curcumin and Pulmonary-Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by interstitial remodeling, leading to compromised lung function. Extra vascular fibrin deposition and abnormalities in the fibrinolysis are the major clinical manifestations of lung diseases such as acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS). ALI progresses to pulmonary fibrosis (PF) and makes patient's life miserable. Anti-fibrinolysis and apoptosis are involved in the progression of PF. Apoptotic markers are detectable within IPF lung tissue and senescent cell deletion can rejuvenate pulmonary health. Enhanced expression of p53 due to DNA damage is seen in irradiated lung tissue. The role of fibrinolytic components such as Urokinase Plasminogen activator (uPA), uPA receptor (uPAR) and Plasminogen activator inhibitor-1 (PAI-1) has been detailed in I. Curcumin is known to possess anti-inflammatory and anti-fibrotic effects. Radioprotective effect of curcumin enables it to attenuate radiation-induced inflammation and fibrosis. Understanding the mechanism of radioprotective effect of curcumin in radiation-induced PF and apoptosis can lead to the development of an effective therapeutic to combat acute lung injury and fibrosis.

Topics: Animals; Apoptosis; Curcumin; Humans; Pulmonary Fibrosis; Radiation Injuries; Radiation-Protective Agents

Acute lung injury (ALI) is characterized by acute inflammation and tissue injury results in dysfunction of the alveolar epithelial membrane. If the epithelial injury is severe, a fibroproliferative phase of ALI can develop. During this phase, the activated fibroblast and myofibroblasts synthesize excessive collagenous extracellular matrix that leads to a condition called pulmonary fibrosis. Lung injury can be caused by several ways; however, the present review focus on bleomycin (BLM)-mediated changes in the pathology of lungs. BLM is a chemotherapeutic agent and has toxic effects on lungs, which leads to oxidative damage and elaboration of inflammatory cytokines. In response to the injury, the inflammatory cytokines will be activated to defend the system from injury. These cytokines along with growth factors stimulate the proliferation of myofibroblasts and secretion of pathologic extracellular matrix. During BLM injury, the pro-inflammatory cytokine such as IL-17A will be up-regulated and mediates the inflammation in the alveolar epithelial cell and also brings about recruitment of certain inflammatory cells in the alveolar surface. These cytokines probably help in up-regulating the expression of p53 and fibrinolytic system molecules during the alveolar epithelial cells apoptosis. Here, our key concern is to provide the adequate knowledge about IL-17A-mediated p53 fibrinolytic system and their pathogenic progression to pulmonary fibrosis. The present review focuses mainly on IL-17A-mediated p53-fibrinolytic aspects and how curcumin is involved in the regulation of pathogenic progression of ALI and pulmonary fibrosis.

Topics: Acute Lung Injury; Alveolar Epithelial Cells; Animals; Bleomycin; Curcumin; Humans; Inflammation; Interleukin-17; Pulmonary Fibrosis; Tumor Suppressor Protein p53

Pulmonary fibrosis is characterized by damage to the epithelial cells and alveolar-capillary basement membrane. The increased expression levels of transforming growth factor β (TGF-β) and TGF-β-receptor-1 induced differentiation of lung fibroblasts to myofibroblasts, an alarming sign and considered the hallmark event development of pulmonary fibrosis. In the current study, the stability of phytochemicals of

Topics: Curcuma; Molecular Docking Simulation; Pulmonary Fibrosis; Tinospora; Transforming Growth Factor beta

Topics: Apoptosis; Cell Line, Tumor; Curcumin; Humans; Immunoglobulin G4-Related Disease; Macrophages; Pulmonary Fibrosis; Reproducibility of Results; Toll-Like Receptor 9

Persistent injuries and chronic inflammation paired with dysregulated healing process in the lungs leads to scarring and stiffening of the tissue leading to a condition called pulmonary fibrosis. There is no efficacious therapy against the condition because of the poorly understood pathophysiology of the disease. Curcumin is well known anti-inflammatory natural compound and is shown to have beneficial effects in many diseases. It is also reported to show antifibrotic activities in pulmonary fibrosis. There are evidences that fibrinolytic system plays a crucial role in the development of pulmonary fibrosis. We aimed to see whether curcumin could regulate inflammation and fibrinolysis in murine model of pulmonary fibrosis. We prepared BLM induced pulmonary fibrosis model by administering BLM at a dose of 2 mg/ kg bodyweight. Curcumin (75 mg/kg body wt) was instilled intraperitoneally on different time points. The effect of curcumin on inflammatory cytokines and fibrinolytic system was studied using molecular biology techniques like RT-PCR, western blot and immunohistochemistry/immunofluorescence. We observed that BLM brought changes in the expressions of components in the fibrinolytic system, i.e. BLM favoured fibrin deposition by increasing the expression of PAI-1 (plasminogen activator inhibitor) and decreasing the expression of uPA (Urokinase plasminogen activator) and uPAR (Urokinase plasminogen activator receptor). We also demonstrate that curcumin could restore the normal expression of fibrinolytic components, uPA, uPAR and PAI-1. Curcumin could also minimize the expression of key enzymes in tissue remodeling in pulmonary fibrosis, MMP-2 and MMP-9, which were elevated in the BLM treated group. Our data suggest that curcumin exerts an anti-inflammatory and antifibrotic effect in lungs. We highlight curcumin as a feasible adjuvant therapy option against pulmonary fibrosis.

