CURCUMIN PROTECTS FROM DRUG-INDUCED LUNG INJURY

XIV. CURCUMIN PROTECTS FROM DRUG-INDUCED LUNG INJURY

Cyclophosphamide causes lung injury in rats through its ability to generate free radicals with subsequent endothelial and epithelial cell damage. Venka- tesan and Chandrakasan examined the effect of curcumin on cyclophospha- mide-induced early lung injury (117). To observe the protective effects of curcumin on cyclophosphamide-induced early lung injury, healthy, patho- gen-free male Wistar rats were exposed to 20 mg/100 g body weight of cyclophosphamide, given intraperitoneally as a single injection. Prior to cyclophosphamide intoxication, curcumin was administered orallydaily for 7

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days. At various times (2, 3, 5, and 7 days postinsult) serum and lung samples were analyzed for angiotensin-converting enzyme (ACE), 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 increased lavage

fluid total protein, albumin, ACE, LDH, N-acetyl-h- D -glucosaminidase, alkaline phosphatase, acid phosphatase, lipid peroxide, GSH, and ascorbic acid levels 2, 3, 5, and 7 days after cyclophosphamide intoxication. Increased levels of lipid peroxidation and decreased levels of GSH and ascorbic acid were seen in serum, lung tissue, and lavage cells of cyclophosphamide-treated groups. Serum ACE activity increased, coinciding with the decrease in lung tissue levels. Activities of antioxidant enzymes were reduced with time in the lungs of cyclophosphamide-treated group, whereas a significant reduction in the lavage fluid biochemical constituents and lipid peroxidation products in the serum, lung, and lavage cells, with concomitant increase in antioxidant defense mechanisms, occurred in curcumin-fed cyclophosphamide rats. Therefore, the study indicated curcumin as an effective agent in moderating the cyclophosphamide-induced early lung injury.

In another study, Venkatesan et al. investigated the effect of curcumin on bleomycin (BLM)-induced lung injury (118). The data indicated that BLM-mediated lung injury resulted in increases in lung lavage fluid bio-

markers such as total protein, ACE, LDH, N-acetyl-h- D -glucosaminidase, lipid peroxidation (LPO) products, SOD, and catalase. BLM administration also resulted in increased levels of malondialdehyde in bronchoalveolar lavage fluid and bronchoalveolar lavage (BAL) cells and greater amounts of alveolar macrophage (AM) superoxide dismutase activity. By contrast, lower levels of reduced GSH were observed in lung lavage fluid, BAL cell, and

AM. Stimulated superoxide anion and H 2 O 2 release by AM from BLM- treated rats were higher. Curcumin treatment significantly reduced lavage fluid biomarkers. In addition, it restorated the antioxidant status in BLM rats. These data suggested 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.

Punithavathi et al. also evaluated the ability of curcumin to suppress BLM-induced pulmonary fibrosis in rats (119). A single intratracheal instil- lation of BLM (0.75 U/100 g, sacrificed 3, 5, 7, 14, and 28 days post-BLM) resulted in significant increases in total cell numbers, total protein, and ACE and in alkaline phosphatase activities in bronchoalveolar lavage fluid. Animals with fibrosis had a significant increase in lung hydroxyproline content. AM from BLM-treated rats elaborated significant increases in

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TNF-a release, and superoxide anion and nitric oxide production in culture medium. Interestingly, oral administration of curcumin (300 mg/kg) 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-treated rats. Furthermore, curcumin remarkably suppressed the BLM-induced AM production of TNF-a, superoxide anion, and nitric oxide. These findings suggest curcumin as a potent anti-inflamma- tory and antifibrotic agent against BLM-induced pulmonary fibrosis in rats.

Paraquat (PQ), a broad-spectrum herbicide, can cause lung injury in humans and animals. An early feature of 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, suppressing early lung injury before the development of irrevers- ible fibrosis would be an appropriate therapeutic goal. Venkatesan showed that curcumin confers remarkable protection against PQ-induced lung injury (120). A single intraperitoneal injection of PQ (50 mg/kg) significantly

increased the levels of protein, ACE, alkaline phosphatase, N-acetyl-h- D - glucosaminidase (NAG), TBARS, and neutrophils in the BALF, while it decreased GSH levels. In PQ-treated rats BAL cells, TBARS concentration was increased with a simultaneous decrease in glutathione content. In addition, the data demonstrated that PQ caused a decrease in ACE and glutathione levels and an increase in levels of TBARS and myeloperoxidase activity in the lung. Interestingly, curcumin prevented the general toxicity and mortality induced by PQ and blocked the rise in BALF protein, ACE, alkaline phophatase, N-acetyl glucosaminidase, 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 were abolished by curcumin treatment. These findings indicate that curcumin has important therapeutic implications in facilitating the early suppression of PQ lung injury.