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 [PaO] 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.

<p>Evaluating the Therapeutic Efficacy and Safety of Landiolol Hydrochloride for Management of Arrhythmia in Critical Settings: Review of the Literature</p>

“…68 Hagiwara et al also used LPS-induced, systemically inflamed rats to evaluate cardioprotective effects of landiolol and found it to both normalize cardiac function and significantly reduce serum levels of High-mobility group box 1 (HMGB-1), an inflammatory mediator critical to the development of sepsis. Surprisingly, it was reported that landiolol ameliorates not only heart but also kidney 71,72 and lung 73 damage in animal sepsis models. However, Kurita et al revealed that landiolol administration causes reductions in cerebral tissue oxygenation 74 in an LPS-induced, systemically inflamed swine model by measuring hemodynamics, blood variables, and cerebral tissue oxygenation index (TOI) by near-infrared spectroscopy.…”

Interleukin IL-5 alleviates sepsis-induced acute lung injury by regulating the immune response in rats

“…The main mechanisms of sepsis-induced ALI are activated neutrophil infiltration, monocyte infiltration, inflammatory cytokine disorder, pulmonary surfactant dysfunction, increased vascular permeability and others [ 12 , 13 ]. Among them, inflammatory cytokine disorder has been focused in recent years [ 14 ].…”

Argon reduces the pulmonary vascular tone in rats and humans by GABA-receptor activation

“…In this study, PVR was increased by ET-1 to mimic a characteristic of PH. Notably, increased ET-1-levels play a role in sepsis, sepsis-related organ dysfunction 46–48 and within the pathogenesis of acute lung injury 46,49 . This issue is emphasised by the fact that ET-1-antagonists attenuate the occurrence of acute lung injury 50–52 .…”