Abstract
Objective The lipopolysaccharide- (LPS-) induced acute intestinal dysfunction model has been widely applied in recent years. Here, our aim was to investigate the effect of triggering receptor expressed on myeloid cells-1 (TREM1) inhibitor in LPS-induced acute intestinal dysfunction. Methods Male rats were randomly assigned into normal (saline injection), model (LPS and saline injection), and LP17 (LPS and LP17 (a synthetic TREM1 inhibitor) injection) groups. The levels of intestinal TREM1 expression were evaluated by immunohistochemistry and western blot. Intestinal permeability and apoptosis were separately assessed by the lactulose/mannitol (L/M) ratio and TUNEL assay. The levels of soluble TREM1 (sTREM1), TNF-α, IL-6, and IL-1β were measured in the plasma and intestinal tissues by ELISA. The expression levels of NF-κB, high-mobility group box 1 (HMGB1), and toll-like receptor 4 (TLR-4) were measured with RT-qPCR and western blot. After transfection with si-TREM1 in LPS-induced intestinal epithelium-6 (IEC-6) cells, p-p65 and p-IκBα levels were detected by western blot. Results LP17-mediated TREM1 inhibition alleviated the intestine tissue damage in rats with LPS-induced acute intestinal dysfunction. LP17 attenuated the LPS-induced increase in sTREM1, TNF-α, IL-6, and IL-1β levels in the plasma and intestinal tissues. Furthermore, intestine permeability and epithelial cell apoptosis were ameliorated by LP17. LP17 attenuated the LPS-induced increase in the expression of TREM1, HMGB1, TLR-4, and NF-κB in the intestine tissues. In vitro, TREM1 knockdown inactivated the NF-κB signaling in LPS-induced IEC-6 cells. Conclusion LP17 could ameliorate LPS-induced acute intestinal dysfunction, which was associated with inhibition of intestinal apoptosis and inflammation response.
Highlights
Intestinal inflammation is the host’s invasion defense response through microbial toxins (such as lipopolysaccharide (LPS)) or pathogens [1], which is a key risk factor for highly fatal diseases like colorectal cancer [2]
Since LP17 is a specific inhibitor of triggering receptor expressed on myeloid cells-1 (TREM1), we set out to determine whether the expression of TREM1 in small intestinal tissues was affected by LPS injection and LP17 administration by immunohistochemistry staining and western blot assays
The immunohistochemistry staining results demonstrated that the model group had higher expressions of TREM1 than the normal group, while the LP17 group significantly attenuated the increase of TREM1 expression caused by LPS treatment (Figures 1(e) and 1(f))
Summary
Intestinal inflammation is the host’s invasion defense response through microbial toxins (such as lipopolysaccharide (LPS)) or pathogens (such as Escherichia coli) [1], which is a key risk factor for highly fatal diseases like colorectal cancer [2]. Immunity imbalance and mucosal barrier destruction are the main mechanisms of intestinal inflammation [3]. Inflammation may thin the mucosal layer, reduce the lumen coverage and the adhesion, and destroy the integrity of the intestine by increasing the apoptosis and permeability of epithelial cells and inhibiting cell proliferation, inducing the loss of barrier function, and leading to acute intestinal dysfunction [4,5,6]. Previous studies on biomarkers of intestinal failure have demonstrated that the disease severity and intensive care unit mortality have both been linked to elevated expression of intestinal fatty acid-binding protein (I-FABP, a biomarker of enterocyte damage), decreased expression of citrulline (a biomarker of enterocyte mass and damage), and increased intestinal permeability [7, 8]. No targeted therapeutics for acute intestinal dysfunction have been approved for clinical use [9]
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