Narayanan Venkatesan

Curcumin attenuation of acute adriamycin myocardial toxicity in rats.

The protective effect of curcumin on acute adriamycin (ADR) myocardial toxicity was analysed in rats. ADR toxicity, induced by a single intraperitoneal injection (30 mg kg−1), was revealed by elevated serum creatine kinase (CK) and lactate dehydrogenase (LDH). The level of the lipid peroxidation products, conjugated dienes and malondialdehyde, was markedly elevated by ADR. ADR caused a decrease in myocardial glutathione content and glutathione peroxidase activity. In contrast, cardiac catalase activity was increased in ADR rats. Curcumin treatment (200 mg kg−1, seven days before and two days following ADR) significantly ameliorated the early manifestation of cardiotoxicity (ST segment elevation and an increase in heart rate) and prevented the rise in serum CK and LDH exerted by ADR. ADR rats that received curcumin displayed a significant inhibition of lipid peroxidation and augmentation of endogenous antioxidants. These results suggest that curcumin inhibits ADR cardiotoxicity and might serve as novel combination chemotherapeutic agent with ADR to limit free radical‐mediated organ injury.

Curcumin prevents adriamycin nephrotoxicity in rats.

The present study investigated the effect of curcumin on adriamycin (ADR) nephrosis in rats. The results indicate that ADR‐induced kidney injury was remarkably prevented by treatment with curcumin. Treatment with curcumin markedly protected against ADR‐induced proteinuria, albuminuria, hypoalbuminaemia and hyperlipidaemia. Similarly, curcumin inhibited ADR‐induced increase in urinary excretion of N‐acetyl‐β‐D‐glucosaminidase (a marker of renal tubular injury), fibronectin and glycosaminoglycan and plasma cholesterol. Curcumin restored renal function in ADR rats, as judged by the increase in GFR. The data also demonstrated that curcumin protected against ADR‐induced renal injury by suppressing oxidative stress and increasing kidney glutathione content and glutathione peroxidase activity. In like manner, curcumin abolished ADR‐stimulated kidney microsomal and mitochondrial lipid peroxidation. These data suggest that administration of curcumin is a promising approach in the treatment of nephrosis caused by ADR.

Curcumin inhibition of bleomycin-induced pulmonary fibrosis in rats

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)‐α 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‐α, superoxide and nitric oxide. These findings suggest curcumin as a potent anti‐inflammatory and anti‐fibrotic agent against BLM‐induced pulmonary fibrosis in rats.

Modulation of cyclophosphamide-induced early lung injury by curcumin, an anti-inflammatory antioxidant

Cyclophosphamide causes lung injury in rats through its ability to generate free radicals with subsequent endothelial and epithelial cell damage. In order to observe the protective effects of a potent anti-inflammatory antioxidant, curcumin (diferuloyl methane) on cyclophosphamide-induced early lung injury, healthy pathogen free male Wistar rats were exposed to 20 mg/100 g body weight of cyclophosphamide, intraperitoneally as a single injection. Prior to cyclophosphamide intoxication oral administration of curcumin was performed daily for 7 days. At various time intervals (2, 3, 5 and 7 days post insult) serum and lung samples were analyzed for angiotensin converting enzyme, lipid peroxidation, reduced glutathione and ascorbic acid. Bronchoalveolar lavage fluid was analyzed for biochemical constituents. The lavage cells were examined for lipid peroxidation and glutathione content. Excised lungs were analyzed for antioxidant enzyme levels. Biochemical analyses revealed time course increases in lavage fluid total protein, albumin, angiotensin converting enzyme (ACE), lactate dehydrogenase, N-acetyl-β-D-glucosaminidase, alkaline phosphatase, acid phosphatase, lipid peroxide levels and decreased levels of glutathione (GSH) and ascorbic acid 2, 3, 5 and 7 days after cyclophosphamide intoxication. Increased levels of lipid peroxidation and decreased levels of glutathione and ascorbic acid were seen in serum, lung tissue and lavage cells of cyclophosphamide groups. Serum angiotensin converting enzyme activity increased which coincided with the decrease in lung tissue levels. Activities of antioxidant enzymes were reduced with time in the lungs of cyclophosphamide groups. However, a significant reduction in lavage fluid biochemical constituents, lipid peroxidation products in serum, lung and lavage cells with concomitant increase in antioxidant defense mechanisms occurred in curcumin fed cyclophosphamide rats. Therefore, our results suggest that curcumin is effective in moderating the cyclophosphamide induced early lung injury and the oxidant-antioxidant imbalance was partly abolished by restoring the glutathione (GSH) with decreased levels of lipid peroxidation.

