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.
Highlights
Cecal ligation and puncture (CLP) is an inflammatory condition that leads to multisystemic organ failure
Cecal ligation and puncture (CLP) is an experimental model of shock that reproduces all the pathologic sequelae of sepsis that occur in intensive care patients [1]
Six mice per group were subjected to sham operation or CLP, and nuclear factor (NF)-B, MAP kinases, tumor necrosis factor-a (TNF-a), IL-6, IL-10, and b-arrestin 2 expression was determined in the lung and liver after 18 hours
Summary
Cecal ligation and puncture (CLP) is an inflammatory condition that leads to multisystemic organ failure. Cecal ligation and puncture (CLP) is an experimental model of shock that reproduces all the pathologic sequelae of sepsis that occur in intensive care patients [1]. Despite a massive effort invested in developing potential therapies, to date, severe sepsis is still a common, factor (NF)-B/IB system activation that exerts transcriptional regulation on proinflammatory genes and encodes various adhesion molecules, cytokines, and other proinflammatory mediators. It was demonstrated that b-arrestins, adaptor proteins involved in G protein-coupled receptor (GPCR) desensitization, are implicated in regulation of TLR signaling and proinflammatory gene expression. It has been suggested that b-arrestin 1 and 2 differentially regulate TLR4 signaling pathways and, in particular, b-arrestin 2 negatively regulates the inflammatory response in CLP-induced mortality [5,6]. Severe sepsis associated with hypotension, acute respiratory distress syndrome (ARDS), hepatic failure, disseminated intravascular coagulation, and organ dysfunction, is characterized by a poor prognosis; these changes are well documented first in the lung and in the liver [11]
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