Anti-inflammatory effects of novel curcumin analogs in experimental acute lung injury
- Yali Zhang†1,
- Dandan Liang†1,
- Lili Dong3,
- Xiangting Ge3,
- Fengli Xu3,
- Wenbo Chen1,
- Yuanrong Dai3,
- Huameng Li1,
- Peng Zou2,
- Shulin Yang2Email author and
- Guang Liang1Email author
© Zhang et al.; licensee BioMed Central. 2016
Received: 18 September 2014
Accepted: 27 February 2015
Published: 24 March 2015
Acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) have been the leading cause of morbidity and mortality in intensive care units (ICU). Currently, there is no effective pharmacological treatment for acute lung injury. Curcumin, extracted from turmeric, exhibits broad anti-inflammatory properties through down-regulating inflammatory cytokines. However, the instability of curcumin limits its clinical application.
A series of new curcumin analogs were synthesized and screened for their inhibitory effects on the production of TNF-α and IL-6 in mouse peritoneal macrophages by ELISA. The evaluation of stability and mechanism of active compounds was determined using UV-assay and Western Blot, respectively. In vivo, SD rats were pretreatment with c26 for seven days and then intratracheally injected with LPS to induce ALI. Pulmonary edema, protein concentration in BALF, injury of lung tissue, inflammatory cytokines in serum and BALF, inflammatory cell infiltration, inflammatory cytokines mRNA expression, and MAPKs phosphorylation were analyzed. We also measured the inflammatory gene expression in human pulmonary epithelial cells.
In the study, we synthesized 30 curcumin analogs. The bioscreeening assay showed that most compounds inhibited LPS-induced production of TNF-α and IL-6. The active compounds, a17, a18, c9 and c26, exhibited their anti-inflammatory activity in a dose-dependent manner and exhibited greater stability than curcumin in vitro. Furthermore, the active compound c26 dose-dependently inhibited ERK phosphorylation. In vivo, LPS significantly increased protein concentration and number of inflammatory cells in BALF, pulmonary edema, pathological changes of lung tissue, inflammatory cytokines in serum and BALF, macrophage infiltration, inflammatory gene expression, and MAPKs phosphorylation. However, pretreatment with c26 attenuated the LPS induced increase through ERK pathway in vivo. Meanwhile, compound c26 reduced the LPS-induced inflammatory gene expression in human pulmonary epithelial cells.
These results suggest that the novel curcumin analog c26 has remarkable protective effects on LPS-induced ALI in rat. These effects may be related to its ability to suppress production of inflammatory cytokines through ERK pathway. Compound c26, with improved chemical stability and bioactivity, may have the potential to be further developed into an anti-inflammatory candidate for the prevention and treatment of ALI.
Acute lung injury (ALI) is defined as acute inflammatory lung injuries associated with histopathological changes including neutrophilic alveolar infiltrates, impaired alveolar fluid clearance, fibrin deposition and lung edema. Despite advances in therapies, the outcomes of ALI in critically ill patients remain dismal with a morbidity and mortality rate around 40% [1-3]. With improved understanding of the pathogenesis of ALI, accumulating evidence shows that the release of pro-inflammatory cytokines play a critical role in inflammation-induced lung injury. Previous reports indicated that tumor necrosis factor (TNF)α, interleukin (IL)6, IL-1β, and IL8 are the key inflammatory mediators involved in the progression of ALI [4-6].
Numerous pharmacological agents were investigated in an effort to attenuate the release of these pro-inflammatory cytokines involved in ALI. In pre-clinical experiments, these anti-inflammatory agents have demonstrated potent inhibitory effects on the release of inflammatory mediators and protective effects on ALI [7-10]. However, several pharmacological therapeutic trials failed to demonstrate any benefit in patients with ALI [11,12]. The failure of prior clinical trials of several pharmacological agents may be partly due to the delay of therapy which occurred several days after the onset of ALI. Therefore, pharmacological therapies for prevention or early intervention of ALI have emerged as a new paradigm . Some of the most promising therapeutic agents for early treatment of ALI include aspirin, statins, beta-2 adrenergic agonists, corticosteroids, vitamin D, and butyrate [3,13-15].
