Penehyclidine hydrochloride inhibits TLR4 signaling and inflammation, and attenuates blunt chest trauma and hemorrhagic shock-induced acute lung injury in rats

摘要

Blunt chest trauma with hemorrhagic shock (THS) frequently induces pulmonary inflammation that leads to acute lung injury (ALI). Penehyclidine hydrochloride (PHC) possesses anti-inflammatory properties that may attenuate the systemic inflammatory response. The present study aimed to evaluate the molecular mechanism of PHC in modifying THS-induced ALI in rats. Rats underwent either THS or a sham procedure. At 6 h subsequent to blunt chest trauma, arterial blood was drawn for blood gas and pro-inflammatory factors analyses, and lung tissue samples were collected to examine pulmonary histopathological alterations, the wet/dry weight ratio, myeloperoxidase activity, and the protein expression levels of Toll-like receptor 4 (TLR4), phosphorylated (p-)p38 mitogen-activated protein kinase (MAPK), nuclear factor (NF)-kappa B and activator protein-1 (AP-1). THS caused significant reductions in heart rate and mean arterial blood pressure, and was associated with significant increases in tumor necrosis factor-alpha, interleukin (IL)-6, IL-1, p-p38MAPK, NF-kappa B and AP-1 activation, in addition to TLR4 expression, in the lung. PHC effectively attenuated THS-induced ALI, and inhibited TLR4 expression, reduced the activation of p-p38MAPK, NF-kappa B and AP-1, and downregulated the expression of pro-inflammatory mediators. In conclusion, the results of the present study demonstrated that PHC may exert an anti-inflammatory effect and attenuate THS-induced ALI by inhibiting the TLR4 signaling pathway. These preclinical findings may offer a novel therapeutic strategy to restrict TLR4 overactivation in ALI.