RETRACTED ARTICLE: Flavocoxid, a dual inhibitor of COX-2 and 5-LOX of natural origin, attenuates the inflammatory response and protects mice from sepsis

Abstract

IntroductionCecal ligation and puncture (CLP) is an inflammatory condition that leads to multisystemic organ failure. Flavocoxid, a dual inhibitor of cyclooxygenase (COX-2) and 5-lipoxygenase (5-LOX), has been shown in vitro to possess antiinflammatory activity in lipopolysaccharide (LPS)-stimulated rat macrophages by reducing nuclear factor (NF)-κB activity and COX-2, 5-LOX and inducible nitric oxide synthase (iNOS) expression. The aim of this study was to evaluate the effects of flavocoxid in a murine model of CLP-induced polymicrobial sepsis.MethodsC57BL/6J mice were subjected to CLP or sham operation. In a first set of experiments, an intraperitoneal injection of flavocoxid (20 mg/kg) or vehicle was administered 1 hour after surgery and repeated every 12 hours. Survival rate was monitored every 24 hours throughout 120 hours. Furthermore, additional groups of sham and CLP mice were killed 18 hours after surgical procedures for blood-sample collection and the lung and liver were collected for biomolecular, biochemical and histopathologic studies.ResultsCOX-2, 5-LOX, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10, extracellular-regulated-kinase 1/2 (ERK), JunN-terminal kinase (JNK), NF-κB, and β-arrestin 2 protein expression were evaluated in lung and liver with Western blot analysis. In addition, leukotriene B4 (LTB4), prostaglandin E2 (PGE2), cytokines, and lipoxin A4 serum content were measured with an enzyme-linked immunosorbent assay (ELISA). Flavocoxid administration improved survival, reduced the expression of NF-κB, COX-2, 5-LOX, TNF-α and IL-6 and increased IL-10 production. Moreover, flavocoxid inhibited the mitogen-activated protein kinases (MAPKs) pathway, preserved β-arrestin 2 expression, reduced blood LTB4, PGE2, TNF-α and IL-6, and increased IL-10 and lipoxin A4 serum levels. The treatment with flavocoxid also protected against the histologic damage induced by CLP and reduced the myeloperoxidase (MPO) activity in the lung and liver.ConclusionsFlavocoxid protects mice from sepsis, suggesting that this dual inhibitor may represent a promising approach in such a life-threatening condition.

Flavocoxid attenuates gentamicin-induced nephrotoxicity in rats

“…However, flavocoxid administration resulted in reversing that increase. This result agreed with Bitto et al (2012) who reported that flavocoxid decreased the expression of NF-κB and the level of MPO, a marker of neutrophil accumulation, thus suggesting that the dual inhibitor of COX-2 and 5-LOX may work as an NF-κB inhibitor.…”

Pivotal Role of the 5-Lipoxygenase Pathway in Lung Injury after Experimental Sepsis

“…Although the 5-LO pathway has been implicated in lung injury, including that elicited by LPS administration (26), its role in sepsisinduced lung injury has not previously been examined. Recently, a study demonstrated that a dual inhibitor of cyclooxygenase 2 and 5-LO attenuates the inflammatory response and improves survival in murine CLP, but the independent contributions of these two enzymatic pathways were not distinguished (27). Moreover, no previous studies have determined the role of 5-LO products in the physiologic derangements associated with acute lung injury (ALI).…”

β-Arrestins in the Immune System

“…β-arrestin 2 protein expression was reduced in a murine model of CLP-induced polymicrobial sepsis 134 . β-arrestin 2 deficient mice exhibit decreased mortality, increased IL-6 and elevated caecal myeloperoxidase in a mouse model of polymicrobial sepsis by caecal ligation and puncture (CLP).…”

“…β-arrestins play a role in bacterial-induced inflammation and clearance, such as in sepsis 34; 134; 135 , and Cryptococcus infections 27 . For example, deficiency in β-arrestin-2 in mice showed decreased mortality and reduced infections.…”