Topics: Animals; Curcumin; Cytokines; Fibrinolysis; Inflammation; Mice; Plasminogen Activator Inhibitor 1; Pulmonary Fibrosis; Urokinase-Type Plasminogen Activator

Oral administration of curcumin has been shown to inhibit pulmonary fibrosis (PF) despite its extremely low bioavailability. In this study, we investigated the mechanisms underlying the anti-PF effect of curcumin in focus on intestinal endocrine. In bleomycin- and SiO

Topics: Administration, Oral; Animals; Colon; Curcumin; Cyclic AMP Response Element-Binding Protein; Female; Fibroblasts; Hepatocyte Growth Factor; Humans; Lung; Macrophages; Mice; Mice, Inbred ICR; PPAR gamma; Prostaglandin D2; Pulmonary Fibrosis; RAW 264.7 Cells; Up-Regulation

Acute lung injury is one of the common conditions caused due to bleomycin therapy which leads to pulmonary fibrosis, which is one of the severe interstitial lung diseases most commonly affecting the elderly individuals. EGFR and Ki67 can be marked as beneficial markers for detecting pulmonary fibrosis based on which clinicians can guide the therapy.. The aim of the study was to evaluate the effect of curcumin as an intervention on two prognostic markers EGFR and Ki67 in bleomycin-induced basal alveolar epithelial cells and C57BL/6 mice. Protein expressions and pathological expressions of EGFR and Ki67 were evaluated to analyze the effect of curcumin via both in vitro and in vivo approaches.. The effect of curcumin was investigated both on cell lines (A549) and animal model (both normal and bleomycin-induced mice, n=6) via techniques like western blotting for protein expression. Techniques like immunofluorescence and immunohistochemistry were carried out and examined under confocal microscopy and phase contrast microscopy to analyze the expressions of the said biomarkers. Bleomycin was used as a causative agent to induce inflammation.. The natural polyphenol curcumin could downregulate the expressions levels of Ki67 and EGFR both in vitro and in vivo. Immunofluorescence analysis of proliferative marker Ki67 showed a reduced expression on curcumin treatment in vitro. The pathological sections from treated lungs showed a significant decrease in EGFR and Ki67 levels when exposed to curcumin.. We conclude that curcumin, a well-known natural bioactive compound holds strong antiproliferative effects on Ki67 and EGFR expressions.We observed that a clinical outcome in the diagnosis of pulmonary fibrosis remains to be unconvincing so far. Curcumin can be considered as a potential therapeutic.

Topics: A549 Cells; Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Proliferation; Curcumin; ErbB Receptors; Humans; Ki-67 Antigen; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis

The present study investigated the therapeutic effect of curcumin on bleomycin (BLM)-induced alterations in glycoprotein components in the fibrotic lungs. Analysis of the bronchoalveolar lavage fluid (BALF) demonstrated increased fibronectin content at 3, 5, 7, and 14 days after BLM administration. Similarly, lung tissue fibronectin content revealed a progressive increase at various times (days 3, 5, 7, 14, and 28) during the development of lung fibrosis. In addition, alveolar macrophage release of fibronectin was also elevated in BLM-treated rats. Analysis of carbohydrate moieties of glycoproteins revealed an increase in total hexose, fucose, sialic acid and hexosamine levels at 7, 14, and 28 days after BLM treatment. Furthermore, the activities of lung glycosidases such as N-acetyl-β-D-glucosaminidase, β-glucosidase, β-galactosidase, and β-fucosidase in the fibrotic rats were elevated. Importantly, curcumin significantly inhibited the BLM-induced increases in BALF and lung fibronectin levels. Treatment of BLM rats with curcumin dramatically suppressed alveolar macrophage release of fibronectin. Curcumin also inhibited the increases in complex carbohydrates and glycosidases in the fibrotic lungs. These findings suggest that BLM-induced lung fibrosis is associated with accumulation of glycoproteins, and curcumin has the ability to suppress the enhanced deposition of glycoproteins in the fibrotic lung.

Topics: Acetylglucosaminidase; Animals; Antibiotics, Antineoplastic; beta-Galactosidase; beta-Glucosidase; Bleomycin; Bronchoalveolar Lavage Fluid; Curcumin; Fibronectins; Fucose; Glycoproteins; Hexosamines; Hexoses; Macrophages, Alveolar; Male; N-Acetylneuraminic Acid; Pulmonary Fibrosis; Rats; Rats, Wistar

Acute lung injury (ALI) remains to be the major cause of mortality. Bleomycin (BLM) injury activates the pro-inflammatory cytokine Interleukin L-17A which regulates the expression of COX-2 and inhibits P-AMPKα in BLM/IL-17A exposed mice upon activation of NFκB and other inflammatory molecules the actual mechanism behind which remains unclear. The current investigation was carried out to assess the role of IL-17A with COX-2 and P- AMPKα and to highlight the important contribution of adjunctive use of curcumin as a promising preventive strategy for the BLM-induced ALI. Immunofluorescence analysis reveals that the natural spice curcumin blocks the expressions of COX-2, NF-κB-p65, fibronectin (FBN), and expresses P-AMPKα in vivo. Curcumin could also suppress the expressions of NF-κB-p105 in BLM/IL-17A exposed mice. mRNA expressions showed reduced expressions of PDGFA, PDGFB, CTGF, IGF1, NFκB1, NFκB2, MMP-3, MMP-9, and MMP-14 on curcumin treatment. Our study implicates a critical role of AMPKα/COX- 2 in the emergence of pulmonary fibrosis via exerting the potential role of curcumin as an adjuvant anti-inflammatory therapeutic for treating lung injury.

Topics: Acute Lung Injury; AMP-Activated Protein Kinases; Animals; Bleomycin; Curcumin; Cyclooxygenase 2; Interleukin-17; Lung; Mice, Inbred C57BL; NF-kappa B; Pulmonary Fibrosis