Curcumin, a natural product isolated from turmeric, has been found to have broad anti-inflammatory activities both in vitro and in vivo. However, the poor solubility and chemical instability of curcumin, under physiological conditions, limit its bioavailability and clinical efficacy [16-18]. Curcumin analogs have been designed to improve bioavailability and bioactivity. Among them, mono-carbonyl analogs of curcumin (MACs) demonstrate excellent chemical stability and pharmacokinetic profiles [19-21]. We previously synthesized and identified a mono-carbonyl analog of cucurmin (C66), which demonstrated excellent chemical stability and potent anti-inflammatory effects both in vivo and in vitro [22,23]. Recent studies indicate that curcumin has potential protective effects for ALI [24-26]. However, there is no report on the effects of curcumin analogs on lipopolysaccharide (LPS)-induced ALI. We considered that the investigation of the effects of novel curcumin analogs with improved chemical stability may discover novel anti-inflammatory candidate agents for the prevention or treatment of ALI.
Materials and methods
Animals and reagents
Male ICR mice (6 wk, 18-20 g) and Sprague–Dawley (SD) rats (6 wk, 180-200 g) were obtained from Shanghai SLAC Laboratory Animal Center, CAS (SLACCAS). Mice were housed under specific pathogen-free conditions with a 12-hour/12-hour light–dark cycle and maintained on a normal diet at Wenzhou Medical University Animal Center. All mice and in vivo experiments were performed in accordance with procedures approved by Wenzhou Medical University Animal Policy and Welfare Committee (Approval Documents: 2013/APWC/0361).
LPS was purchased from Sigma (St. Louis, MO). Enzyme-linked immunosorbent assay (ELISA) kits of TNF-α and IL-6 were obtained from eBioscience, Inc. (San Diego, CA, USA). Extracellular signal-regulated kinase (ERK), p-ERK and CD68 antibodies were purchased from Santa Cruz Biotechnology, Inc., (Santa Cruz, CA, USA). Antibodies of p-P38, P38, p-Jun N-terminal kinase (JNK), and JNK were obtained from Cell Signaling Technology, Inc., (Danvers, MA, USA).
Harvest and culture of mouse primary peritoneal macrophages (MPMs)
ICR mice were stimulated by intraperitoneal injection of 6% thioglycolate broth (0.3 g beef extract, 1 g tryptone, 0.5 g NaCl and 6 g starch dissolved in 100 mL H2O, 1.5 mL/mouse) for 3 days before sacrificed for MPMs harvest. MPMs were then centrifuged and suspended in RPMI-1640 medium (Gibco/BRL life Technologies, Eggenstein, Germany) supplemented with 10% FBS and 1% penicillin/streptomycin. The cells were incubated overnight at 37°C in a 5% CO2-humidified air.
Detection of TNF-α and IL-6 expression by ELISA
The MPMs harvested were pre-treated with curcumin (10 μM), compounds (10 μM), or DMSO (control) for 30 minutes, which was followed by the treatment of 0.5 μg/mL LPS. After treatment, the cells were incubated for 24 hours. The media were collected to measure the amount of TNF-α and IL-6 through the use of ELISA kit (eBioScience, San Diego, CA) according to manufacturer’s protocol. The total protein concentrations in viable cell pellets were measured. The amounts of TNF-α and IL-6 were normalized to the total proteins in cells.
Chemical stability analysis of curcumin analogs by UV absorbance spectroscopy
Curcumin or the active compounds were dissolved in DMSO (1 mM) and diluted with PBS (pH 7.4) to 20 μM. The absorbance spectra were taken from 250 to 600 nm at 25°C on SpectraMax® M5 (Molecular Devices LLC, Sunnyvale, CA, USA). Absorbance spectral readings were recorded for over a time span of 25 minutes at 5 minute intervals.
Western blot analysis
The macrophages harvested from mice were pretreated with the active compounds or DMSO (control) for 30 minutes and then incubated with 0.5 μg/mL LPS for 20 minutes. After treatment, protein samples were collected, separated by SDS-PAGE, and transferred to PVDF membranes. Membranes were incubated with a blocking solution of 5% non-fat milk for 1.5 h at room temperature. Proteins on membranes were then separately probed with the primary antibodies overnight. Protein samples were further incubated with horseradish peroxidase-conjugated (HRP) secondary antibodies for 1 h, and visualized using enhanced chemiluminescence reagents (Bio-Rad Laboratories).
