on bleomycin-induced pulmonary fibrosis in prophylactic use; however, it was not studied in the treatment of the fibrosis. This study investigated the role of resveratrol on the treatment of bleomycin-induced pulmonary fibrosis. Intratracheal bleomycin (2.5 mg/kg) was given in fibrosis groups and saline in controls. First dose of resveratrol was given 14 days after bleomycin and continued until sacrifice. On 29th day, fibrosis in lung was estimated by Aschoft's criteria and hydroxyproline content. Bleomycine increased the fibrosis score (3.70 ± 1.04) and hydroxyproline levels (4.99 ± 0.90 mg/g tissue) as compared to control rats (1.02 ± 0.61 and 1.88 ± 0.59 mg/g), respectively. These were reduced to 3.16 ± 1.58 (P = 0.0001) and 3.08 ± 0.73 (P > 0.05), respectively, by resveratrol. Tissue malondialdehyde levels in the bleomycin-treated rats were higher (0.55 ± 0.22 nmol/mg protein) than that of control rats (0.16 ± 0.07; P = 0.0001) and this was reduced to 0.16 ± 0.06 by resveratrol (P = 0.0001). Tissue total antioxidant capacity is reduced (0.027 ± 0.01) by bleomycine administration when compared control rats (0.055 ± 0.012 mmol Trolox Equiv/mg protein; P = 0.0001) and increased to 0.041 ± 0.008 (P = 0.001) by resveratrol. We concluded that resveratrol has some promising potential on the treatment of bleomycin-induced pulmonary fibrosis in rats. However, different doses of the drug should be further studied.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Bleomycin; Bronchoalveolar Lavage Fluid; Cell Count; Hydroxyproline; Idiopathic Pulmonary Fibrosis; Lung; Male; Malondialdehyde; Oxidative Stress; Pulmonary Fibrosis; Random Allocation; Rats; Rats, Wistar; Resveratrol; Stilbenes

The authors investigated the role of resveratrol (RV), a natural poliphenolic molecule with several biological activities, in transforming growth factor-β (TGF-β)-induced proliferation and differentiation of ex vivo human pulmonary fibroblasts into myofibroblasts. The effects of RV treatment were evaluated by analyzing TGF-β-induced α-smooth muscle actin (α-SMA) expression and collagen production, as well as cell proliferation of both normal and idiopathic pulmonary fibrosis (IPF) lung fibroblasts. Results demonstrate that RV inhibits TGF-β-induced cell proliferation of both normal and pathological lung fibroblasts, attenuates α-SMA expression at both the mRNA and protein levels, and also inhibits intracellular collagen deposition. In order to understand the molecular mechanisms, the authors also investigated the effects of RV treatment on signaling pathways involved in TGF-β-induced fibrosis. The authors show that RV inhibited TGF-β-induced phosphorylation of both extracellular signal-regulated kinases (ERK1/2) and the serine/threonine kinase, Akt. Moreover, RV treatment blocked the TGF-β-induced decrease in phosphatase and tensin homolog (PTEN) expression levels.

Topics: Actins; Cell Differentiation; Cell Line; Cell Proliferation; Collagen; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Gene Expression; Humans; Lung; Myofibroblasts; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Pulmonary Fibrosis; Resveratrol; RNA, Messenger; Signal Transduction; Stilbenes; Transforming Growth Factor beta

