Penehyclidine prevents nuclear factor-kB activation in acute lung injury induced by lipopolysaccharide

Abstract

Penehyclidine (PHCD) has been proposed to reduce lung and lethal toxicity. The present study was undertaken to investigate the mechanisms responsible for the protective effect of PHCD against acute lung injury (ALI) in rats. Tail-vein injection of lipopolysaccharide (LPS; 5 mg kg(-1)) was used to induce ALI in rats. Secondary increases in total protein, lactate dehydrogenase activity in bronchoalveolar lavage fluid and myeloperoxidase in lung tissue were used to evaluate the effects of PHCD on ALI in rats. Activated DNA binding activity and expression of nuclear factor kappaB (NF-kappaB) in lung tissue were measured using electrophoretic mobility shift assays assay and immunohistological staining. Levels and mRNA expression of tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) were measured by enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction. Pretreatment with PHCD (0.03 mg kg(-1), 0.1 mg kg(-1) and 0.3 mg kg(-1) i.p.) significantly attenuated the LPS-induced changes in lung injury parameters and inhibited the activation and expression of NF-kappaB in lung tissue. Furthermore, PHCD also substantially reduced the LPS-induced TNF-alpha and IL-1beta mRNA expression and production in lung tissue and suppressed neutrophil recruitment. The results suggest that PHCD attenuates LPS-induced acute lung responses through inhibition of NF-kappaB activation and LPS-induced TNF-alpha and IL-1beta production and resulting neutrophil recruitment associated with acute lung inflammation and injury. PHCD may be a useful adjuvant to treatment strategies targeting clinical situations of acute inflammation.