title: Landiolol hydrochloride ameliorates acute lung injury in a rat model of early sepsis through the suppression of elevated levels of pulmonary endothelin-1.
abstract: Among the dysfunctions and pathologies associated with sepsis, the underlying molecular mechanisms of sepsis-induced acute lung injury (ALI) are poorly understood. Endothelin (ET)-1, a potent vasoconstrictor and pro-inflammatory peptide, is known to be involved in the pathogenesis of ALI in a rat model of sepsis. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting β-blocker, plays a crucial role in ameliorating and attenuating LPS-induced ALI through modulation of the ET-1 system. Male Wistar rats at 8weeks of age were administered with either saline or lipopolysaccharide (LPS) for three hours (3h) and some of the LPS-administered rats were continuously treated with landiolol for 3h. ALI was induced by LPS, including levels of both circulatory and pulmonary TNF-α and IL-6 but [PaO2] was significantly decreased. LPS also induced a significant increase in levels of pulmonary ET-1 and ET-A receptor, but levels of ET-B receptor, which has vasodilating effects, were remarkably diminished. Further, LPS administration upregulated the pulmonary expression of HIF-1α. Finally, the treatment of LPS-administered rats with landiolol for 3h ameliorated and prevented ALI, normalized the altered levels of pulmonary ET-1 and ET-A receptors. Landiolol also induced significant down-regulation of ET-B receptor in lung tissues in the early hours (phase) of sepsis. However, Landiolol treatment had no effect on the up-regulated inflammatory mediators (TNF-α, IL-6) in both plasma and lung tissues during sepsis, and expression of pulmonary HIF-1α also remained unchanged after landiolol treatment. Collectively, these data led us to conclude that landiolol may ameliorate sepsis-induced ALI via the pulmonary ET system.
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: 0326yujiro@gmail.com.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Matsuishi
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Faculty of Health and Sports Science, Advanced Research Initiatives for Human High Performance (ARIHHP), University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: jsubrina@gmail.com.
authors.forename: Subrina
authors.initials: S
authors.lastname: Jesmin
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: kawano_s@md.tsukuba.ac.jp.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kawano
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: gongehead@yahoo.co.jp.
authors.forename: Sakuramoto
authors.initials: S
authors.lastname: Hideaki
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: nokeshimojo@yahoo.co.jp.
authors.forename: Nobutake
authors.initials: N
authors.lastname: Shimojo
authors.affiliation: Department of Biology, Appalachian State University, NC, USA. Electronic address: mowacn@appstate.edu.
authors.forename: Chishimba Nathan
authors.initials: CN
authors.lastname: Mowa
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Shila
authors.initials: S
authors.lastname: Akhtar
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Sohel
authors.initials: S
authors.lastname: Zaedi
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Tanzila
authors.initials: T
authors.lastname: Khatun
authors.affiliation: Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: chabo448@yahoo.co.jp.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tsunoda
authors.affiliation: Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: t-kiwamoto@md.tsukuba.ac.jp.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kiwamoto
authors.affiliation: Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: nhizawa@md.tsukuba.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hizawa
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: yinoue@md.tsukuba.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: mizutani@md.tsukuba.ac.jp.
authors.forename: Taro
authors.initials: T
authors.lastname: Mizutani
mesh_terms: D055371:Acute Lung Injury / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects*; D019332:Endothelin-1 / Q000032:analysis / Q000235:genetics*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009025:Morpholines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D017208:Rats, Wistar; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014508:Urea / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000319:Adrenergic beta-Antagonists; D019332:Endothelin-1; D009025:Morpholines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C077049:landiolol; D014508:Urea
keywords: Acute lung injury; Endothelin; Landiolol hydrochloride; Rat model; Sepsis