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. 2016 Apr 8;21(3):307–313. doi: 10.1007/s12603-016-0722-1

Efficacy and therapeutic potential of curcumin against sepsis-induced chronic lung injury in male albino rats

Y-F Liu 1,*, C-W Yang 1,*, H Liu 1,*, S-G Sui 1,*, Xiang-Dong Li 1,*
PMCID: PMC12879759  PMID: 28244571

Abstract

The present study investigates curcumin effect against sepsis-induced chronic lung injury (CLI) of male albino rats. Rats were grouped into four groups such rats undergoing a sham cecal ligature puncture (CLP), rats undergoing CLP, rats undergoing CLP and treated with saline and rats undergoing CLP and treated with curcumin (100 mg/kg bwt). After 45 days of treatment, bronchoalveolar fluid (BALF), blood and lung tissues were collected from the each animal. The total protein content, wet and dry (W/D) weight of lung tissues and some inflammatory cells in the BALF were measured. Histopathological analysis was carried out to investigate the alteration of the cellular architecture of lung tissues. Lipid peroxidation malondialdehyde (MDA), superoxide dismutase (SOD) and myeloperoxidase (MPO) levels were determined. Cytokines such as interleukin-8 (IL- 8), tumor necrosis factor-alpha (TNF-a) and macrophage inhibitory factor (MIF) were measured in the BALF. Curcumin administration significantly reduced CLP-induced inflammation and pulmonary edema. Curcumin treatment is significantly reduced MPO activity, and inflammatory cell accumulation in the BALF and also protein level, MDA, SOD, and W/D ratio were significantly reduced in the lung tissues. Also, curcumin reduced the expression of IL-A, TNF-a and MIF levels in the lung tissues. Histopathological study revealed the significant reduction of CLP-induced CLI in the curcumin-treated male albino rats. Taking all these data together, it is concluded that curcumin can act as a suitable therapeutic agent against CLP-induced CLI of male albino rats.

Key words: Curcumin, sepsis, rats, inflammation, chronic

Introduction

T2D is characterised by hyperglycaemia, elevated glCurcumin is a is the principal curcuminoid of turmeric, and belongs to a member of the ginger family. Turmerics exist as desmethoxycurcumin and bis-desmethoxycurcumin. The yellow color of turmeric due to natural phenols. Curcumin exists in various tautomeric forms, such as 1, 3-diketo shape, and two equivalent enol forms. The keto form is energetically less stable than enol form (1). Curcumin is known to have antioxidant and anti-inflammatory potential (2., 3., 4., 5.). Curcumin has been reported as an effect compound to improve mitochondrial function in Alzheimer's disease induced mouse model (6). Curcumin reported as promising compound against cerebral ischemia, and cerebral vasospasm in subarachnoid hemorrhage-induced rats. A tremendous imbalance between reactive oxygen species (ROS) and a cellular system's capacity to detoxify the less reactive intermediates will reflect oxidative stress. Changes in the normal redox state of cells could affect normal cell physiology via the generation of free radicals and peroxides. Those radicals, which affects DNA, proteins and lipids. Oxidative stress is known to cause strand breaks in DNA (7). Oxidative stress is known to damage and protein misfolding such as glutamate transporters (8).

Sepsis is one of the leading causes of excessive tissue damage and up to 50 % of intensive care unit patient death (9). Respiratory distress syndrome and lung injury handle mortality and morbidity. Lung dysfunction in sepsis is the key starting point for several organ failures and dysfunction (10). The destruction of pulmonary endothelium and alveolar epithelium are critical injuries in chronic lung injury (CLI). Usually, these injuries are mediated by the activated macrophages and neutrophils. Interleukins (ILs), cytokine tumor necrosis factor (TNF)- a and oxygen metabolites are inflammatory mediators that are produced macrophages and neutrophils (11). The appropriate and ethical level of care to be taken for the patients due to tremendous associated risk with treatment (12).

