title: Rikkunshito ameliorates cachexia associated with bleomycin-induced lung fibrosis in mice by stimulating ghrelin secretion.
abstract: Cachexia is a frequent complication in patients with respiratory failure, such as lung fibrosis, and it is a determining factor for functional capacity, health status, and mortality. Reductions in body weight and skeletal muscle mass are key features of cachexia that are resistant to current therapies. Rikkunshito (RKT), a traditional Japanese herbal medicine, is widely used for the treatment for patients with gastrointestinal symptoms and known to stimulate ghrelin secretion. By using bleomycin (BLM)-induced lung fibrosis mice in this study, we tested our hypothesis that RKT administration could ameliorate pulmonary cachexia. After BLM administration, mice were provided with either RKT or distilled water on a daily basis. Compared with the BLM-injected mice, the RKT-treated mice had smaller reductions of food intake and body weight. Skeletal muscle weights were retained in the RKT-treated mice, in conjunction with reduced expressions of MuRF-1 and atrogin-1 in the lysates of skeletal muscle found in lung fibrosis. Rikkunshito administration restored the plasma concentrations of ghrelin in BLM-injected mice. The anticachectic efficacies of RKT administration in BLM-injected mice were canceled by the concurrent treatment of a ghrelin receptor antagonist. Rikkunshito administration did not decrease the degree of loss of body weight or food intake reduction in either ghrelin-deficient mice or growth hormone secretagogue receptor-deficient mice. Our results indicate that RKT administration exerts protective effects on pulmonary cachexia by ameliorating skeletal muscle wasting and food intake reduction as mediated by the ghrelin system and, thus, highlight RKT as a potential therapeutic agent for the management of lung fibrosis.
authors.affiliation: Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Tsubouchi
authors.affiliation: Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Yanagi
authors.affiliation: Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Miura
authors.affiliation: Tsumura Research Laboratories, Tsumura and Co, 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Mogami
authors.affiliation: Tsumura Research Laboratories, Tsumura and Co, 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yamada
authors.affiliation: Tsumura Research Laboratories, Tsumura and Co, 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Iizuka
authors.affiliation: Tsumura Research Laboratories, Tsumura and Co, 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan. Electronic address: nakazato@med.miyazaki-u.ac.jp.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Nakazato
mesh_terms: D000818:Animals; D001761:Bleomycin; D002100:Cachexia / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D004435:Eating / Q000187:drug effects*; D002149:Energy Intake / Q000187:drug effects; D054439:Ghrelin / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism / Q000517:prevention & control; D008517:Phytotherapy; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000150:complications*; D054440:Receptors, Ghrelin / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: D004365:Drugs, Chinese Herbal; D054439:Ghrelin; D009124:Muscle Proteins; D054440:Receptors, Ghrelin; D000070584:Tripartite Motif Proteins; C084136:liu-jun-zi-tang; D001761:Bleomycin; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Bleomycin; Cachexia; Ghrelin; Lung fibrosis; Mice; Rikkunshito