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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 62  |  Issue : 5  |  Page : 203-209

Magnesium sulfate attenuates lipopolysaccharides-induced acute lung injury in mice


Department of Pathogenic Microbiology, Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Yinchuan; Department of Microbiology and Molecular Biology, College of Life Science, Ningxia University, Yinchuan, Ningxia, China

Date of Submission14-Jun-2019
Date of Decision05-Sep-2019
Date of Acceptance24-Sep-2019
Date of Web Publication24-Oct-2019

Correspondence Address:
Prof. Guangcun Deng
College of Life Science, Ningxia University, 539 W. Helanshan Road, Yinchuan, Ningxia 750021
China
Prof. Yujiong Wang
College of Life Science, Ningxia University, 539 W. Helanshan Road, Yinchuan, Ningxia 750021
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CJP.CJP_48_19

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  Abstract 

Acute lung injury (ALI) is a common and severe respiratory disease with high morbidity and mortality. Although some progress has been made in the past years, the pathogenesis of ALI is still poorly understood and the therapeutic outcome has still not been significantly improved. It is well-recognized that magnesium sulfate (MgSO4) possesses potent anti-inflammation capacity. The present study was designed to investigate the protective effects of MgSO4 in lipopolysaccharides (LPSs)-induced ALI taken into account that excessive inflammatory response plays critical role in the development of ALI. In this study, Kunming mice were intravenously injected with LPS through tail vein to establish the ALI model and in parallel, A549 cells were used to establish cell model. The lung wet-to-dry weight ratio, malondialdehyde (MDA) levels in lung tissue, lung permeability index, hematoxylin and eosin staining, cytokines in the serum and bronchoalveolar lavage fluid (BALF), neutrophil counts in BALF, LPS-induced A549 cell apoptosis as well as apoptosis-inducing factor (AIF), and Poly(ADP-ribose) polymerase-1 (PARP-1) expression in both mice and A549 cells were detected. Our results demonstrated that MgSO4 significantly attenuated the LPS-induced ALI, oxidative stress (decreased MDA levels), and lung inflammatory response. Moreover, MgSO4 exerted protective effects by mitigating LPS-induced A549 cell apoptosis. Furthermore, MgSO4 decreased the AIF and PARP-1 expression both in vivo and in vitro. Our results, taken together, demonstrated that MgSO4 is a potential therapeutic agent for ALI taken into consideration that MgSO4 is commonly used in clinical settings.

Keywords: Acute lung injury, apoptosis, inflammation, lipopolysaccharides, magnesium sulfate


How to cite this article:
Li W, Wu X, Yu J, Ma C, Zhuang P, Zeng J, Zhang J, Deng G, Wang Y. Magnesium sulfate attenuates lipopolysaccharides-induced acute lung injury in mice. Chin J Physiol 2019;62:203-9

How to cite this URL:
Li W, Wu X, Yu J, Ma C, Zhuang P, Zeng J, Zhang J, Deng G, Wang Y. Magnesium sulfate attenuates lipopolysaccharides-induced acute lung injury in mice. Chin J Physiol [serial online] 2019 [cited 2019 Nov 20];62:203-9. Available from: http://www.cjphysiology.org/text.asp?2019/62/5/203/269836

Wu Li and Xiaoling Wu contributed equally to this study.



  Introduction Top


Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) are common and highly lethal diseases in humans that are mainly caused by pneumonia and Gram-negative sepsis.[1],[2] To understand the molecular mechanisms responsible for ALI and ARDS, a number of animal models have been developed, among which lipopolysaccharide (LPS)-induced ALI is the most popular and well-established model that has been extensively used.[3],[4],[5],[6],[7] Although some progress has been made in the past years, the pathogenesis of ALI is still poorly understood, and the therapeutic outcome has still not been significantly improved.[8],[9] Therefore, there is an urgent need to find the effective therapeutic strategy and new agents for the benefit of the patients.

