Rikkunshito ameliorates bleomycin-induced acute lung injury in a ghrelin-independent manner

Abstract

Acute lung injury (ALI) is a critical syndrome consisting of acute respiratory failure associated with extensive pulmonary infiltrates. The pathological characterization of ALI includes injuries of alveolar epithelial cells (AECs), alveolar neutrophilic infiltration, and increases in proinflammatory cytokines, which cause destruction of the alveolar capillary barrier and subsequent devastating lung fibrosis. Rikkunshito (RKT), a traditional Japanese herbal medicine, is widely used for the treatment of patients with gastrointestinal symptoms and is known to stimulate ghrelin secretion. The therapeutic effects of RKT on organ inflammation and fibrosis remain unknown. We investigated the pharmacological potential of RKT in the treatment of ALI by using a bleomycin-induced ALI model in mice. RKT or distilled water (DW) was given to mice daily starting 12 h after bleomycin administration. The RKT-treated mice showed a definitively higher survival rate than the DW-treated mice after injury. They also had smaller reductions in body weight and food intake. The amelioration of neutrophil alveolar infiltration, pulmonary vascular permeability, induction of proinflammatory cytokines, activation of the NF-κB pathway, apoptosis of AECs, and subsequent lung fibrosis were notable in the RKT-treated mice. RKT administration increased the plasma ghrelin levels in wild-type mice, and it also mitigated the ALI response in both ghrelin-deficient mice and growth hormone secretagogue receptor-deficient mice after lung injury. Our results indicate that RKT administration exerts protective effects against ALI by protecting the AECs and regulating lung inflammation independently of the ghrelin system, and they highlight RKT as a promising therapeutic agent for the management of this intractable disease.