Abstract
BackgroundToll-like receptor 4 (TLR4) is essential in lipopolysaccharide (LPS)-induced fibroblast activation and collagen secretion in vitro. However, its effects on the process of lung fibroblast activation and fibrosis initiation during LPS induced acute lung injury (ALI) remain unknown. The goal of the present study was to determine the effect of inhibiting TLR4 on LPS-induced ALI and fibrosis in vivo.MethodsThe ALI model was established by intraperitoneal injection of LPS in mice. TLR4-small hairpin RNA (shRNA) lentivirus was injected intravenously into the mice to inhibit TLR4 expression. mRNA and protein levels were detected by real-time PCR and Western-blot analysis, respectively. The contents of the C-terminal propeptide of type I procollagen (PICP) in bronchoalveolar lavage fluid (BALF) were detected by ELISA, and the degree of fibrosis was detected by van Gieson collagen staining, the hydroxyproline assay, and alpha smooth muscle actin (α-SMA) immunohistochemical staining.ResultsOverexpression of TLR4, type I procollagen, alpha-SMA, and p-AKT in murine pulmonary tissue after intraperitoneal injection of LPS at 72 hours and 28 days were detected. Moreover, the degree of fibrosis was shown to increase by ELISA analysis of PICP in BALF, van Gieson collagen staining, the hydroxyproline assay, and α-SMA immunohistochemical staining. All of these changes were alleviated by intravenous infection with TLR4-shRNA lentivirus.ConclusionsInhibiting TLR4 signaling could ameliorate fibrosis at the early stage of ALI induced by LPS.
Highlights
Toll-like receptor 4 (TLR4) is essential in lipopolysaccharide (LPS)-induced fibroblast activation and collagen secretion in vitro
TLR4-mediated pulmonary fibrosis induced by LPS First, we determined the role of TLR4 in the activation of lung fibroblasts and collagen secretion at the tissue level
PICP is a segment of type I procollagen degraded from the C-terminal by the procollagen C-endopeptidase, and it is IFnifglaumrme a1tion and fibrosis in mouse lung tissue after LPS challenge Inflammation and fibrosis in mouse lung tissue after LPS challenge. (A) The pathological changes in mouse lung tissue 72 hours and 28 days after intraperitoneal injection of LPS were observed by means of HE staining (HE, A, magnification ×200)
Summary
Toll-like receptor 4 (TLR4) is essential in lipopolysaccharide (LPS)-induced fibroblast activation and collagen secretion in vitro. Its effects on the process of lung fibroblast activation and fibrosis initiation during LPS induced acute lung injury (ALI) remain unknown. The goal of the present study was to determine the effect of inhibiting TLR4 on LPSinduced ALI and fibrosis in vivo. Lipopolysaccharides (LPSs), which constitute the principal endotoxin of Gram-negative bacteria, are important factors in acute lung injury (ALI). Toll-like receptor 4 (TLR4) is a widely distributed LPS receptor in lung tissue. The role of TLR4 in infectious and even non-infectious induced fibrosis has aroused increasing concern[2,3]. LPSs exert their biological effects through TLR4. LPSs promote TLR4 expression in the mononuclear phagocytic sys-
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