Even though, there are several research reports on the sepsis-induced tissue damage and its molecular mechanism, the treatment of chronic lung injury still questionable and mortality rate still increasing due to sepsis (13). There are promising drugs against CLI. Therefore, the identification of new medicines would be effective against inflammation and to reduce mortality rats. Curcumin has been reported as an effective agent against chronic inflammatory diseases such atherosclerosis, rheumatism, cancer and diabetes (14). Curcumin has been reported as safe compound even up to high doses (15). It has been reported an effective agent against sepsis of liver, kidney and small bowel (16). Thus, the present study investigates the possible effect and mechanism of curcumin against chronic lung injury in male albino rats.

Materials and methods

Curcumin (C1386-5G) was purchased from Sigma-Aldrich (Sigma-Aldrich, St. Louis, MO 63178 USA). All the other materials used in this study were purchased from Welgene (Welgene, Seoul, Korea). Healthy male albino rats purchased from the animal house, Shangai, China, weighing (160-180 g) have selected for the present study. They kept in polypropylene cages, at temperature 25± 0.5 C, relative humidity 60 ±5% and a photoperiod of 12 h/day. The rats were grouped into four groups of 6 rats each. All the animals were handled according to the internationally accepted ethical committee procedures (Medical Ethics Committee of First Affiliated Hospital of Dalian Medical University, 2014-13).

Experimental groups and doses

We have conducted preliminary studies on the effect of curcumin on lung injury with various concentrations such as 1, 25, 50, 100 and 200 mg/kg bwt. Curcumin showed a significant impact on the recovery of lung injury at 50 and 100 mg/kg bwt. Therefore, we selected 50 and 100 mg/kg bwt for our investigation.

Group I: Control rats

Group II: CLI

Group III: CLI + 50 mg/kg bwt of curcumin

Group IV: CLI + 100 mg/kg bwt of curcumin

Induction of CLI

Cecal ligature puncture (CLP) is a generalized animal model to investigate sepsis-induced disease conditions. Male albino rats were anesthetized with chloral hydrate solution. The abdominal incision was created to expose cecum, and the continuity of intestine was maintained. After that, the puncture was created in the cecum area with gauge needle and cecal contents were released into the puncture wound. Finally, the saline solution was given after closing of the incision (17).

Treatment

Curcumin dissolved in saline and administered orally to the male albino rats. The dose was continued for 45 consecutive days. Control rats were given saline as treatment. At the end of treatment, animals were anesthetized, and blood and bronchoalveolar lavage fluid was collected.

Determination of protein content

The total protein content determined in the BALF supernatant with the use of the bicinchoninic acid assay to analyze vascular permeability of airways. The protein content was expressed as mg/ml in the supernatant of BALF (17).

Determination of W/D ratio of lung tissues

The wet weight was determined by excision of the right upper pulmonary lobe, and dry weight was determined by placing wet upper pulmonary lobe in an oven at 60C for one day. Tissue edema of male albino rats was determined by calculating the wet and dry weight of lung tissues (17).

Determination of total cell count

The BALF was centrifuged, and pellets were obtained and suspended in normal saline. Wright-Giemsa staining solution was used for the staining for 10 minutes. Lymphocytes, neutrophils, and total cell counts were carried out (17).

Determination of MDA content

Malondialdehyde (MDA) is determined by the method of Umrani and Paknikar (18) in the lung tissues. MDA is one of the products of membrane lipid peroxidation. A mixture of 0.1 ml supernatant and 1.9 ml of 0.1 M sodium phosphate buffer (pH 7.4) is incubated at 37°C for 1 h. Following precipitation with 5% TCA, it is centrifuged, and the supernatant is collected. Then, 1.0 ml of 1% TBA is added to the supernatant and placed in the boiling water for 15 min. After cooling to room temperature, absorbance is measured at 532 nm and expressed in nmol/mg protein.

Determination of antioxidant enzyme activities

SOD and catalase enzyme activities were assayed according to Weydert and Cullen (19).

Determination of inflammatory cytokines

Inflammatory cytokines such as interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-a) and migration inhibitory factor (MIF) were determined in the serum of sepsis-induced male albino rats. Cytokines were determined according to with the use of kit methods according to manufacturer's instruction (17) (Sigma-Aldrich, USA).