Animal models of ALI
SD rats were randomly placed into three groups (n = 6, each group). The rats were anesthetized and the tracheas were surgically exposed. Group 1 (CON group) received an intratracheal injection of saline. Group 2 (LPS group) received a drop-wise intratracheal injection of LPS (5 mg/kg, 50 μL), Group 3 (CUR + LPS group) and Group 4 (c26 + LPS group) received an intra-gastric administration of compound c26 (20 mg/kg/day) daily for seven days prior to the administration of LPS (50 μL, 5 mg/kg). Six hours after LPS administration, all animals were anesthetized by chloral hydrate and sacrificed. Broncho-alveolar lavage fluids (BALF) were collected for determination of total protein concentration and inflammatory cell infiltration. The lobes of the right lung were harvested for the study of curcumin and c26 on LPS induced lung injury analysis.
Thoracotomy and ligation of the left lung were performed. The left lung was infused three times with 1 mL phosphate buffered saline (PBS) in order to obtain BALF as previously described . The collected BALF was centrifuged for 10 minutes at 1,000 rpm. Cell-free supernatant was used for measurement of target protein cytokines. The cell pellets obtained from BALF were washed and re-suspended in 50 μL PBS for cell counting with a Hemocytometer.
Lung wet/dry weight ratio
The right upper lobe of lung was excised. After removal of the excessive water on the tissue surface, the wet weight was recorded. The sample was then dried at 60°C for 48 h until no weight change to record the dry weight. The wet weight/dry weight ratio (W/D) was calculated and used as an index of lung edema.
Pulmonary histopathology and immunohistochemistry analysis
The right lower lobe of lung was excised and fixed with 4% formalin. The lung tissues were embedded with paraffin, sliced to 5 μm sections, and stained with hematoxylin and eosin (HE). Rat lung histopathology images were acquired using a microscope (Nikon Model Eclipse 80i, Nikon, Tokyo, Japan). The immunohistochemistry analysis was performed following the anti-CD68 antibody staining protocol.
The lung injury was evaluated by Lung injury scoresas described previously . In brief, no injury = score of 0; injury in 25% of the field = score of 1; injury in 50% of the field = score of 2; injury in 75% of the field = score of 3; and injury through out the field = score of 4. Ten random microscopic fields from each slide were analyzed. The average score of the 10 slides was used to assess the severity of lung injury.
Real-time PCR analysis for mRNA expressions of TNF-α, IL-6, IL-1β and COX-2
Total RNA was isolated from Beas-2B cells or lung tissue of rats with ALI using Trizol, then reversely transcribed to cDNA using M-MLV according to guidelines of the manufacturer. Gene specific primers used for TNF-α, IL-6, IL-1β, COX-2 and β-actin are listed in Additional file 1: Table S1.
Data collected from experiments were analyzed using Graphpad prism 5.0 software. Values were expressed as mean ± SEM. One way ANOVA test was employed to analyze the differences between sets of data. A p-value of < 0.05 was considered as statistically significant and denoted as*. In vitro experiments were performed with n ≥ 3 independent repeats. In vivo experiments were performed with n ≥ 5 rats in each group.
Screening of curcumin analogs for inhibition of the expression of cytokines TNF-α and IL-6
The effects of a17, a18, c9 and c26 on the expression of IL-6 and TNF-α
Chemical stability analysis of bioactive compounds a17, a18, c9 and c26
Effect of c26 on the phosphorylation of ERK, JNK, and p38 in MAPK pathways
The effects of c26 on pulmonary histopathological changes of lungs in rats with ALI
Effect of c26 on inflammatory cell infiltrations in rat lungs with ALI
The potential anti-inflammatory mechanism of c26 in vivo
Inhibition of IL-6 and IL-1β mRNA expression in human pulmonary epithelial cells
Acute lung injury (ALI) plays a pivotal role in the death of patients in intensive care unit. There is considerable experimental and clinical evidence indicates that inflammatory cytokines play a major role in the pathogenesis of LPS-induced lung injury [4,30]. A variety of new medications have appeared for the treatment of acute lung injury and new research on traditional therapies has been performed . However, numerous pharmacological therapies for established ALI, including corticosteroids and steroids, have failed to show any therapeutic benefit in clinical trials [31,32].