Pulmonary protective effects of curcumin against paraquat toxicity.

An early feature of paraquat (PQ) toxicity is the influx of inflammatory cells, releasing proteolytic enzymes and oxygen free radicals, which can destroy the lung epithelium and result in pulmonary fibrosis. Therefore, the ability to suppress early lung injury seems to be an appropriate therapy of pulmonary damage before the development of irreversible fibrosis. Here I show curcumin confers remarkable protection against PQ lung injury. A single intraperitoneal injection of PQ (50 mg/kg) resulted in a significant rise in the levels of protein, angiotensin converting enzyme (ACE), alkaline phosphatase (AKP), N-acetyl-beta-D-glucosaminidase (NAG) and thiobarbituric acid reactive substances (TBARS), and neutrophils in the bronchoalveolar lavage fluid (BALF), while a decrease in glutathione levels. In paraquat rats bronchoalveolar lavage (BAL) cell TBARS concentration was increased with a simultaneous decrease in glutathione content. In addition, the data also demonstrated that PQ caused a decrease in ACE and glutathione levels and an increase in levels of TBARS and myeloperoxidase (MPO) activity in the lung. Interestingly, curcumin prevented the general toxicity and mortality induced by PQ and blocked the rise in BALF protein, ACE, AKP, NAG TBARS and neutrophils. Similarly, curcumin prevented the rise in TBARS content in both BAL cell and lung tissue and MPO activity of the lung. In addition, PQ induced reduction in lung ACE and BAL cell and lung glutathione levels was abolished by curcumin treatment. These findings indicate that curcumin has important therapeutic implications in facilitating the early suppression of PQ lung injury.

Protective effects of curcumin against amiodarone-induced pulmonary fibrosis in rats

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. Tumor necrosis factor‐α (TNF‐α) 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‐β1 (TGF‐β1) expression, collagen deposition, type I collagen expression and c‐Jun protein in lungs. 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‐α release and PMA‐stimulated superoxide generation were significantly suppressed by curcumin. Furthermore, curcumin inhibited the increases in lung MPO activity, TGF‐β1 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.

Curcumin protects bleomycin-induced lung injury in rats

The present study was designed to determine the protective effects of curcumin against bleomycin (BLM)-induced inflammatory and oxidant lung injury. The data indicate that BLM-mediated lung injury resulted in increases in lung lavage fluid biomarkers such as total protein, angiotensin-converting enzyme (ACE), lactate dehydrogenase (LDH), N-acetyl-beta-D-glucosaminidase (NAG), lipid peroxidation (LPO) products, superoxide dismutase (SOD) and catalase. Bleomycin administration also resulted in increased levels of malondialdehyde (MDA) in bronchoalveolar lavage fluid (BALF) and bronchoalveolar lavage (BAL) cells and greater amounts of alveolar macrophage (AM) superoxide dismutase activity. By contrast, lower levels of reduced glutathione (GSH) were observed in lung lavage fluid, BAL cells and AM. Stimulated superoxide anion and hydrogen peroxide release by AM from BLM rats were found to be higher. Curcumin treatment resulted in a significant reduction in lavage fluid biomarkers. In addition, curcumin treatment resulted in the restoration of antioxidant status in BLM rats. These data suggest that curcumin treatment reduces the development of BLM-induced inflammatory and oxidant activity. Therefore, curcumin offers the potential for a novel pharmacological approach in the suppression of drug or chemical-induced lung injury.

Protection from acute and chronic lung diseases by curcumin.