Histopathology

Histopathology

The histopathological analysis was carried out according to Muthuraman et al., (20). The lower lobe pulmonary was immersed in 10% formalin solution and embedded in paraffin. Tissue sections were made into the size of 4 μm and stained with hematoxylin-eosin and viewed under a light microscope (Olympus, Japan). Interstitial edema, neutrophil infiltration, hemorrhage, congestion, and necrosis are critical features of CLI.

Statistical Analysis

All the values were expressed mean ± SD. The control and treated groups were compared by using ANOVA test. A p<0.05 was considered as statistically significant.

Results

Effect of curcumin on protein level

Protein content significantly increased in the BALF of CLP of male albino rats (group II). Curcumin significantly reduced the total protein content 36.58 % and 41.84 % at 50 and 100 mg/kg bwt curcumin treatment respectively (p<0.05). The total protein content was 200 and 380 μg/ml of the group I and group II respectively (Figure 1). The total protein content was increased in the group II and compare to the group I.

Figure 1.

Figure 1

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Effect of curcumin on the protein content of sepsis-induced CLI of male albino rats. Curcumin 50 and 100 mg/kg bwt were given to the rats for 45 consecutive days. Values were expressed mean ± SD

Effect of curcumin on W/D ratio

The W/D ratio of lung tissues was determined to investigate the degree of pulmonary edema. The W/D ratio of lung tissues significantly increased in the CLP of male albino rats (group II). Curcumin significantly reduced the W/D ratio 36.36 and 45.45 % of lung tissues at 50 and 100 mg/kg bwt curcumin treatment respectively (p<0.05). The W/D ratio of lung tissues of control rats (group I) was lower than Group II (Figure 2).

Figure 2.

Figure 2

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Effect of curcumin on W/D ratio of sepsis-induced CLI of male albino rats. Curcumin 50 and 100 mg/kg bwt were given to the rats for 45 consecutive days. Values were expressed mean ± SD

Effect of curcumin on total cell counts

Total cell counts, neutrophils, and lymphocytes were significantly increased in the BALF of CLP of male albino rats (group II) than normal rats (Figure 3, p<0.05). Curcumin significantly reduced the total cell counts 32 and 64 % at 50 and 100 mg/kg bwt curcumin treatment respectively (Figure 3A). Curcumin significantly reduced the neutrophil counts 28.57 % and 61.9 % at 50 and 100 mg/kg bwt curcumin treatment respectively (Figure 3B, p<0.05). Curcumin significantly reduced the lymphocyte counts 30% and 65 % at 50 and 100 mg/kg bwt curcumin treatment respectively (Figure 3C, p<0.05). The total cell counts, neutrophils, and lymphocyte of control rats (group I) was lower than group II (Figure 3, p<0.05).

Figure 3.

Figure 3

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Effect of curcumin on total cell counts (A), neutrophils (B) and lymphocytes (C) of sepsis-induced CLI of male albino rats. Curcumin 50 and 100 mg/kg bwt were given to the rats for 45 consecutive days. Values were expressed mean ± SD

Effect of curcumin on myeloperoxidase activity

Myeloperoxidase enzyme activity was significantly increased in the BALF of CLP of male albino rats (group II). Curcumin significantly reduced the myeloperoxidase enzyme activity 26.32 % and 63.16% at 50 and 100 mg/kg bwt curcumin treatment respectively (group III & IV, p<0.05). The myeloperoxidase enzyme activity of control rats (Group I) was lower than group II (Figure 4).

Figure 4.

Figure 4

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Effect of curcumin on myeloperoxidase activity of sepsisinduced CLI of male albino rats. Curcumin 50 and 100 mg/kg bwt were given to the rats for 45 consecutive days. Values were expressed mean ± SD

Effect of curcumin on lipid peroxidation

MDA content indicates the level of lipid peroxidation in lung tissues. MDA content significantly increased in the CLP of male albino rats (group II). Curcumin significantly reduced the lipid peroxidation 25 % and 39.28 % at 50 and 100 mg/kg bwt curcumin treatment respectively (group III & IV, p<0.05). The MDA content of control rats (Group I) was lower than group II (Figure 5).

Figure 5.

