Penehyclidine ameliorates acute lung injury by inhibiting Toll-like receptor 2/4 expression and nuclear factor-κB activation

Abstract

Abstract. The aim of the present study was to investigate the effect of penehyclidine (PHC) on endotoxin-induced acute lung injury (ALI), as well as to examine the mechanism underlying this effect. A total of 60 rats were randomly divided into five groups, including the control (saline), LPS and three LPS + PHC groups. ALI was induced in the rats by injection of 8 mg lipopolysaccharide (LPS)/kg body weight. The rats were then treated with or without PHC at 0.3, 1 or 3 mg/kg body weight 1 min following LPS injection. After 6 h, serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were determined by ELISA. In addition, the mRNA expression levels of toll-like receptor (TLR)2 and TLR4 were examined by reverse transcription-quantitative polymerase chain reaction in the lung tissue samples, and nuclear factor (NF)-κB p65 protein expression levels were examined by western blot analysis. The results demonstrated that lung injury was ameliorated by treatment with PHC (1 and 3 mg/kg body weight) as compared with treatment with LPS alone. Injection of LPS significantly increased the mRNA expression levels of TLR2 and TLR4, as well as the protein expression levels of NF-κB p65 in the lung tissue samples. Serum levels of TNF-α and IL-6 were also upregulated by LPS injection. Treatment of the rats with PHC following LPS injection suppressed the LPS-induced increase in TLR2/4 mRNA and NF-κB p65 protein expression levels. PHC also inhibited the increase in TNF-α and IL-6 serum levels. In addition, PHC reduced LPS-induced ALI and decreased the serum levels of TNF-α and IL-6, possibly by downregulating TLR2/4 mRNA expression and inhibiting NF-κB activity, and consequently alleviating the inflammatory response.

Lats2-Underexpressing Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate LPS-Induced Acute Lung Injury in Mice

“…We also observed that Lats2-underexpressing BMSCs improved acute lung inflammation in ALI lung tissue. One of the pathophysiologies of ALI is essentially dysregulated inflammation that manifested by imbalance between proinflammatory and anti-inflammatory response in the lung [36, 37]. Several previous studies indicated that MSCs could enhance the resolution of inflammation in adult ALI patients [16, 35], and sufficient evidence also showed the same modulatory effect: Proinflammatory cytokines such as interferon- γ , IL-1 β , and IL-6 were reduced, while the anti-inflammatory cytokines IL-4 and IL-10 were increased [38].…”

Prophylactic Penehyclidine Inhalation for Prevention of Postoperative Pulmonary Complications in High-risk Patients: A Double-blind Randomized Trial

“…In both clinical and experimental studies, the drug also moderates infectious and noninfectious inflammation within the respiratory system, possibly by inhibiting Toll-like receptors. [31][32][33][34] Penehyclidine is effective for treatment of acute exacerbations of COPD and acute respiratory distress syndrome, possibly by dilating bronchioles, improving pulmonary compliance, and inhibiting airway inflammation. We therefore tested the hypothesis that inhalation of penehyclidine, a long-acting muscarinic antagonist, reduces a composite of pulmonary complications in high-risk noncardiac surgical patients over the initial 30 postoperative days.…”

“…Experimental and clinical studies report that penehyclidine ameliorates acute lung injury by alleviating inflammation. [31][32][33]50 For example, retrospective analyses report that patients who inhaled tiotropium have lower leukocyte counts and lower C-reactive protein concentrations. 27 It is therefore possible that penehyclidine provides additional lung protection by reducing inflammation, although we did not evaluate this mechanism.…”

Systematic identification of the interventional mechanism of Qingfei Xiaoyan Wan (QFXYW) in treatment of the cytokine storm in acute lung injury using transcriptomics-based system pharmacological analyses

“…Among these hub genes, TLR2 is an inflammation-related receptor that is involved in inflammation-induced diseases, especially that induced by LPS, which serves as a transduction and transmembrane molecule (Wang et al. 2016 ). Key inflammatory cytokines (IL-6 and TNF-α) have been reported to play a key role in the early stage of ALI (Simons et al.…”