Magnesium, the second-most abundant intracellular cation and the fourth-most common cation in the body, has a wide range of biological functions.[10],[11] Magnesium is a cofactor in more than 300 enzymatic reactions involved in cellular homeostasis, energy metabolism, and protein and nucleic acid synthesis. It also possesses the potent anti-inflammation capacity. Investigators have demonstrated that magnesium may also have potential biological functions and therapeutic applications to respiratory diseases. The use of magnesium in acute asthma has been found to produce benefits to patients with respect to the improvement of pulmonary function and clinical conditions.[12],[13],[14] In an LPS-induced rat model, investigators found that magnesium sulfate (MgSO4) could mitigate ALI through antagonizing the L-type calcium channels and the N-methyl-d-aspartate receptor.[15] Magnesium has been shown to be easy and safe to use. However, to the best of our knowledge, the use of this agent in ALI has still not been very clearly demonstrated and much of work is still needed.

In the present study, the effects of MgSO4 on LPS-induced ALI were evaluated both in vivo and in vitro. Our results presented in this report demonstrate that MgSO4 is able to attenuate LPS-induced ALI and lung inflammatory response, suggesting that it may be a promising therapeutic candidate for the treatment of ALI.


  Materials and Methods Top


Animals and reagents

Female Kunming mice between 6 and 8 weeks of age were purchased from the Animal Facility of Ningxia Medical University (Yinchuan, China) and maintained in special pathogen-free conditions with free access to food and water. The mice were raised at the Experimental Animal Center of Ningxia University (Yinchuan, China). All experiments using animals were conducted following the guidelines of the Chinese Council on Animal Care and approved by the Ethics Committee for the Conduct of Animal Research of Ningxia University (NXU-ACAU-201703, 12-Mar-2017). LPS from  Escherichia More Details coli 055:B5 (Sigma, USA) was used to induce ALI.

Experimental protocol

Female Kunming mice (20 ± 5 g) were randomly divided into four groups with 12 mice per group (n = 48). (1) control group: mice were intravenously injected, through the tail vein, with 50 μl of sterile phosphate-buffered saline (PBS) alone, (2) LPS group: mice were injected intravenously with 50 μl LPS (5 mg/kg), (3) MgSO4 group: mice were injected intravenously with 50 μl MgSO4(100 mg/kg), (4) LPS + MgSO4 group: mice were injected intravenously with MgSO4(100 mg/kg) immediately after LPS exposure.

Alveolar permeability index

Mice were sacrificed 18 h after LPS treatment by exsanguination under anesthesia with diethyl ether. Blood samples from the mice were collected and serum samples were obtained from centrifuged blood samples, the obtained serum samples were stored at −80°C until use. Bronchoalveolar lavage fluid (BALF) was collected as described previously.[16] The protein level in the BALF and serum was quantified by a bicinchoninic acid (BCA) Protein Assay kit (KeyGen, China). The BALF to serum fluorescence ratio was calculated and used as a measure of pulmonary epithelial permeability, as previously described.[17]

Malondialdehyde content assay

To evaluate the level of oxidative stress, malondialdehyde (MDA) contents in the lung tissue were examined using an assay kit (Beyotime, China). Briefly, the lung tissue samples were homogenized in cool normal saline (lung tissue-to-normal saline ratio, 1:10). The homogenate was then assessed according to the manufacturer's protocol. The concentration of MDA was measured by absorbance at 535 nm and was expressed in units of μmol/mg protein.

Measurement of lung wet-to-dry weight ratio

The Wet-to-Dry weight ratio (W/D) of the lung was measured to evaluate pulmonary edema. Briefly, the left lung was excised and the wet weight was measured immediately after the mice were sacrificed, the lung was then dried in an oven at 55°C for 72 h and weighed again. The W/D ratio was calculated as follows: wet lung weight (LW)/dry LW.

Cytokines measurements in the serum and bronchoalveolar lavage fluid and neutrophil counts in bronchoalveolar lavage fluid

Mice were sacrificed 18 h after LPS administration, and BALF and serum samples were collected. The concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in both BALF, and serum were determined using an enzyme-linked immunosorbent assay cytokine detection system (Neobioscience Technology, China) according to the manufacturer's instruction. For neutrophil counts, lungs of the mice were infused three times, with 0.7 ml of PBS (pH 7.5). BALF was extracted and then centrifuged at 1200 rpm for 10 min at 4°C. The pellet was resuspended in PBS, and neutrophil differential counts were determined using Wright-Giemsa staining.

