The Preventative Role Of Curcumin On The Lung Injury Induced By Cardiopulmonary Bypass In Rats

Cardiac surgery with cardiopulmonary bypass (CPB) has been associated with a frequent incidence of acute lung injury. Although considerable progress has been made in surgical techniques and extracorporeal circulation (ECC), ALI remains a serious complication of cardiac surgery. Until now, CPB-induced lung injury is thought to be associated with systemic inflammatory response syndrome (SIRS) and ischemia-reperfusion (I/R) injury. Numerous studies have shown that inflammatory cytokines and oxidative stress markers play a pivotal role in the pathogenesis of post-CPB pulmonary dysfunction. Recently in vitro data suggests that TLR4-mediated MyD88-dependent signaling pathway is involved in the pathogenesis of inflammatory response. Meanwhile, it has been increasingly recognized that heme oxygenase-1(HO-1) plays an important role in removing harmful free radicals. Nonetheless, there are few data available that demonstrate the relationship between these transcription factors and lung protection after CPB. The need for studies concentrating on mechanisms of lung injury induced by CPB is essential.Curcumin is an active component of the rhizome curcuma longa. A number of researches have demonstrated that curcumin has beneficial effects such as anti-inflammation, anti-oxidation, anti-cancer, and immunmoregulation. It was suggested that curcumin enhanced the activities of detoxifying enzymes, scavenged superoxide and hydroxyl radicals, attenuated the reactivity of oxygen free radical species suppressed circulating pro-inflammatory cytokines and increased neutrophil apoptosis. Despite the above facts, little is known about the mechanism of curcumin in lung tissues after CPB. Therefore, the aim of this study was to determine the potential effect of curcumin on the expression of inflammatory cytokines and oxidative stress markers.Part I:Study of lung injury in a rat cardiopulmonary bypass modelObjective:It is well-accepted that there are two related pathophysiologic mechanisms to explain lung injury after cardiac surgery with cardiopulmonary bypass (CPB):the systemic inflammatory response syndrome (SIRS) and oxidative stress. We designed this study to test the mechanisms of CPB-induced lung damage in a rat model. For this purpose, the expression of inflammatory cytokines and oxidative stress markers in plasma and lung tissues were determined. Meanwhile, the levels of upstream signaling molecules were also examined.Materials and Methods:A total of20male Sprague-Dawley rats were randomly divided into the following two groups (n=10, per group):sham group, CPB group. Blood samples were collected immediately after heparinization, at the termination of CPB, and at1,2,4,24h postoperatively. Rats were killed24h after CPB, the histologic appearance of the lung, inflammatory cytokines and oxidative stress markers were determined. The expressions of toll-like receptor4(TLR4), myeloid differentiation factor88(MyD88), nuclear factor-B (NF-κB), and heme oxygenase-1(HO-1) proteins were examined using western blotting.Results:CPB group had significantly lower ratio of PaO2/FiO2than sham group (p<0.05). We observed that TLR4, MyD88and NF-κB expressions were higher after surgery. The levels of interleukin-8, tumor necrosis factor-a, and matrix metalloproteinase-9in plasma, bronchoalveolar lavage fluid and lung tissues increased in CPB group.Compared with the sham group, there was a considerable increase in tissue concentration of malondialdehyde (MDA) and myeloperoxidase (MPO) and a significant decrease in tissue concentration of superoxide dismutase (SOD) in CPB group24h after surgery (p<0.05for all comparisons). Furthermore, CPB injury was associated with a slight increase of HO-124h after surgery.Light microscopic finding in the lung specimens indicated that rats in CPB group had severe lung parenchyma, interstitial edema, neutrophil infiltration, and alveolar hemorrhage.Conclusion:Our findings showed that CPB induced lung injury in a rat model, as evidenced by biochemical indices and histopathologic examination. Part Ⅱ:Effect of curcumin on the lung injury inflammatory response induced by cardiopulmonary bypassObjective:We aimed to investigate whether pretreatment with curcumin could ameliorate lung inflammatory response in a rat CPB model.Materials and Methods:A total of40male Sprague-Dawley rats were randomly divided into the following four groups (n=10):control (CPB); vehicle; low-dose curcumin (L-Cur); and high-dose curcumin (H-Cur). Animals were pretreated with a single intraperitoneal injection of vehicle, L-Cur (50mg/kg), or H-Cur (200mg/kg)2h prior to CPB. Blood samples were collected at the beginning, at the end of CPB, and at1,2,4,24h postoperatively. Lung tissues and bronchoalveolar lavage fluid were harvested24h after CPB.Results:Curcumin-treated groups had significantly higher ratio of PaO2/FiO2than the control group (p<0.05). The levels of interleukin-8(IL-8), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase-9(MMP-9) in plasma, bronchoalveolar lavage fluid, and lung tissues were up-regulated24h post-CPB, whereas curcumin pretreatment markedly reduced these inflammatory markers in a partially dose-dependent manner. Curcumin had effective inhibitory effects on the expression of toll-like receptor4(TLR4), myeloid differentiation factor88(MyD88), and nuclear factor-B (NF-κB) in lung tissues24post-CPB (p<0.05versus vehicle group). Furthermore, pretreatment with curcumin had a lower lung injury score.Conclusion:Curcumin may be an alternative therapy for protecting CPB-induced lung injury by suppressing the expression of inflammatory cytokines, this anti-anti-inflammatory effect of curcumin is partly related to the inhibition of TLR4, MyD88, and NF-κB. Part Ⅲ:Curcumin attenuates cardiopulmonary bypass-induced lung oxidative damage in ratsObjective:The mainly aims of this study were to explore whether curcumin pretreatment could up-regulate heme oxygenase-1(HO-1) and ameliorates lung injury in a rat CPB model.Materials and Methods:Male Sprague-Dawley rats were randomly divided into the following four groups (n=10): control (CPB); vehicle; low-dose curcumin (L-Cur); and high-dose curcumin (H-Cur). Animals were pretreated with a single intraperitoneal injection of vehicle, L-Cur (50mg/kg), or H-Cur (200mg/kg)2h prior to CPB. Blood samples were collected at the beginning, at the end of CPB, and at1,2,4,24h postoperatively. Lung tissues, plasma, and bronchoalveolar lavage fluid were harvested24h after CPB.Results:In the control group, CPB-induced lung injury was confirmed by histopathologic examination and a significantly increased wet-to-dry lung weight ratio and pulmonary permeability index value was observed. Administration of curcumin ameliorated lung damage and reversed the oxidative stress markers in a partially dose-dependent manner (p<0.05versus vehicle group). Furthermore, HO-1protein expression was elevated to a greater extent in the lungs after curcumin pretreatment compared with the vehicle pretreatment (p<0.05).Conclusion:Curcumin has the potential to provide protection from CPB-induced lung damage reflected in expression of oxidative stress markers. The antioxidant effect of curcumin maybe partly related to up-regulation of HO-1.