TNF-α and IL-6 are important pro-inflammatory cytokines that can stimulate production of a host of other cytokines . They have been measured to be elevated in ARDS BALF, however, measured values do not predict clinical outcome . IL-6 gene-deficient mice are insensitive to pneumococcal pneumonia following intranasal inoculation of Streptococcus pneumonia . Previous reports indicated that natural products have the ability to attenuate LPS-induced acute lung injury via down-regulation of TNF-α and IL-6 production [36-38]. In our study, the majority of the synthesized compounds had the ability to reduce LPS-induced TNF-α and IL-6 production (Figure 2). Furthermore, the active compounds a17, a18, c9 and c26 showed a dose-dependent inhibitory activity (Figure 3). These results demonstrated that the synthesized compounds have the potential to treat ALI by inhibiting inflammatory cytokines production.
After LPS incubation, TLR4 signaling was initiated, thus leading to the activation of NF-kB and MAPK . NF-κB is a nuclear transcription factors that controls transcription of DNA . Many researchers have reported that curcumin and curcumin analogs have the ability to inhibit the LPS-induced activation of NF-κB [21,41]. Unfortunately, the compounds in our research exhibited no effect on the activation of NF-κB (Data not shown). MAPK are a family of protein serine/threonine kinases that contain three subunits which include ERK, JNK, and P38 MAPK . Increased activity of MAPK and their involvement in the regulation of the synthesis of inflammatory mediators at the level of transcription and translation, make them potential targets for anti-inflammatory therapeutics [43,44]. Zhan et al. reported that penehyclidine hydrochloride ameliorated acute lung injury through the inhibition of ERK1/2 and p38 MAPK activation in septic mice . In this study, we found that LPS could activate all of three pathways of MAPKs (Figure 3A). Interestingly, compound c26 exhibited no inhibitory ability on the phosphorylation of JNK and p38, however, it dose-dependently inhibited ERK phosphorylation induced by LPS (Figure 5). These results suggest that the inhibition of the production of TNF-α and IL-6 by c26 may be mediated by the down-regulation of the ERK signaling. The underlying mechanism of the anti-inflammatory action of c26 needs to be further investigated.
It has been reported that sepsis, especially gram negative bacteria infection, is the main cause of ALI/ARDS [46,47]. LPS, a major component of gram negative bacteria cell walls, was usually used to induce ALI in animals [48,49]. In our in vivo study, the model of acute lung injury was induced by intratracheal instillation LPS. LPS significantly increased protein concentration and the number of inflammatory cells in BALF, pulmonary edema, pulmonary histopathological changes, inflammatory cytokines in serum and BALF, macrophages infiltration, inflammatory cytokine mRNA levels and inflammatory pathway (Figures 6, 7 and 8). However, pretreatment with c26 attenuated the increase of these markers induced by LPS through inhibited the phosphorylation of ERK. In summary, the most active compound, c26, exhibited its anti-inflammatory activity in vitro and attenuated LPS-induced acute lung injury by reducing inflammatory responses in vivo through ERK pathway. This article provides a potential compound for the treatment of acute lung injury.
In conclusion, we designed and synthesized 30 curcumin analogs based on the structure of curcumin and C66. In vitro, most curcumin analogs showed better activity on LPS-induced production of TNF-α and IL-6 than C66. Active compounds, a17, a18, c9, and c26, exhibited their anti-inflammatory activity in a dose-dependent manner and showed high chemical stability in vitro. From the perspective mechanisms, compound c26 dose-dependently inhibited LPS-induced ERK phosphorylation in macrophages. In rat models with ALI, pretreatment with c26 significantly attenuated LPS-induced pulmonary edema, pathological changes, inflammatory cytokines in serum and BALF, inflammatory cell infiltration, inflammatory cytokine mRNA expression and ERK phosphorylation. This presents the possibility that curcumin analogs might serve as potential agents for the treatment of ALI. Although the anti-inflammatory mechanism and underlying targets are still unknown, the beneficial effects of these compounds on LPS-induced inflammation make c26 one of important leads in the continuing drug development and research.
Financial support was provided by the National Natural Science Funding of China (81302642, 81202462, and 21272179), Zhejiang Provincial Natural Science Funding (LQ14H310003), High-level Inovative Talent Funding of Zhejiang Department of Health (G. L.), National “863” project (2011AA02A113).
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