Disordered collagen production by fibroblasts in response to tissue injury contributes to pulmonary fibrosis (PF). Therefore, elimination of collagen deposition has becoming a potential target in PF treatment which despite standard anti-fibrosis regiment still remains challenge. Curcumin and curcumol are regarded as the main active components extraction from the rhizomes of Curcuma zedoaria, which is widely used for inhibition the proliferation of multiple cells. However, the molecular basis for the function of curcumin and curcumol in limiting fibrogenesis still unknown. In this study, we have investigated the effects of curcumin and curcumol in the fibroblast overproliferation model human lung fibroblast (HLF) inducing by TGF-β1. The growth-inhibitory effects of the components wasn't observed from 8 to 64 μg/ml. Administration of curcumin or curcumol significantly diminished the level of hydroxyproline hydroxyproline and α-smooth muscle actin (α-SMA), also the collagen Ⅰ (Col-Ⅰ) and collagen Ⅲ (Col-Ⅲ) deposition were reduced in the HLF. Furthermore, related to the collagen synthesis proteins including N-terminal pro-peptide for Type Ⅰ collagen (PⅠNP), N-terminal pro-peptide for Type Ⅲ collagen (PⅢNP) and prolyl-hydroxylase (PHD) were degraded gracefully at dose-dependent manner. Autophagy as the scavenger was crippled in TGF-β1-fibroblast overproliferation HLF, conversely the increased autophagosomes have been spotted in cytoplasm under transmission electron microscope which is consistent with up-regulation of Beclin1 and ATG7 after treatment with curcumin or curcumol in this study. Additionally, blocking autophagy by inhibitor chloroquine (CQ) caused collagen deposition, providing further evidence regard to autophagy activation capacity of curcumin and curcumol. Our findings provide a detailed understanding that the function of curcumin and curcumol on decreasing collagen deposition mediating by autophagy mechanism, which may also inspire the further research on PF at different perspectives.

Topics: Autophagy; Cells, Cultured; Collagen; Curcuma; Curcumin; Fibroblasts; Humans; Plant Extracts; Pulmonary Fibrosis; Sesquiterpenes

Bleomycin (BLM)-induced pulmonary fibrosis is characterized by inflammation in the alveoli, subsequent deposition of extracellular matrix (ECM) and myofibroblasts, and an impaired fibrinolytic system. Here, we describe major hematological changes, the IL-17A-mediated p53-fibrinolytic pathway, and the high throughput hits of liquid chromatography-mass spectrometry (LC-MS) analysis during the progression of pulmonary fibrosis and the therapeutic potential of curcumin against disease progression. C57BL/6 mice were exposed to BLM, followed by curcumin intervention after 24 and 48 h. Mice were sacrificed after 7 days to validate the hematological parameters, molecular pathways, and proteomics. Various techniques such as western blotting, immunofluorescence, reverse transcriptase polymerase chain reaction (RT-PCR), hematoxylin and eosin staining, Masson's trichrome staining, and immunohistochemistry were used to validate the proposed theory. LC-MS analysis was performed using a Q-Orbitrap mass spectrometer. The Schrödinger approach was used to perform the

Topics: Animals; Bleomycin; Curcumin; Inflammation; Lung; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Proteomics; Pulmonary Fibrosis

Pulmonary fibrosis is associated with irreversible, or partially reversible, airflow obstruction and ultimately unresponsiveness to asthma therapies such as corticosteroids. Intranasal curcumin, an anti-inflammatory molecule, has been found effective in allergic asthma. To study the effect of intranasal curcumin on airway remodeling and fibrosis in murine model of chronic asthma, BALB/c mice were sensitized to ovalbumin (OVA) and exposed to OVA aerosol (2%) from day 21 (after sensitization) for 5 weeks (twice/week). Curcumin (intranasal) was administered during the OVA aerosol challenge. Mice exposed to OVA developed inflammation dominated by eosinophils which lead to fibrosis and airway remodeling. Intranasal administration of curcumin significantly inhibited airway inflammation and pulmonary fibrosis, where MMP-9 activities were decreased along with α-smooth muscle actin (α-SMA), MMP-9, TIMP-1, and eotaxin expressions. These results suggest that intranasal curcumin regulates airway inflammation and remodeling in chronic asthma.

Topics: Actins; Administration, Intranasal; Airway Remodeling; Animals; Asthma; Chronic Disease; Curcumin; Eosinophils; Inflammation; Matrix Metalloproteinase 9; Mice; Ovalbumin; Pulmonary Fibrosis; Tissue Inhibitor of Metalloproteinase-1

To explore the mechanism of paraquat (PQ) poisoning and to observe the changes in inflammatory cytokines in PQ-exposed rats treated in different ways.. Fifty 8-week-old clean male Wistar rats were randomly divided into high-dose curcumin plus conventional treatment group, low-dose curcumin plus conventional treatment group, high-dose curcumin group, PQ poisoning group, and blank control group. On days 1, 3, 5, 7, 14, and 21 after PQ exposure, serum levels of transforming growth factor-β₁(TGF-β₁) , tumor necrosis factor-α (TNF-α) , and interleukin-6 (IL-6) were measured. The pathological changes in lung tissue were evaluated by HE staining.. Compared with the blank control group, the high-dose curcumin plus conventional treatment group, low-dose curcumin plus conventional treatment group, high-dose curcumin group, and PQ poisoning group had significantly increased serum levels of TGF-β₁, TNF-α, and IL-6 (P<0.05) , and the three cytokines in each group reached peak levels on day 14 after exposure. Compared with the PQ poisoning group, the high-dose curcumin group had significantly reduced serum levels of TGF-β₁, TNF-α, and IL-6 (P<0.05). On day 21 after exposure, there were no significant differences in serum levels of TGF-β₁, TNF-α, and IL-6 between the high-dose curcumin plus conventional treatment group and the low-dose curcumin plus conventional treatment group (P>0.05). The HE staining revealed alveolar inflammatory changes on days 1~7 and massive pulmonary fibrosis on days 14~21 in the high-dose curcumin plus conventional treatment group, low-dose curcumin plus conventional treatment group, high-dose curcumin group, and PQ poisoning group, but the above changes were milder in the high-dose curcumin group than in the PQ poisoning group.. For rats with PQ poisoning, curcumin can significantly reduce inflammatory response and pathological changes in lung tissue and inhibit and delay the development and progression of body injury.

