The Anti-Lnflammatory Effects Of Protease-Me Inhibitor MG-132in Rats With Acute Lung Injury Induced By Lipopolysaccharide

Background Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) isa common and serious disease，which with high perinatal mortality and morbidityrates. The major clinic characters of this syndrome include respiratory distress,intractable hypoxemia and non-cardiogenic pulmonary edema.The pathogenesis ofALI/ARDS is complex, has not yet completely clear, it may product by inflammatorymediators, oxidative stress, alveolar epithelial injury and vascular, apoptosis, andother factors. Currently it is considered infection is a major pathogenic factor in ALI.A variety of the lungs cells involved in the process of inflammation in ALI,inflammation cells and its effect on the release of its neurotransmitters and cytokines,resulting in acute lung injury. So in view of the immunity reaction ofanti-inflammatory therapy is becoming a hot spot of research. Nuclear factor-kappaB(NF-κB) is one of transcriptional regulatory factors,which can be found in all kinds ofcells and be capable of producing multiplex biological effects. It contributes toinflammatory,immunological apoptosis,apoptosis and acute stress reaction.The studyfound that the NF-κB pathway in rats with acute lung injury plays an important role inpathological changes. Nuclear factor-kappa B (nuclear factor kappaB, NF-κB) is akind of diversity of widely exists in all types of cells, pleiotropic transcriptionregulatory factors, it participate in the regulation of immue response, inflammation,apoptosis and acute stress reactions, and so on related gene transcription. TNF-α、ICAM-1、IL-1、IL-6、IL-8、IL-12、GM—CSF, etc. were regulated by NF-κB. LPS activated neutrophils (PNM) or the NF-κB in lung tissue, leading to the release ofinflammatory medium and alveoli inflammatory cell infiltration, eventually lead tolung damage.At present, the proteasome inhibitor MG-132for lipopolysaccharideinduced acute lung injury rats. But there is not yet proteasome inhibitor MG-132oninflammatory effects of lipopolysaccharide(LPS) induced acute lung injury(ALI)in rats reported. This study aims to observe the effect of MG-132on expression ofICAM-1、TNF-α、NF-κB P65on endotoxin induced acute lung injury in rate, and tofurther explore the effects and mechanism of MG-132on NF-κB signaling andinflammatory in endotoxin induced acute lung injury.Objective To explore the anti-inflammatory mechanism of the proteasome inhibitor MG-132on rats with acute lung injury(ALI).Methods Fifty-four male SD rats were randomly divided into3groups: control group (Group A), ALI group(Group B),MG-132group (Group C).LPS5mg/kg was injected via tail vein in Group B and C, while the normal saline wasgiven instead in Group A. MG-13210mg/kg was injected intraperitoneally at30min before LPS administration in Group C. Six rats in each group were sacrificed at2,4,and8h after normal saline or LPS administration. Then the following parameters were observed including pathology changes of lung tissue, wetto dry weight ratio of lung tissue (W/D), the levels of ICAM-1and TNF-αinbronchoalveolar lavage fluid(BALF) via ELISA, ICAM-1、NF-κB P65mRNAlevels were determined by RT-PCR,and the protein level of ICAM-1、NF-kappaB P65in lung tissue by Western blot.Results①Pathological change in Group A were visible pulmonary interstitialand alveolar congestion, edema, inflammation; the pathological observationshowed the typical ALI performance, as obviously pulmonary tissue congestion,edema, a large number of inflammatory cells infiltration in Group B. These inflammatory performance were obviously reduced in Group C.②Compared with Group A, W/D, the levels of ICAM-1and TNF-α in BALF, the mRNA levels of ICAM-1、NF-kappaB P65and the expression of the protein NF-kappaB P65in lung tissue of rats at2,4and6h in Group B were significantly increased(P<0.05), while compared with Group B, W/D, the levels of ICAM-1andTNF-α in BALF, the mRNA levels of ICAM-1、NF-κB P65and the expression of the protein NF-κB P65at2,4and6h in Group C were significantly decreased(P<0.05).③The levels of ICAM-1and TNF-α in the BALF were significantly positively related with the levels of NF-κB P65mRNA(r=0.654～0.863，P<0.01),and were significantly positively related with the levels of NF-κB P65protein expression(r=0.732～0.982，P<0.01). The expression of the mRNA ICAM-1was significantly positive related with the levels of NF-κB P65mRNA andprotein expression(r=0.682～0.856，P<0.01).Conclusions1. Using the method of tail vein injection of LPS5mg/kg could besuccessfully copied acute lung injury model in rats.2.In ALI rats models, the activation of NF-κB increase the expressionof inflammation related factors such as TNF-α, ICAM-1,the NF-κB inflammatorysignaling pathways were involved in ALI rat development process.3.MG-132could reduce inflammatory response in rats with acute lunginjury induced by lipopolysaccharide, its mechanism may be related to reduce theexpression of inflammation related factors such as TNF-α and ICAM-1throughinhibiting the activation of the NF-κB.