Effect of siRNA against NF-κB on sepsis-induced acute lung injury in a mouse model

Abstract

The aim of the present study was to explore the protective effect of small interfering RNA (siRNA) against nuclear factor κB (NF-κB) p65 on sepsis-induced acute lung injury (ALI) in mice. In total, 70 male Kunming mice were randomly divided into a healthy control group, a sepsis group, a specific interfering group and a scrambled control group (Sc), and the latter three groups were divided into post-operational 6 and 12 h subgroups, each of which consisted of 10 mice. The mice were administered with NF-κB siRNA, scrambled siRNA and normal saline via tail vein injection. Following 1 h, a mouse model of septic ALI was produced by cecal ligation and puncture (CLP) in the two siRNA groups and the sepsis control group. At 6 and 12 h post-operation, the experimental mice were sacrificed and the lung tissue samples were collected. Histopathological changes, wet/dry ratio of lung weight, NF-κB protein and NF-κB p65 mRNA levels, matrix metalloproteinase-9 (MMP-9) mRNA and protein activity were detected. Compared with the sepsis group and the Sc at the corresponding time, the expression levels of NF-κB p65 mRNA, the lung injury of experimental mice, the wet/dry ratio and the levels of MMP-9 mRNA and protein activity decreased, and significant differences were observed at 6 h post-operation (P<0.05). RNA interference against NF-κB p65 was able to decrease the expression of NF-κB and further inhibit the early phasic excessive inflammatory reaction in sepsis, which may alleviate ALI.

Small interfering RNA targeting NF-κB attenuates lipopolysaccharide-induced acute lung injury in rats

“…4). Our results are in line with previously published reports and further provide evidence for the central role of NF-kB in ALI and immunity [9, 10]. …”

“…5). Multiple attempts have been made through the years to suppress ALI by blocking NF-κB pathway, including stabilization of IκBα [8, 9, 11, 12], inhibition of binding between activated NF-κB dimers and target genes via decoy oligonucleotides [3], and transcriptional inhibition of key components of the NF-κB pathway via antisense technology [17]. Recently, drugs such as butyrate [14] and pitavastatin [19] were found to be effective in preventing the initiation of ALI by interacting with NF-κB pathway.…”

“…6a and b, NF-κB siRNA effectively suppressed levels of TNF-α mRNA transcription and concentrations of TNF-α in BALF, providing evidence to support the possibility that the mechanism of NF-κB siRNA’s anti-inflammatory effects is likely associated with the reduction of proinflammatory cytokines. TNF-α, however, can be regulated by other pathways, and should e further investigated but are beyond the scope of this manuscript [9]. …”

“…These include the inhibition of ubiquitination and proteosomal degradation of inhibitor of kappa B (IκB) and blocking of activated NF-κB’s binding to DNA but proved to be impractical in a clinical setting due largely to lack of specificity or necessity of pretreatment before insults. siRNA with high specificity, however, can target and decompose the complementary NF-κB mRNA [9], making it a perfect candidate for inhibiting the initially inflammatory cascade during ALI development via inhibition of NF-κB pathway activation.…”

Modulatory effect of silymarin on pulmonary vascular dysfunction through HIF-1α-iNOS following rat lung ischemia-reperfusion injury

“…Reduction in the inflammatory response is therefore an important strategy to attenuate lung I/R injury. NF-κB is an important signal transduction molecule in the inflammatory response, with a central role in the inflammatory response to lung I/R injury (16,17). Activation of the NF-κB pathway induces the expression of adhesion molecules and chemokines, and the expression of pro-inflammatory factors; this response leads to leukocyte adhesion, aggregation and infiltration in the ischemic region, aggravating lung I/R injury (18).…”