Anti-inflammatory Effects of Novel Curcumin Analogs in Experimental Acute Lung Injury

Yali Zhang; Dandan Liang; Lili Dong; Xiangting Ge; Fengli Xu; Wenbo Chen; Yuanrong Dai; Huameng Li; Peng Zou; Shulin Yang; Guang Liang

Disclosures

Respiratory Research. 2015;16(43) 

In This Article

Abstract and Introduction

Abstract

Background 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.

Methods 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.

Results 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.

Conclusions 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.

Introduction

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.[3] 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.

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