Interleukin-6 RNA knockdown ameliorates acute lung injury induced by intestinal ischemia reperfusion in rats by upregulating interleukin-10 expression

Abstract

Acute lung injury (ALI) is a common complication following intestinal ischemia/reperfusion (II/R) injury and contributes to the associated high mortality rate. However, the underlying mechanism is poorly understood and treatments are limited. RNA interference (RNAi) has been demonstrated to provide a promising disease treatment strategy both in vitro and in vivo. Therefore, the present study aimed to test whether blocking the proinflammatory cytokine IL-6 by RNAi may protect the lungs from remote organ injury following II/R, and to investigate the potential underlying mechanisms. A total of 176 adult healthy male Sprague-Dawley rats were randomly divided into sham, II/R, negative-control and IL-6-short hairpin (sh)RNA groups. The rats underwent II/R injury with occlusion of the superior mesenteric artery and coeliac artery to induce ischemia for 40 min, and were subsequently reperfused for 0–48 h. The negative-control group received a control lentiviral vector containing scrambled or non-specific sequences, and the IL-6-shRNA groups were administered with a vector containing an IL-6 shRNA sequence to affect RNAi-mediated knockdown of IL-6. ALI severity was determined by lung edema (lung wet/dry ratio) and histological analysis (lung injury scores). IL-6 localization, and mRNA and protein expression levels, were detected by immunofluorescence, reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. IL-10 expression induced by IL-6 knockdown in lung tissues was additionally detected. IL-6 RNAi was revealed to significantly reduce the expression of IL-6, which was associated with upregulated IL-10 expression in lung tissues. Consequently, the severities of ALI and edema induced by II/R were substantially improved. In conclusion, the present study demonstrated that IL-6 RNAi may protect the lung from ALI induced by II/R, and that this protective role may be associated with upregulation of IL-10. These findings may contribute to the development of an IL-6-RNAi-based therapeutic strategy for the treatment of II/R-induced ALI.

Cold-inducible RNA-binding protein-derived peptide C23 attenuates inflammation and tissue injury in a murine model of intestinal ischemia-reperfusion

“…23 That study did however demonstrate that TNF-α is elevated in intestinal tissue after intestinal I/R and appears to be responsible in part for intestinal inflammation. The importance of IL-6 in lung inflammation seen after intestinal I/R has been further demonstrated by Yuan et al 24 They revealed that IL-6 knockdown ameliorates ALI induced by intestinal I/R in rats demonstrating that IL-6 is a significant driver of lung inflammation in intestinal I/R. 24 It is for these reasons that we focused on the measurement and difference of IL-6 in the lung tissue as a marker for inflammatory activation in the lung tissue instead of TNF-α, which was used as a marker for inflammation in the intestinal tissue.…”

Inhibitors of IFN gene stimulators (STING) improve intestinal ischemia–reperfusion-induced acute lung injury by activating AMPK signaling

“…Endogenous toxins released from intestinal bacteria can shift to the circulatory system after intestinal ischemia–reperfusion injury, resulting in systemic inflammation, including lung injury [ 25 ]. In addition to endogenous toxins, inflammatory factors, including IL-1 and IL-6, produced during ischemia enter the circulatory system [ 26 ]. In the current study, we showed that serum DAO and IL-1β were significantly increased after reperfusion, which indicates that circulation mediators were released from intestinal tissue.…”

Inhibitors of IFN Gene Stimulators (STING) Improve Intestinal Ischemia-Reperfusion Induced Acute Lung Injury by Activating AMPK Signal

“…Endogenous toxins released from intestinal bacteria can shift to the circulatory system after intestinal ischemia-reperfusion injury, resulting in systemic in ammation, including lung injury [24]. Besides endogenous toxins, in ammatory factors including IL-1 and IL-6 produced during ischemia enter the circulatory system [25]. Relevant studies revealed that distant lung injury occurs during the process of reperfusion after intestinal ischemia; however, the mechanism of lung injury after intestinal ischemiareperfusion injury remains unclear [26,27].…”