Figure 5

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Effect of curcumin on lipid peroxidation of sepsis-induced CLI of male albino rats. Curcumin 50 and 100 mg/kg bwt were given to the rats for 45 consecutive days. Values were expressed mean ± SD

Effect of curcumin on SOD activity

SOD enzyme activity indicates the level of antioxidant status in lung tissues. SOD activity significantly reduced in the CLP of male albino rats (group II). Curcumin significantly increased the SOD activity 34.48 % and 110% at 50 and 100 mg/kg bwt curcumin treatment respectively (group III & IV, p<0.05). The MDA content of control rats (group I) was lower than group II (Figure 6).

Figure 6.

Figure 6

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Effect of curcumin on SOD enzyme activity of sepsis-induced CLI of male albino rats. Curcumin 50 and 100 mg/kg bwt were given to the rats for 45 consecutive days. Values were expressed mean ± SD

Effect of curcumin on catalase activity

Catalase enzyme activity indicates the level of antioxidant status in lung tissues. Catalase activity is significantly reduced in the CLP of male albino rats (group II). Curcumin significantly increased the catalase activity 57.14 % and 123.8% at 50 and 100 mg/kg bwt curcumin treatment respectively (group III & IV, p<0.05). The catalase activity of control rats (group I) was lower than group II (Figure 7).

Figure 7.

Figure 7

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Effect of curcumin on catalase enzyme activity of sepsisinduced CLI of male albino rats. Curcumin 50 and 100 mg/kg bwt were given to the rats for 45 consecutive days. Values were expressed mean ± SD

Effect of curcumin on inflammatory cytokines

Inflammatory cytokines such as IL-8, TNF-a and MIF were significantly increased in the serum of CLP of male albino rats (group II) than normal rats (Figure 8). Curcumin significantly reduced the IL-8 content 26.83 % and 68. 29 % at 50 and 100 mg/kg bwt curcumin treatment respectively (Figure 8A). Curcumin significantly reduced the TNF-a content 38.23 % and 78. 23% at 50 and 100 mg/kg bwt curcumin treatment respectively (Figure 8B). Curcumin significantly reduced the MIF content 27.27 % and 63.63 % at 50 and 100 mg/kg bwt curcumin treatment respectively (Figure 8C, group III & IV, p<0.05). The IL-8, TNF-a and MIF content of control rats (group I) was lower than group II (Figure 8, p<0.05).

Figure 8.

Figure 8

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Effect of curcumin on IL-8 (A), TNF-a (B) and MIF (C) of sepsis-induced CLI of male albino rats. Curcumin 50 and 100 mg/kg bwt were given to the rats for 45 consecutive days. Values were expressed mean ± SD

Effect of curcumin on cellular architecture of lung tissues

Histopathological analysis showed normal tissue histology in control rats (Figure 9-A), whereas the lungs of sepsis-induced rats showed remarkable proinflammatory changes including neutrophilic infiltration and edema (Figure 9-B). Curcumin significantly reversed the proinflammatory changes at both doses (Figure 9-C & D, p<0.05).

Figure 9.

Figure 9

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Histopathological analysis showed normal tissue histology in control rats (Figure 9-A), whereas the lungs of sepsis-induced rats showed remarkable proinflammatory changes including neutrophilic infiltration and edema (*) (Figure 9-B). Curcumin significantly reversed the proinflammatory changes at both doses (Figure 9-C & D, p<0.05). Sections were scored with OARSI and HHGS scale. Moderate reversal of inflammation was observed at a low dose of curcumin treatment (#), whereas significant reversal of inflammation was found at a higher dose of curcumin treatment (##)

Discussion

CLI associated with sepsis that leads to severe morbidity and mortality of animals. This is the starting point for the development of several organ dysfunction syndromes. Therefore, CLI prevention and management is the key point for the therapeutic approach. Natural compounds are widely used in the prevention and management of several diseases such as immune and inflammatory-related diseases. Non-toxic, abundance, efficacy, low cost, and availability are key salient features of any natural compounds for the application of illness prevention and management of the human and animal system.