Topics: Animals; Curcumin; Cytokines; Interleukin-6; Lung; Male; Paraquat; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Rats, Wistar; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The study was aimed to investigate the protective effect of green tea extract (GTE), curcumin, and N-acetyl cysteine (NAC) on experimentally induced pulmonary fibrosis. Curcumin (200 mg/kg b.w), GTE (150 mg/kg b.w), and NAC (490 mg/kg b.w) were administered orally for 14 days with concomitant administration of cyclophosphamide (CP). Lung fibrosis was assessed by measuring hydroxyproline and elastin levels and confirmed by histopathological examination. Oxidative stress was also observed in the CP group. Lung myeloperoxidase activity was significantly decreased in animals of the CP group. N-acetyl-β-d-glucosaminidase, leukotriene C₄, and protein were increased in bronchoalveolar lavage fluid (BALF). Transforming growth factor-β, interleukin -1β, and histamine were increased in both serum and BALF. All modulators markedly attenuated the altered biochemical parameters as compared to CP-treated rats. These results suggest the possibility of using these treatments as protective agents with chemotherapy and as protective agents for lung fibrosis.

Topics: Acetylcysteine; Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Camellia sinensis; Curcumin; Cyclophosphamide; Dietary Supplements; Disease Models, Animal; Inflammation Mediators; Lipid Peroxidation; Lung; Male; Plant Extracts; Plant Leaves; Protective Agents; Pulmonary Fibrosis; Rats; Rats, Wistar; Tea

Lung fibrosis is characterized by fibroblast proliferation and the deposition of collagens. Curcumin, a polyphenol antioxidant from the spice tumeric, has been shown to effectively counteract fibroblast proliferation and reducing inflammation and fibrotic progression in animal models of bleomycin-induced lung injury. However, there is little mechanistic insight in the biological activity of curcumin. Here, we study the effects of curcumin on the expression and activity of cathepsins which have been implicated in the development of fibrotic lung diseases.. We investigated the effects of curcumin administration to bleomycin stimulated C57BL/6 mice and human fetal lung fibroblasts (HFL-1) on the expression of cathepsins K and L which have been implicated in matrix degradation, TGF-β1 modulation, and apoptosis. Lung tissues were evaluated for their contents of cathepsins K and L, collagen, and TGF-β1. HFL-1 cells were used to investigate the effects of curcumin and cathepsin inhibition on cell proliferation, migration, apoptosis, and the expression of cathepsins K and L and TGF-β1.. Collagen deposition in lungs was decreased by 17-28% after curcumin treatment which was accompanied by increased expression levels of cathepsins L (25%-39%) and K (41%-76%) and a 30% decrease in TGF-β1 expression. Moreover, Tunel staining of lung tissue revealed a 33-41% increase in apoptotic cells after curcumin treatment. These in vivo data correlated well with data obtained from the human fibroblast line, HFL-1. Here, cathepsin K and L expression increased 190% and 240%, respectively, in the presence of curcumin and the expression of TGF-β1 decreased by 34%. Furthermore, curcumin significantly decreased cell proliferation and migration and increased the expression of surrogate markers of apoptosis. In contrast, these curcumin effects were partly reversed by a potent cathepsin inhibitor.. This study demonstrates that curcumin increases the expression of cathepsins K and L in lung which an effect on lung fibroblast cell behavior such as proliferation, migration and apoptosis rates and on the expression of TGF-β1 in mouse lung and HFL-1 cells. These results suggest that cathepsin-inducing drugs such as curcumin may be beneficial in the treatment of lung fibrosis.

Topics: Animals; Antifibrinolytic Agents; Bleomycin; Cathepsin K; Cathepsin L; Cells, Cultured; Curcumin; Fibroblasts; Humans; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Up-Regulation

The effectiveness of lung radiotherapy is limited by radiation tolerance of normal tissues and by the intrinsic radiosensitivity of lung cancer cells. The chemopreventive agent curcumin has known antioxidant and tumor cell radiosensitizing properties. Its usefulness in preventing radiation-induced pneumonopathy has not been tested previously. We evaluated dietary curcumin in radiation-induced pneumonopathy and lung tumor regression in a murine model. Mice were given 1% or 5% (w/w) dietary curcumin or control diet prior to irradiation and for the duration of the experiment. Lungs were evaluated at 3 weeks after irradiation for acute lung injury and inflammation by evaluating bronchoalveolar lavage (BAL) fluid content for proteins, neutrophils and at 4 months for pulmonary fibrosis. In a separate series of experiments, an orthotopic model of lung cancer using intravenously injected Lewis lung carcinoma (LLC) cells was used to exclude possible tumor radioprotection by dietary curcumin. In vitro, curcumin boosted antioxidant defenses by increasing heme oxygenase 1 (HO-1) levels in primary lung endothelial and fibroblast cells and blocked radiation-induced generation of reactive oxygen species (ROS). Dietary curcumin significantly increased HO-1 in lungs as early as after 1 week of feeding, coinciding with a steady-state level of curcumin in plasma. Although both 1% and 5% w/w dietary curcumin exerted physiological changes in lung tissues by significantly decreasing LPS-induced TNF-alpha production in lungs, only 5% dietary curcumin significantly improved survival of mice after irradiation and decreased radiation-induced lung fibrosis. Importantly, dietary curcumin did not protect LLC pulmonary metastases from radiation killing. Thus dietary curcumin ameliorates radiation-induced pulmonary fibrosis and increases mouse survival while not impairing tumor cell killing by radiation.

