Landiolol hydrochloride ameliorates acute lung injury in a rat model of early sepsis through the suppression of elevated levels of pulmonary endothelin-1

Among the dysfunctions and pathologies associatedwith sepsis, the underlyingmolecularmechanisms of sepsis- induced acute lung injury (ALI) are poorly understood. Endothelin (ET)-1, a potent vasoconstrictor and pro-in- flammatory peptide, is known to be involved in the pathogenesis of ALI in a rat model of sepsis. Here,we inves- tigated whether landiolol hydrochloride, an ultra-short-acting β-blocker, plays a crucial role inameliorating and attenuating LPS-induced ALI throughmodulation of the ET-1 system.MaleWistar rats at 8weeks of agewere ad- ministered with either saline or lipopolysaccharide (LPS) for three hours (3 h) and some of the LPS-administered ratswere continuously treated with landiolol for 3 h. ALIwas 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 re- markably diminished. Further, LPS administration upregulated the pulmonary expression of HIF-1α.Finally, the treatment of LPS-administered ratswith landiolol for 3 h 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-regu- lated inflammatorymediators (TNF-α, IL-6) in both plasma and lung tissues during sepsis, and expression of pul- monary 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.