Curcumin has been known to modulate several signaling pathways that are necessary for the several chronic diseases (21). It has been reported as a potential compound for the prevention of several chronic diseases such as arthritis, diabetes, cardiovascular disease, cancer and neurological diseases. Therefore, the present was aimed to investigate the effect of curcumin on sepsis-induced CLI of male albino rats. The edema is a common symptom of inflammation. The W/D weight ratio indicates the severity of pulmonary edema. In our study, curcumin significantly reduced the W/D weight ratio of lung tissues that demonstrate the curcumin inhibits the serous fluid leakage into the lungs.

Protein content indicates the severity of permeability of lungs. The total protein content was determined in the BALF of male albino rats. Curcumin reduced total protein content that indicates the reduction of pulmonary lung permeability. Our results demonstrate that curcumin reduced the formation of pulmonary edema, and it was supported that the role of inflammatory cells in the pathogenesis of CLI (22). Inflammatory cells such as lymphocytes and neutrophils were increased in the sepsis-induced lungs of male albino rats. Curcumin treatment could significantly reduce these inflammatory cells towards the normal range. In addition to these findings, histopathological analysis showed that the curcumin reduced lung inflammation such as neutrophil infiltration, alveolar distortion and pulmonary edema in the sepsis-induced CLI of male albino rats. Overall, these finding confirms that the curcumin is acting as a strong protective agent against inflammation of lung tissues.

Measurement of oxidative stress could be useful to evaluate the mechanism of curcumin action against sepsis-induced CLI of male albino rats. The functional role of oxidative stress has been extensively studied in the pathogenesis of CLI. Reactive oxygen species (ROS) is readily reactive and react with macromolecules. It induces lipid peroxidation that leads to mutation of DNA and formation of inactive proteins. Neutrophils produce superoxide molecules under respiratory burst during inflammation. Increased production of ROS is toxic to cells and interacts with macromolecules that lead to severe pathogenesis (23).

Antioxidants have controlled sepsis-induced disease and inflammation through enhancement of defense system (24). In sepsis-induced CLI, superoxide scavenging enzyme SOD and catalase has been drastically reduced (25). Our results showed that CLP increased oxidative stress and MDA content that are significant markers for antioxidant status. Curcumin treatment significantly increased SOD and catalase activity that leads to a reduction of lipid peroxidation. Thus, curcumin treatment could significantly reduce oxidative stress and may be a potent therapeutic agent for the treatment of inflammation.

Inflammatory cytokines have been known to play in the inflammation. Therefore, the investigation of curcumin effect on cytokines production in sepsis-induced lungs of male albino rats is mandatory. Proinflammatory factor TNF-a produced from macrophages and monocytes that initiate the inflammatory reaction and participates in the worsening of lung injury (26). The increased level of TNF-a has been directly associated with recruitment of neutrophils in the lungs (27). Our study showed that CLP increased TNF-a in the lungs of male albino rats, whereas curcumin significantly reversed the level of TNF-a towards the normal level. Our results are consistent with the report of another researcher (28). IL-8 is key neutrophil chemokine involving in the neutrophil-mediated capillary leak, ischemia-reperfusion injury and endothelial activation (29). Lung tissue destruction has been initiated through IL-8 mediated release of elastase, alkaline phosphatase and 5-oxoeicosatetraenoic acid (30). Curcumin has been known to reduce the IL-8 level in the epithelial cells (31). MIF is another cytokine has been known to increase in the sepsis-induced lung infection (32) and regulates immunosuppressive and antiinflammatory effects (33). MIF was significantly increased in the lungs of CLP of male albino rats during treatment of curcumin significantly reduced this level towards normal. Xiao et al., (17) have reported the use of curcumin in the range of 50-200 mg/kg bwt significantly improved sepsis-induced acute lung injury in rats. Our results were strongly agreed with these findings. Baum et al., (34) have reported the oral administration of curcumin (1 and 4 g/day) did not produce side effects and effected lipid profile after absorption in the human subjects.

Conclusion

In summary, our study confirms that curcumin treatment could act against CLP-induced CLI. Curcumin therapeutic effect against inflammation was evidenced by the reduction of protein level, W/D weight of lung tissue, inflammatory cells, and inflammatory cytokines.

Conflict of interest

There is no any conflict interest in this study.

Ethical Standards

This study has been approved by the ethics committee of the second hospital of Dalin University.

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