<p>Paclitaxel alleviated sepsis-induced acute lung injury by activating MUC1 and suppressing TLR-4/NF-κB pathway</p>

Abstract

PurposeIt has been reported that approximately 40% of ALI (acute lung injury) incidence resulted from sepsis. Paclitaxel, as a classic anti-cancer drug, plays an important role in the regulation of inflammation. However, we do not know whether it has a protective effect against CLP (cecal ligation and puncture)-induced septic ALI. Our study aims to illuminate the mitigative effects of paclitaxel on sepsis-induced ALI and its relevant mechanisms.Materials and methodsThe survival rates and organ injuries were used to evaluate the effects of paclitaxel on CLP mice. The levels of inflammatory cytokines were tested by ELISA. MUC1 siRNA pre-treatment was used to knockdown MUC1 expression in vitro. GO203 was used to inhibit the homodimerization of MUC1-C in vivo. The expression levels of MUC1, TLR 4 and p-NF-κB/p65 were detected by Western blot.ResultsOur results showed that paclitaxel improved the survival rates and ameliorated organ injuries especially lung injury in CLP-induced septic mice. These were accompanied by reduced inflammatory cytokines in sera and BALF (bronchoalveolar lavage fluid). We also found paclitaxel could attenuate TLR 4-NF-κB/p65 activation both in lung tissues of septic mice and LPS-stimulated lung type II epithelial cell line A549. At the upstream level, paclitaxel-upregulated expression levels of MUC1 in both in vivo and in vitro experiments. The inhibitory effects of paclitaxel on TLR 4-NF-κB/p65 activation were reversed in lung tissues of septic mice pre-treated with MUC1 inhibitor and in MUC1-knockdown A549 cells. Protection of paclitaxel on sepsis-induced ALI and decrease of inflammatory cytokines were also abolished by inhibition of MUC1.ConclusionCollectively, these results indicated paclitaxel could significantly alleviate acute lung injury in CLP-induced septic mice and LPS-stimulated lung type II epithelial cell line A549 by activating MUC1 and suppressing TLR-4/NF-κB pathway.

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

“…During the inflammatory process of ALI/ARDS, several signal transduction pathways such as nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3), toll like receptors (TLRs), adrenergic receptors and JAK/STAT signaling pathways are involved [ [25] , [26] , [27] ]. Inhibition of NF-κB expression can inhibit the expression of inflammatory cytokines in the lungs, significantly reduce the inflammatory response in the lungs and improve the survival rate of lipopolysaccharide (LPS)-induced ALI mice [ 28 ]. In addition, the ablation of proteins such as NAMPT, Rip2 and Pfkfb3, which could activate the NF-κB signaling pathway, were found to prevent lung injury and inflammatory response in ischemia-reperfusion (I/R), LPS or cigarette smoke-induced ALI mice [ [29] , [30] , [31] , [32] ].…”

Pellino1 promoted inflammation in lung injury model of sepsis by TRAF6/ NF-κB signal pathway

“…Accumulative studies have confirmed that the activation of NF-kB plays an important role in the occurrence and development of many critical illnesses, and the activation of NF-kB is also associated with a variety of inflammatory factors [ 22 ]. As a pleiotropic regulatory factor, NF-kB is at the core of inflammation and anti-inflammation [ 23 ].…”

Emodin protects against intestinal and lung injury induced by acute intestinal injury by modulating SP-A and TLR4/NF-κB pathway

“…Consistent with previous studies, in our study, we found that TLR4 levels were remarkedly decreased in serum, intestinal and lung tissues of rats with acute intestinal injury, which were ameliorated by emodin treatment. TLR4/NF-κB pathway has been reported to be closely related to acute intestinal/lung injury [2,25,26]. The NF-κB family consists of five members: P50, P52, p65/RelA, RelB and c-Rel.…”