Topics: Administration, Oral; Animals; Antioxidants; Blotting, Western; Bronchoalveolar Lavage Fluid; Carcinoma, Lewis Lung; Chromatography, High Pressure Liquid; Curcumin; Female; Heme Oxygenase (Decyclizing); Lung; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Radiation Injuries; Spectrometry, Mass, Electrospray Ionization; Survival Analysis; Tandem Mass Spectrometry

To study the effects of curcumin on TNF-alpha and TGF-beta1 in serum and lung tissue of SiO2-induced fibrosis in mice.. 75 mice were divided into five groups. After treated with curcumin 6 and 9 mice of each group were sacrificed on day 14 and 42 respectively to take their blood and lung tissue. The level of TNF-alpha and TGF-beta1 was observed by ELISA.. The infection reaction of lung tissue and fibrosis in model group was obvious. Compared with sham operation group, TNF-alpha and TGF-beta1 in serum and lung tissue increased significantly(P<0.01), but decreased in different degrees after treated with curcumin(P<0.05).. Curcumin can decrease the level of TNF-alpha and TGF-beta1 in serum and lung tissue of SiO2-induced fibrosis in mice and have the anti-fibrosis role by deregulating cytokine level.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Enzyme-Linked Immunosorbent Assay; Histocytochemistry; Lung; Male; Mice; Pulmonary Fibrosis; Silicon Dioxide; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

To investigate the effect of curcumin on apoptosis of pulmonary fibroblasts from rats and the molecular mechanisms.. Twenty 6 week old male SD rats were randomly divided into 2 groups with 10 rats in each group: the normal control group (NLF) and the model group (MLF). The pulmonary fibrosis models were made by intratracheally instillation of bleomycin. The rats were sacrificed on the 28 day of experiment, and the pathologic changes of the lung tissues were investigated. Fibroblasts were derived from lung tissues and were cultured in vitro. Then the cells were treated with curcumin at different concentrations (5, 10, 20 and 40 micromol/L). TUNEL staining was used to detect apoptosis. The Caspase-3 and Caspase-8 expression of each group were determined by flow cytometry (FCM). The expression changes of apoptosis-regulating proteins of Caspase-9 in cells were examined by immunohistochemical staining.. In the MLF group treated with 4 different concentrations of curcumin for 12 h, apoptotic morphological changes were observed in the cells. Apoptotic index (AI) was (30.17 +/- 0.53)%, (37.20 +/- 0.25)%, (45.12 +/- 0.31)%, (51.90 +/- 0.27)% respectively, which were significantly higher than that of the control group without curcumin (4.59 +/- 0.19)%. The expression of Caspase-3 was (53.1 +/- 0.7)%, (60.5 +/- 0.6)%, (69.1 +/- 0.9)%, (74.9 +/- 0.7)%, which were significantly higher than that of the control group (5.5 +/- 0.8)%. The expression of Caspase-8 were (37.2 +/- 0.5)%, (46.8 +/- 0.4)%, (56.5 +/- 0.3)%, (67.3 +/- 0.3)%, which were significantly higher than that of the control group (4.6 +/- 0.6)%. The expression of Caspase-9 were (39.38 +/- 0.88)%, (47.51 +/- 0.24)%, (57.75 +/- 0.63)%, (68.36 +/- 0.29)%, which were significantly higher than that of the control group (4.92 +/- 0.34)%. Curcumin did not induce apoptosis of NLF, the expressions of Caspase-3, Caspase-8, Caspase-9 being not statistically different from that of the control group without curcumin.. Curcumin can induce apoptosis of pulmonary fibroblasts in rats with bleomycin-induced pulmonary fibrosis and the mechanism may be related to the activation of Caspase-3, Caspase-8, and Caspase-9.

Topics: Animals; Apoptosis; Caspase 3; Caspase 8; Caspase 9; Curcumin; Fibroblasts; Lung; Male; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley

To study the effects of curcumin on the expressions of collagen type I protein and transforming growth factor-beta1 mRNA in lung tissues of rats with pulmonary fibrosis.. 96 male SD rats were randomly divided into four groups with 24 rats in each group: the normal control group, the model group, the prednisone treated group, and the curcumin treated group. Pulmonary fibrosis was induced by intra-bronchial injection of bleomycin A5. From the 15(th) day after bleomycin administration, rats in the prednisone treated group and the curcumin treated group were given prednisone (5 mg/kg) or curcumin (300 mg/kg) respectively once daily by intragastric administration. In the same way, rats in the normal control group and the model group were given 1% Sodium Carboxymethyl Cellulose (10 ml/kg) once daily. The histological changes of lung tissue were evaluated by Haematoxylin-eosin (HE) and Masson's trichrome. The rats were randomly sacrificed on the 21(st), 28(th), 42(nd) and 56(th) day after bleomycin administration. The type I collagen expression was analyzed by immunohistochemistry. The transforming growth factor-beta(1) (TGF-beta(1)) mRNA expression of lung was detected by the semi-quantitative reverse transcription polymerase chain reaction (RT-PCR).. Pulmonary fibrosis in the curcumin treated group was significantly reduced as compared with the model group and the prednisone treated group on the 42(nd) and 56(th) day (P < 0.05). The expression of type I collagen protein in the curcumin treated group was significantly decreased than that in the model group and the prednisone treated group on the 28(th), 42(nd) and 56(th) day after bleomycin administration (P < 0.05). The TGF-beta(1) mRNA expression in the curcumin treated group was 0.61 +/- 0.09 and 0.48 +/- 0.16 respectively on the 21(st) and 28(th) day after bleomycin administration (P < 0.05). It was significantly decreased than that in the model group on the 21(st), 28(th) day after bleomycin administration and lower as compared with the prednisone treated group on the 21(st) day (P < 0.05).. Curcumin could suppress BLM-induced pulmonary fibrosis in rats at the fibrosing stage, with the possible mechanism of inhibiting the synthesis and deposition of type I collagen protein and depressing the overexpression of TGF-beta(1) mRNA. The therapeutic effect of curcumin on pulmonary fibrosis is better than prednisone.