To observe the effects of three different doses of polydatin (PD) on pulmonary interstitial fibrosis in rats induced by bleomycin.. One hundred and twenty-nine healthy Sprague-Dawley rats three months old, were randomly divided into six groups. Group A: normal control group; group B: model group treated with bleomycin (pretreatment with saline 1 mL x kg(-1) intraperitoneally before bleomycin); group C: PD 10 mg x kg(-1) (pretreatment with PD 10 mg x kg(-1) intraperitoneally before bleomycin); group D: PD 20 mg x kg(-1) (pretreatment with PD 20 mg x kg(-1) intraperitoneally before bleomycin); group E: PD 40 mg x kg(-1) (pretreatment with PD 40 mg x kg(-1) intraperitoneally before bleomycin), group F: dexamethason (DXM) treated group (pretreatment with saline 1 mL x kg(-1) intraperitoneally before bleomycin and then with DXM 1 mg x kg(-1) x d(-1)). At day 3, 7, 14, 28 after injection of bleomycin, eight rats in each group were randomly chosen to be killed. The right lungs of dead rats were removed and appropriately processed for hematoxylin and eosin (H&E) stain, histologically observed under light microscope. The hydroxyproline content and the PLA2 activity in pulmonary homogenate were measured with alkaline hydrolysis assay and acid modified microtitrimetic method. The levels of leukotriene C4 (LTC4), prostaglandin E2 (PGE2), transforming growth factor-beta1 (TGF-beta1) in bronchoalveolar lavage fluid (BALF) were measured with enzyme-linked immunosorbent assay (ELISA).. At day 3, 7, 14, 28 after intratracheal instillation of bleomycin in rats of group B, the PLA2 activity in lung homogenate and the levels of its metabolic products PGE2, LTC4 as well as TGF-beta1 in BALF increased significantly compared with those in group A (P < 0.01). And lung hydroxyproline concentration began to grow up markedly at day 7 compared with those in group A (P < 0.05), reaching its maximum at day 28. Compared with group B, three different doses of PD and DXM significantly reduced the activity of the PLA2 and hydroxyproline concentration in lung homogenate as well as the levels of PGE2, LTC4, TGF-beta1 in BALF at various periods (P < 0.05). There was statistically significant difference between three different doses of PD groups (P < 0.05). And the group E (PD 40 mg x kg(-1)) was lower than group D (PD 20 mg x kg(-1)), group D was lower than group C (PD 10 mg x kg(-1)) (respectively, P < 0.01). Group E and DXM group were no significant difference. However, all these observation parameters were higher than the normal level (compared with group A, P < 0.01). Histological studies revealed that it was showed less inflammation and a lower degree of fibrosis in the lungs treated with PD than bleomycin model group.. PD has the protective effect on pulmonary interstitial fibrosis. However, it can't completely block the process of pulmonary fibrosis.

Topics: Animals; Bleomycin; Dinoprostone; Drugs, Chinese Herbal; Female; Glucosides; Leukotriene C4; Male; Phospholipases A2; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Stilbenes

Antioxidant therapy may be useful in diseases with impaired oxidant-antioxidant balance such as pulmonary fibrosis. This study was designed to examine the effects of resveratrol, an antioxidant agents, against bleomycin-induced pulmonary fibrosis and oxidative damage. Wistar albino rats were administered a single dose of bleomycin (5 mg/kg; via the tracheal cannula) followed by either saline or resveratrol (10 mg/kg; orally) for 14 days. The effect of resveratrol on pulmonary oxidative damage was studied by cell count and analysis of cytokine levels (TGF-beta, TNF-alpha, IL-1beta and IL-6) in the bronchoalveolar lavage fluid (BALF) and biochemical measurements of malondialdehyde (MDA), an end product of lipid peroxidation; glutathione (GSH), a key antioxidant; and myeloperoxidase (MPO) activity, an index of neutrophil infiltration, in the lung tissue. Bleomycin-induced lung fibrosis was determined by lung collagen contents and also microscopically. Bleomycin caused a significant decrease in lung GSH, which was accompanied with significant increases in MDA level, MPO activity, and collagen contents of the lung tissue concomitant with increased levels of the pro-inflammatory mediators and cell count in BALF. On the other hand, resveratrol treatment reversed all these biochemical indices as well as histopathological alterations induced by bleomycin. The results demonstrate the role of oxidative mechanisms in bleomycin-induced pulmonary fibrosis, and resveratrol, by its antioxidant properties, ameliorates oxidative injury and fibrosis due to bleomycin. Thus, an effective supplement with resveratrol as an adjuvant therapy may be a very promising agent in alleviating the side effects of bleomycin, an effective chemotherapeutic agent.

Topics: Administration, Oral; Animals; Antibiotics, Antineoplastic; Antioxidants; Bleomycin; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Glutathione; Lipid Peroxidation; Lung; Male; Malondialdehyde; Neutrophil Infiltration; Peroxidase; Pulmonary Fibrosis; Rats; Rats, Wistar; Resveratrol; Stilbenes