Biochemical and Biophysical Research Communications
The therapeutic effect of verapamil in lipopolysaccharide-induced acute lung injury
Introduction
Acute lung injury (ALI) is one of the most common acute critical diseases with significant morbidity and mortality [1]. Serious ALI can lead to acute respiratory distress syndrome (ARDS) respiratory failure [2]. ALI is characterized by the infiltration of alveolar inflammatory cell, activation of macrophages, and increase in pro-inflammatory cytokine levels [3]. Currently, no specific effective therapeutic options are available for this condition [4]. Thus, potentially effective novel curative candidates are strongly needed to improve the treatment of ALI.
Lipopolysaccharide (LPS) is commonly recognized to induce an ALI model [5]. LPS is a major component of the outer membrane of gram-negative bacteria, which induces the excessive activation and release of various inflammatory factors leading to the development of ALI [6]. The increase in inflammatory cytokines impairs epithelial cell permeability and cause pulmonary oedema [7]. LPS also causes oxidative stress, such as excessive production of myeloperoxidase (MPO) and malondialdehyde (MDA) and reduction of antioxidant enzymes superoxide dismutase (SOD) [8]. Recently, it has reported that LPS activates NF-κB, which is the upstream of the activation of NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome [9]. NLRP3 inflammasome mediates the activation of caspase-1, leading to the secretion of IL-1β and IL-18, which in turn amplify the inflammation response [10].
Calcium channel blockers can not only regress inflammation, but also exhibit antioxidant properties diminishing tissue injury [11,12]. Verapamil is an L-type voltage-dependent calcium channel blocker, which has been widely used in the treatment of cardiovascular abnormalities [13]. It has been reported that Verapamil suppressed LPS-induced production of pro-inflammatory cytokines of serum in sepsis [14]. Verapamil also reduces acute liver injury, including down-regulated production of pro-inflammatory cytokines (TNF-α and IL-6) and inhibited NF-κB activation in vivo [15]. In vitro studies have shown that verapamil effectively reduces the production of pro-inflammatory cytokines [16]. However, few studies have investigated the exact therapeutic effect of Verapamil on LPS-induced ALI and the mechanisms related to inflammation and oxidative stress.
In the current study, the therapeutic effect of Verapamil in an LPS-induced murine ALI model was investigated. These results support the potential for the development of Verapamil as a novel therapeutic strategy for ALI/ARDS, as well as other inflammatory diseases.
Section snippets
Ethics statement
The Ethics Committee of the Center for Scientific Research with Animal Models at Changzhi medical college (Changzhi, Shanxi) approved the experiments, which were performed in accordance with the guidelines of the National Institutes of Health. Mice were anesthetized with pentobarbital sodium (80 mg/kg, intraperitoneal injection), and necessary efforts were taken to minimize suffering before performing operations.
Animal experiments
Male adult C57bl/6 mice (8-week-old) were randomly divided into four different
Verapamil ameliorates lung injury in LPS-induced ALI mice
Firstly, we confirmed that Verapamil has no effect on the blood pressure including diastolic pressure, systolic pressure, and mean blood pressure (Fig. 1A). As shown in Fig. 1B, the lung tissues of the LPS group exhibited severe pathological changes, such as capillary endothelium and pulmonary epithelium injuries, as well as inflammatory cell infiltration. Verapamil remarkably alleviated LPS-induced lung pathological changes. Verapamil treatment decreased the lung injury score compared with
Discussion
ALI is a life-threatening disease, which has no effective pharmacological therapy [4]. In this study, our work demonstrated Verapamil attenuates ALI in a murine model induced by LPS in vivo and in LPS challenged-primary murine peritoneal macrophages in vitro. In addition, we found that Verapamil suppresses the activation of NLRP3 inflammasome and NK-κB both in vivo and in vitro. These results confirm that Verapamil could be considered as a potential agent for the treatment of ALI in the future.
Data availability
The data used to support the findings of this study are available from the corresponding author upon request.
Competing interests
The authors declare no competing financial interests.
Author contributions
ZHS and YL conceived and designed the experiments. SFL and CYZ performed the experiments. LY and LH analyzed the data. ZHS contributed reagents/materials/analysis tools. ZHS wrote the paper. ZHS and YL critically reviewed the manuscript. All authors had final approval of the submitted versions.
Acknowledgements
This work was supported by grants from the Scientific Foundation from Changzhi Medical College (QDZ201632), and Science Foundation of Shanxi Health and Family Planning Commission (2015159).
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