Topics: Animals; Collagen Type I; Curcumin; Disease Models, Animal; Lung; Male; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta1

To determine the effects of curcumin on bleomycin (BLM)-induced pulmonary fibrosis in rats.. One hundred and forty-four male Sprague-Dawley rats were randomized into 6 groups (24 rats in each group, model group, sham group, prednisone group (0.56 mg x kg(-1) x d(-1)), curcumin with low dose 5 mg group, curcumin with middle dose group 10 mg and curcumin with high dose group 20 mg per 100 g of body weight). Rats in all groups except in sham group were injected with BLM intratracheally. Curcumin with different doses were given by gavage one time everyday for 7, 14 and 28 days. Prednisone were given to rats in prednisone group, po, serving as the positive treatment group. On the 7th, 14th, 28th day, the lung functions (inspiratory resistance, maximal volutary ventilation, forced vital capacity, Fev 0.2/FVC, peak expiratory flow) were determinated in experimental rats, respectively, and the concentrations of hydroxyproline in lung homogenates of each rat were assayed.. Administration of curcumin in different doses improved lung functions of BLM-induced fibrotic rats in the all experimental days; and it decreased the concentration of hydroxyproline in lung homogenates compared with those levels in model control group; and it also lessened the hyperplasia of BLM-induced pulmonary fibrosis in rats.. Administration of curcumin can suppress BLM induced pulmonary fibrosis indicated by improved respiratory function, as well as companied with low content of hydroxyproline in lung tissue of rats.

Topics: Animals; Bleomycin; Curcumin; Hydroxyproline; Lung; Male; Pulmonary Fibrosis; Rats; Time Factors

To compare curcumin with hydrocortisone for treating bleomycin-induced pulmonary fibrosis (BLMPF), four groups of rats were injected with 1.5 mg/kg bleomycin intratracheally. Then the Group HC rats were treated with three injections of 2mg/kg hydrocortisone i.p.; Group CH and CL rats, respectively, were orally given 500 or 250 mg/kg curcumin daily; and Group PC rats were given deionized water alone. After 28 days of treatment, lung samples were examined by H-E staining, Masson's staining and immunohistochemical analyses and pulmonary type I collagen (Col-I), inducible nitric oxide synthetase (iNOS) and transforming growth factor-beta1 (TGF-beta1) were determined by Western blotting and real-time RT PCR analyses. The results showed that (1) Group PC rats had histopathological characteristics of BLMPF with significant increase in their protein/mRNA expressions of Col-I (+114%/+173%), iNOS (+146%/+523%) and TGF-beta1 (+476%/+527%) (P<0.01); (2) in Group HC, CH and CL rats, protein/mRNA expressions of Col-I (-39%/-52%, -31%/-57%, -33%/-58%), iNOS (-31%/-51%, -31%/-79%, -31%/-47%) and TGF-beta1 (-64%/-78%, -75%/-74%, -81%/-79%) were significantly lower than Group PC (P<0.05); (3) except for levels of TGF-beta1 protein, there was no significant difference among Group CH, CL and HC rats (P>0.05). It suggests that curcumin may play a similar role as hydrocortisone in preventing BLMPF.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Bleomycin; Blotting, Western; Collagen Type I; Creatinine; Curcumin; Electrophoresis, Polyacrylamide Gel; Female; Hydrocortisone; Immunohistochemistry; Lung; Nitric Oxide Synthase Type II; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta1

To observe the effect and mechanism of curcumin on pulmonary fibrosis induced by bleomycin in rats.. Fifty-four SD rats were randomly divided into 3 groups, 18 rats each group. The control group received a single intratracheal dose of 2 ml/kg of sterile physiological saline at day 0, and from 14 d, 0.5 ml/kg of sterile physiological saline intraperitoneally every day. The bleomycin group received a single intratracheal dose of 5 mg/kg of bleomycin A(5), and from 14 d, 0.5 ml/kg of suspension of 6% alcohol and 6% polyethylene glycol intraperitoneally every day. The curcumin group received a single intratracheal dose of 5 mg/kg of bleomycin A(5), and from 14 d, 50 mg/kg of curcumin (suspended in 6% alcohol and 6% polyethylene glycol) intraperitoneally every day. Six rats in each group were killed at day 17, 21, 28 in batches. The sections of lungs were stained with hematoxylin-eosin (HE) and Masson's trichrome to evaluate the severity of alveolitis and pulmonary fibrosis. The content of hydroxyproline and the expression of transforming growth factor-beta(1) (TGF-beta(1)) mRNA, interferon-gamma (IFN-gamma) mRNA in lung tissues were analyzed. The concentration of TGF-beta(1) and IFN-gamma in bronchoalveolar lavage fluid (BALF) were measured.. (1) The scores of alveolitis in the curcumin group and the bleomycin group at day 28 were 1.3 +/- 0.5, 2.0 +/- 0.9, respectively, the difference being significant (q = 3.26, P < 0.05). (2) The scores of pulmonary fibrosis in the curcumin group and the bleomycin group were 1.3 +/- 0.5, 1.8 +/- 0.4 at day 21, and 1.2 +/- 0.4, 2.2 +/- 1.0 at day 28, the difference being significant between the two groups (q = 3.33, 4.00, all P < 0.05). (3) The content of hydroxyproline in lung tissues in the curcumin group and the bleomycin group were (1.75 +/- 0.36) microg/g, (2.47 +/- 0.24) microg/g at day 28, the difference being significant (q = 7.20, P < 0.01). (4) The concentration of TGF-beta(1) in BALF in the curcumin group and the bleomycin group were (20 +/- 3) ng/L, (39 +/- 7) ng/L at day 21, and (24 +/- 4) ng/L, (40 +/- 7) ng/L at day 28, all being statistically different between the two groups (q = 5.30, 6.27, all P < 0.05). (5) The expression of TGF-beta(1) mRNA in lung tissues in the curcumin group and the bleomycin group were 0.51 +/- 0.11, 0.59 +/- 0.13 at day 21, and 0.50 +/- 0.07, 0.64 +/- 0.11 at day 28, all being not statistically different between the two groups (q = 1.55, 3.13, all P > 0.05). (6) The concentrations of IFN-gamma in BALF in the curcumin group and the bleomycin group were 0.49 +/- 0.17, 0.50 +/- 0.08 at day 21, and 0.52 +/- 0.15, 0.52 +/- 0.11 at day 28, all being not statistically different between the two groups (q = 1.85, 2.03, all P > 0.05). (7) The expression of IFN-gamma mRNA in the curcumin group and the bleomycin group were (28 +/- 5) ng/L, (35 +/- 13) ng/L at day 21, and (30 +/- 11) ng/L, (39 +/- 13) ng/L at day 28, no significant difference between the two groups (q = 0.17, 0.00, all P > 0.05).. Curcumin can alleviate alveolitis and pulmonary fibrosis induced by bleomycin in rats, possibly through its inhibition of TGF-beta(1).

