Background: Acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) have\nbeen the leading cause of morbidity and mortality in intensive care units (ICU). Currently, there is no effective\npharmacological treatment for acute lung injury. Curcumin, extracted from turmeric, exhibits broad anti-inflammatory\nproperties through down-regulating inflammatory cytokines. However, the instability of curcumin limits its clinical\napplication.\nMethods: A series of new curcumin analogs were synthesized and screened for their inhibitory effects on the\nproduction of TNF-? and IL-6 in mouse peritoneal macrophages by ELISA. The evaluation of stability and mechanism of\nactive compounds was determined using UV-assay and Western Blot, respectively. In vivo, SD rats were pretreatment\nwith c26 for seven days and then intratracheally injected with LPS to induce ALI. Pulmonary edema, protein\nconcentration in BALF, injury of lung tissue, inflammatory cytokines in serum and BALF, inflammatory cell\ninfiltration, inflammatory cytokines mRNA expression, and MAPKs phosphorylation were analyzed. We also\nmeasured the inflammatory gene expression in human pulmonary epithelial cells.\nResults: In the study, we synthesized 30 curcumin analogs. The bioscreeening assay showed that most compounds\ninhibited LPS-induced production of TNF-? and IL-6. The active compounds, a17, a18, c9 and c26, exhibited their\nanti-inflammatory activity in a dose-dependent manner and exhibited greater stability than curcumin in vitro.\nFurthermore, the active compound c26 dose-dependently inhibited ERK phosphorylation. In vivo, LPS significantly\nincreased protein concentration and number of inflammatory cells in BALF, pulmonary edema, pathological\nchanges of lung tissue, inflammatory cytokines in serum and BALF, macrophage infiltration, inflammatory gene\nexpression, and MAPKs phosphorylation. However, pretreatment with c26 attenuated the LPS induced increase\nthrough ERK pathway in vivo. Meanwhile, compound c26 reduced the LPS-induced inflammatory gene expression\nin human pulmonary epithelial cells.\nConclusions: These results suggest that the novel curcumin analog c26 has remarkable protective effects on\nLPS-induced ALI in rat. These effects may be related to its ability to suppress production of inflammatory cytokines\nthrough ERK pathway. Compound c26, with improved chemical stability and bioactivity, may have the potential to be\nfurther developed into an anti-inflammatory candidate for the prevention and treatment of ALI.
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