Pretreatment with atorvastatin ameliorates cobra venom factor-induced acute lung inflammation in mice

Abstract

Background The complement system plays a critical role as the pathogenic factor in the models of acute lung injury due to various causes. Cobra venom factor (CVF) is a commonly used complement research tool. The CVF can cause acute inflammation in the lung by producing complement activation components. Atorvastatin (ATR) is a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor approved for control of plasma cholesterol levels. This inhibitor can reduce the acute pulmonary inflammatory response. However, the ability of ATR in treating acute lung inflammation caused by complement activation is still unknown. Therefore, we investigated the effect of ATR on lung inflammation in mice induced by activation of the complement alternative pathway in this study. Methods ATR (10 mg/kg/day via oral gavage) was administered for 7 days before tail vein injection of CVF (25 μg/kg). On the seventh day, all mice were sacrificed 1 h after injection. The lung lobe, bronchoalveolar lavage fluid (BALF), and blood samples were collected. The myeloperoxidase (MPO) activity of the lung homogenate, the leukocyte cell count, and the protein content of BALF were measured. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), P-selectin, and Intercellular cell adhesion molecule-1 (ICAM-1) in BALF and serum were determined by enzyme-linked immunosorbent assay. The pathological change of the lung tissue was observed by hematoxylin and eosin staining. The deposition of C5b-9 in the lung tissue was detected by immunohistochemistry. The phosphorylation of NF-κB p65 in the lung tissues was examined by immunohistochemistry and western blotting. Results The lung inflammation levels were determined by measuring the leukocyte cell numbers and protein content of BALF, the lung MPO activity, and expression and staining of the inflammatory mediators (IL-6 and TNF-α), and adhesion molecules (P-selectin and ICAM-1) for lung lesion. A significant reduction in the lung inflammation levels was observed after 7 days in ATR pre-treated mice with a CVF-induced lung disease. Deposition of C5b-9 was significantly alleviated by ATR pretreatment. Early intervention with ATR significantly reduced the development of acute lung inflammation on the basis of phosphorylation of NF-κB p65 in the lung. Conclusion These findings suggest the identification of ATR treatment for the lung inflammation induced by activating the complement system on the basis of its anti-inflammatory response. Together with the model replicating the complement activating characteristics of acute lung injury, the results may be translatable to the overactivated complement relevant diseases.

Membrane Attack Complex C5b-9 Promotes Renal Tubular Epithelial Cell Pyroptosis in Trichloroethylene-Sensitized Mice

“…Indeed, as a membrane pore–forming protein, the sub-lytic effects of C5b-9 play a more important role in inflammatory response ( Zhang et al, 2021 ). Studies have shown that sub-lytic C5b-9 worked as a trigger of various intracellular signaling processes such as MAPK ( Zhu et al, 2017 ), NF-κB ( Guo et al, 2020 ), and the NLRP3 ( Zhang et al, 2021 ) signaling. However, whether sub-lytic C5b-9 is involved in TCE-induced RTEC pyroptosis remains unknown.…”

Acteoside attenuates acute lung injury following administration of cobra venom factor to mice

“…Forty-eight mice were randomly divided into six groups ( n = 8 per group): the control group (Control), CVF group (CVF), acteoside 100 mg/kg + CVF group (acteoside 100 mg/kg), acteoside 50 mg/kg + CVF group (acteoside 50 mg/kg), acteoside 20 mg/kg + CVF group (acteoside 20 mg/kg), and PDTC 100 mg/kg + CVF group (PDTC, as a positive control). The mice were subjected to a tail vein injection of CVF (35 μg/kg body weight, dissolved in sterile PBS with PH 7.4) to specifically activate the complement alternative pathway [ 13 , 23 ] and establish the ALI model in mice. The control mice were injected with sterile PBS.…”

“…Several studies have shown that intravenous injection of CVF can trigger a systemic complement activation, resulting in acute inflammation response and changes in lung function and morphology, which are characterized by increased permeability between pulmonary capillary endothelial cells and alveolar epithelial cells, and the accumulation of a large amount of edema fluid in the alveolar space, which is rich in a variety of inflammatory cells dominated by neutrophils to increase ALI [ 13 , 14 , 15 , 16 ]. Previously, we also have successfully constructed ALI mouse model using CVF as reflected by increases in inflammatory mediators in the lung and morphological evidence of lung damage [ 13 ]. Thus, the CVF-mediated ALI model could be used in exploring the pathological changes and effective medications of lung injury.…”

“…Based on previous reports, acteoside can exert protective effects against ALI induced by lipopolysaccharide by regulating the nuclear factor-kappa B (NF-κB) pathway and reducing the levels of pro-inflammatory mediators [ 1 ]. Complement has been involved in the various models of ALI [ 13 ]. However, the role of acteoside on complement-related ALI has not been reported.…”

Sphingosine Kinase 1 Plays an Important Role in Atorvastatin-Mediated Anti-Inflammatory Effect against Acute Lung Injury

“…Simvastatin and rosuvastatin have anti-inflammatory effects against LPS and virus infection such as influenza A [ 6 , 7 ]. Similarly, atorvastatin also attenuated the lung injury and the inflammatory response induced by various stimuli [ 8 , 9 ].…”