Topics: Animals; Bleomycin; Curcumin; Lung; Male; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

To study the protective effects of curcumin on exaggerated extracellular matrix accumulation of pulmonary fibrosis rats.. One hundred and forty-four male Sprague-Dawley rats were randomly divided into 6 groups (24 rats in each group). Rats in the model control group, positive medicine group, and high, moderate and low curcumin groups were injected with a single dose of bleomycin by trachea, and rats in sham-model control group with same volume normal saline. One day after the injection, curcumin solution of different dosages (200, 100, 50 mg x kg(-1) x d(-1)) was respectively given to rats in the high, moderate and low curcumin group daily by gastrogavage, while equal volume of normal saline was given to those in the sham-model control group and model control group, and an equal volume of prednisone (0.56 mg x kg(-1) x d(-1)) was given to those in positive medicine control group. On the 7, 14, 28 days, 8 rats per treatment group were randomly killed, the levels of III-collagen, IV-collagen, laminin and hyaluronic acid in the serum were determined, the determination of hydroxyproline in lung homogenates was analyzed, and the lung was incised to make pathological sections which were stained with HE and Mallory.. Curcumin could decreas the levels of III-collagen, IV-collagen, laminin and hyaluronic acid in the serum, and inhihit the proliferation of fibrous tissue.. Curcumin may play its therapetuic role by leveling down the content of extracellular matrix in rats with pulmonary fibrosis induced by bleomycin.

Topics: Animals; Bleomycin; Body Weight; Collagen Type III; Collagen Type IV; Curcuma; Curcumin; Drugs, Chinese Herbal; Extracellular Matrix Proteins; Hyaluronic Acid; Hydroxyproline; Laminin; Lung; Male; Plants, Medicinal; Protective Agents; Pulmonary Fibrosis; Random Allocation; Rats; Rats, Sprague-Dawley

To study on the effect and mechanism of curcumin on inhibiting injury induced by free radical in pulmonary fibrosis.. One hundred and forty-four male SD rats were randomly divided into 6 groups (24 rats in each group). Rats in the model control group, positive medicine group, and high, moderate and low curcumin groups were injected with a single dose of bleomycin by trachea, and rats in sham-model control group with same volume normal saline. One day after the injection, curcumin solution of different dosages (200,100,50 mg x kg(-1) x d(-1)) was respectively given to rats in the high, moderate and low curcumin group by daily gastrogavage, while equal volume of normal saline was given to those in the sham-model control group and model control group, and an equal volume of prednisone (0.56 mg x kg(-1) x d(-1)) was saline was given to those in positive medicine control group. On the 7, 14, 28 days, the contents of GSH-Px, SOD, MDA and iNOS in pulmonary tissues of different groups were measured.. Curcumin can raise the content of SOD and GSH-Px and lessen the level of MDA and iNOS.. Curcumin can regulate the level of free radical in the body of rats with pulmonary fibrosis and lessen the oxidative injury of pulmonary tissues caused by free radical, in the body of rats with pulmonary fibrosis. The mechanisms of curcumin on idiopathic pulmonary fibrosis lie in adjusting the level of free radical and inhibiting the injury of lung tissue induced by free radical.

Topics: Animals; Antioxidants; Bleomycin; Curcuma; Curcumin; Free Radicals; Glutathione Peroxidase; Lung; Male; Malondialdehyde; Nitric Oxide Synthase Type II; Plants, Medicinal; Pulmonary Fibrosis; Random Allocation; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

A method to detect and quantify curcumin and two curcuminoid metabolites in biological matrices, including mouse serum and mouse lung cell cultures, was developed. Standard curves between 0.04 and 10.00 nmol curcumin were prepared in serum, giving correlation coefficients of 0.94-0.99. Alcoholic extraction, concentration, and addition of dilute hydrochloric acid to stabilize the curcumin were essential to the reproducibility of the protocol. Untreated and curcumin-treated mouse lung fibrotic and nonfibrotic cell cultures were analyzed by matrix-assisted laser desorption ionization time of flight mass spectrometry utilizing this method. Curcumin uptake was calculated to be 7.0-11.6% for the saline-treated cells and 7.4-11.9% for the bleomycin-treated cultures. Curcumin was not detected in untreated cells. Two additional peaks (m/z=399 and 429) were observed in the curcumin-treated cells. These may be curcumin-derived products resulting from HCl treatment of the tissue samples.

Topics: Animals; Bleomycin; Cells, Cultured; Curcumin; Diarylheptanoids; Lung; Mice; Mice, Inbred Strains; Pulmonary Fibrosis; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Scleroderma, a disease involving excessive collagen deposition, can be studied using fibroblasts cultured from affected tissues. We find that curcumin, the active component of the spice turmeric, causes apoptosis in scleroderma lung fibroblasts (SLF), but not in normal lung fibroblasts (NLF). This effect is likely to be linked to the fact that although curcumin induces the expression of the phase 2 detoxification enzymes heme oxygenase 1 and glutathione S-transferase P1 (GST P1) in NLF, SLF are deficient in these enzymes, particularly after curcumin treatment. The sensitivity of cells to curcumin-induced apoptosis and the expression of GST P1 (but not heme oxygenase 1) are regulated by the epsilon isoform of protein kinase C (PKCepsilon). SLF, which contain less PKCepsilon and less GST P1 than NLF, become less sensitive to curcumin-induced apoptosis and express higher levels of GST P1 when transfected with wild-type PKCepsilon, but not with dominant-negative PKCepsilon. Conversely, NLF become sensitive to curcumin-induced apoptosis and express lower levels of GST P1 when PKCepsilon expression or function is inhibited. The subcellular distribution of PKCepsilon also differs in NLF and SLF. PKCepsilon is predominantly nuclear or perinuclear in NLF but is associated with stress fibers in SLF. Just as PKCepsilon levels are lower in SLF than in NLF in vitro, PKCepsilon expression is decreased in fibrotic lung tissue in vivo. In summary, our results suggest that a signaling pathway involving PKCepsilon and phase 2 detoxification enzymes provides protection against curcumin-induced apoptosis in NLF and is defective in SLF. These observations suggest that curcumin may have therapeutic value in treating scleroderma, just as it has already been shown to protect rats from lung fibrosis induced by a variety of agents.