The aim of this review has been to describe the current state of the therapeutic potential of curcumin in acute and chronic lung injuries. Occupational and environmental exposures to mineral dusts, airborne pollutants, cigarette smoke, chemotherapy, and radiotherapy injure the lungs, resulting in acute and chronic inflammatory lung diseases. Despite major advances in treating lung diseases, until now disease-modifying efficacy has not been demonstrated for any of the existing drugs. Current medical therapy offers only marginal benefit; therefore, there is an essential need to develop new drugs that might be of effective benefit in clinical settings. Over the years, there has been increasing evidence that curcumin, a phytochemical present in turmeric (Curcuma longa), has a wide spectrum of therapeutic properties and a remarkable range of protective effects in various diseases. Several experimental animal models have tested curcumin on lung fibrosis and these studies demonstrate that curcumin attenuates lung injury and fibrosis caused by radiation, chemotherapeutic drugs, and toxicants. The growing amount of data from pharmacological and animal studies also supports the notion that curcumin plays a protective role in chronic obstructive pulmonary disease, acute lung injury, acute respiratory distress syndrome, and allergic asthma, its therapeutic action being on the prevention or modulation of inflammation and oxidative stress. These findings give substance to the possibility of testing curcumin in patients with lung diseases.

In vivo administration of taurine and niacin modulate cyclophosphamide-induced lung injury.

The antiinflammatory, antioxidant activity of taurine and niacin against cyclophosphamide-induced early lung injury in rats was investigated. A single intraperitoneal injection of cyclophosphamide markedly altered the levels of several biomarkers in bronchoalveolar lavage fluid: total protein, albumin, angiotensin converting enzyme, lactate dehydrogenase, lactate, N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, acid phosphatase and lipid peroxidation product were significantly elevated. In contrast, decreased levels of total reduced glutathione (GSH) and ascorbic acid were observed. Cyclophosphamide significantly increased malondialdehyde levels in serum and lung. Significant increases in lung content of lipid hydroperoxides were seen that paralleled the decreased levels of total reduced glutathione and total sulfhydryl groups. Pretreatment of rats with daily intraperitoneal injection of taurine plus niacin 7 days prior to and 2 days after cyclophosphamide insult significantly inhibited the development of lung injury, prevented the alterations in lavage fluid biomarkers associated with inflammatory reactions, with less lipid peroxidation and restoration of antioxidants. In conclusion, our results suggest that taurine and niacin in combination is efficient in blunting cyclophosphamide-induced pulmonary damage.

Biochemical and connective tissue changes in cyclophosphamide-induced lung fibrosis in rats

The present investigation was designed to characterize the biochemical and connective tissue components and to correlate the significance of morphological and biochemical perturbations in cyclophosphamide (CP)-induced lung fibrosis in rats. Lung fibrosis was induced in male Wistar rats by intraperitoneal injection of 20 mg/100 g body weight of CP, and their pneumotoxic derangements were characterized during an early destructive phase followed by a proliferative and synthetic phase. Serum angiotensin-converting enzyme (ACE) activity was higher in CP-treated rats at days 2, 3, 5, 7, and 11, but there was a significant decrease in lung ACE activity during the same time period. Elevated levels of beta-glucuronidase activity were observed in the lung lavage fluid of CP-administered rats days 2, 3, 5, and 7. Lung myeloperoxidase activity was higher in CP rats. Of significance was the presence of collagenase and collagenolytic cathepsin in the lavage fluid of CP rats, when compared with the barely detectable levels in controls. A similar increase in these enzyme activities was also noticed in the lung tissue of CP rats during the same experimental period. Lavage fluid hydroxyproline content was higher in CP rats when compared with controls. Similarly, lung protein and DNA levels were elevated significantly after treatment with CP. The pulmonary histamine and serotonin contents were significantly higher in CP rats. The incorporation of [3H]thymidine into lung total DNA, [3H]proline into lung hydroxyproline, and [35S]sulphate into lung glycosaminoglycan, measured as indicators of lung DNA, collagen, and glycosaminoglycan synthesis, respectively, was also higher in CP groups. Increased levels of hydroxyproline, elastin, hexosamine, total hexose, fucose, sialic acid, and uronic acid in the lungs of rats 14, 28, and 42 days after CP insult were characterized as biomarkers of CP-induced interstitial changes. These findings indicate that CP-induced lung fibrosis results in alterations not only in collagen synthesis and accumulation, but also in glycosaminoglycan and glycoprotein content.