Topics: Animals; Apoptosis; Bleomycin; Cell Nucleus; Cell Size; Cells, Cultured; Curcumin; Down-Regulation; Drug Resistance; Female; Fibroblasts; Glutathione Transferase; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; Lung; Male; Membrane Proteins; Mice; Oxidative Stress; Protein Kinase C; Protein Kinase C-epsilon; Pulmonary Fibrosis; Scleroderma, Systemic; Signal Transduction; Stress Fibers; Transfection

(1) We have studied whether curcumin prevents amiodarone-induced lung fibrosis in rats. Intratracheal instillation of amiodarone (6.25 mg kg(-1) on days 0 and 2, and then killed on day 3, day 5, week 1, week 3 and week 5 after amiodarone administration) induced increases in total protein and lactate dehydrogenase (LDH) activity on days 3 and 5 in bronchoalveolar lavage fluid (BALF). Total cell counts, alveolar macrophages, neutrophils and eosinophils recovered by BAL, and lung myeloperoxidase (MPO) activity were significantly higher in amiodarone rats. (2) Tumor necrosis factor-alpha (TNF-alpha) release after lipopolysaccharide (LPS) stimulation and superoxide anion generation after phorbol myristate acetate (PMA) stimulation were higher in the alveolar macrophages of amiodarone rats at 3 and 5 weeks postamiodarone instillation than in controls. Amiodarone also induced increases in transforming growth factor-beta1 (TGF-beta1) expression, collagen deposition, type I collagen expression and c-Jun protein in lungs. (3) Curcumin (200 mg kg(-1) body weight after first amiodarone instillation and daily thereafter for 5 weeks)-treated amiodarone rats had reduced levels of protein, LDH activity, total cell numbers and differential cell counts in BALF. LPS-stimulated TNF-alpha release and PMA-stimulated superoxide generation were significantly suppressed by curcumin. Furthermore, curcumin inhibited the increases in lung MPO activity, TGF-beta1 expression, lung hydroxyproline content, expression of type I collagen and c-Jun protein in amiodarone rats. Our results have important implications for the treatment of amiodarone-induced lung fibrosis.

Topics: Amiodarone; Animals; Bronchoalveolar Lavage Fluid; Collagen Type I; Curcumin; Dose-Response Relationship, Drug; Instillation, Drug; Intubation, Gastrointestinal; L-Lactate Dehydrogenase; Lipopolysaccharides; Lung; Macrophages, Alveolar; Male; Peroxidase; Proto-Oncogene Proteins c-jun; Pulmonary Fibrosis; Rats; Rats, Inbred F344; Superoxides; Time Factors; Trachea; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Up-Regulation

Curcumin, an anti-inflammatory, antioxidant, was evaluated for its ability to suppress bleomycin (BLM)-induced pulmonary fibrosis in rats. A single intratracheal instillation of BLM (0.75 U 100(-1) g, sacrificed 3, 5, 7, 14 and 28 days post-BLM) resulted in significant increases in total cell numbers, total protein, and angiotensin-converting enzyme (ACE), and alkaline phosphatase (AKP) activities in bronchoalveolar lavage fluid. Animals with fibrosis had a significant increase in lung hydroxyproline content. Alveolar macrophages from BLM-administered rats elaborated significant increases in tumour necrosis factor (TNF)-alpha release, and superoxide and nitric oxide production in culture medium. Interestingly, oral administration of curcumin (300 mg kg(-1) 10 days before and daily thereafter throughout the experimental time period) inhibited BLM-induced increases in total cell counts and biomarkers of inflammatory responses in BALF. In addition, curcumin significantly reduced the total lung hydroxyproline in BLM rats. Furthermore, curcumin remarkably suppressed the BLM-induced alveolar macrophage production of TNF-alpha, superoxide and nitric oxide. These findings suggest curcumin as a potent anti-inflammatory and anti-fibrotic agent against BLM-induced pulmonary fibrosis in rats.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Bleomycin; Cell Movement; Collagen; Curcumin; Disease Models, Animal; Drug Interactions; Macrophages, Alveolar; Male; Protective Agents; Pulmonary Fibrosis; Rats; Rats, Wistar

Whole body irradiation of rats (10 Gy as five fractions) found to produce lung fibrosis within 2 months as seen from increased lung collagen hydroxyproline and histopathology. Oral administration of antioxidants curcumin, ellagic acid, bixin and alpha-tocopherol at a concentration 200 mumole/kg body weight significantly reduced the lung collagen hydroxyproline in these animals. In serum and liver lipid peroxidation which were found to be increased by irradiation was reduced significantly by antioxidant treatment. The liver superoxide dismutase and glutathione peroxidase activity were also found to be increased and catalase activity decreased in irradiated control. Superoxide dismutase activity reduced significantly by antioxidant treatment while catalase activity was found to be increased with alpha-tocopherol treatment. The increased frequency of micronucleated polychromatic erythrocytes after whole body irradiation of mice was found to be significantly reduced with antioxidants.

Topics: Animals; Antioxidants; Carotenoids; Curcumin; Ellagic Acid; Lipid Peroxidation; Male; Pulmonary Fibrosis; Radiation Injuries, Experimental; Radiation-Protective Agents; Rats; Rats, Wistar