Histology

Histopathological evaluation was performed on mice that were not subjected to BALF. The lungs from each group of mice were excised, fixed in 10% formalin for 48 h and embedded in paraffin. Tissue sections (4 μm thick) were cut and stained with hematoxylin and eosin (H and E) for histological examination under a light microscope.

A549 cell culture and treatment

Human lung alveolar epithelial (A549) cells were routinely cultured in RPMI 1640 medium supplemented with 100 U/ml of penicillin, 100 μg/ml of streptomycin and 10% fetal bovine serum in a humidified atmosphere at 37°C and with 5% CO2. A549 cells were seeded in six-well plates and were allowed to grow to 80% confluence. Cells were then treated, respectively, with LPS (10 μg/ml, LPS group), MgSO4(10 mM, MgSO4 group), MgSO4(10 mM) immediately after LPS (10 μg/ml) treatment (LPS + MgSO4 group). The control group received an equal volume of PBS. Following 18 h, the A549 cells were collected for further analysis.

Flow cytometric analysis of cell apoptosis in A549 cells

The cells undergoing apoptosis were detected with an AnnexinV-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double staining apoptosis detection Kit (KeyGen, China) following the manufacturer's instructions. Briefly, 18 h after LPS exposure, A549 cells from different groups were digested with 0.25% parenzyme and centrifuged at 1000 ×g for 5 min. The cells were then washed twice with PBS and resuspended in 400 μl of annexin-binding buffer. PI and FITC-conjugated Annexin V were added, and the cell suspension was further incubated in the dark for 15 min at 37°C and then analyzed by the flow cytometry (FACScalibur, BD Biosciences).

Western blot analysis of apoptosis-inducing factor and poly (ADP-ribose) polymerase-1

Mice were sacrificed 18 h after LPS treatment; lungs were removed and homogenized in ice-cold lysis buffer (KeyGen, China) with phosphatase inhibitor and protease inhibitor. Lysates were centrifuged at 14,000 ×g for 20 min at 4°C, and the supernatant was collected as the total protein. To prepare proteins from A549 cells from different group, A549 cells were collected 18 h after LPS treatment and washed twice with pre-cooled PBS before they were lysed using protein extraction buffer (KeyGen, China) following the manufacturer's instructions. The concentration of protein was determined by a BCA assay kit (KeyGen, China). Protein was separated by SDS-PAGE and transferred onto a polyvinylidene difluoride membrane (Bio-Rad, USA). After being blocked with 5% fat-free milk in PBS, the membranes were incubated with pre-diluted antibodies against apoptosis-inducing factor (AIF), cleaved-Poly(ADP-ribose) polymerase-1 (PARP-1) and β-actin (Proteintech, USA). The bound antibodies were detected with horseradish peroxidase-conjugated second antibodies at a 1:6000 dilution (ZSGB-BIO, China) and visualized using the WesternBright -ECL Western blot detection kit (Advansta, USA).

Statistical analysis

Data are presented as the mean ± standard deviation. Data were analyzed using one-way ANOVA. Differences between the groups were assessed for statistical significance using Tukey's post hoc test using the SPSS 13.0 software (SSPS Inc., Chicago, USA). P < 0.05 was considered to indicate a significant difference between groups.


  Results Top


Magnesium sulfate attenuated lipopolysaccharide-induced acute lung injury in mice

The lung W/D weihgt ratio, the lung permeability index and the MDA levels in lung tissue, as well as the histological patterns of the lung, were used to explore the effect of MgSO4 on LPS-induced alteration of the lung. The LPS-treated mice had higher W/D ratios compared with the control and MgSO4 treated mice. However, the W/D ratio was significantly decreased in the mice of the LPS + MgSO4 group as compared to the mice treated with LPS [Figure 1]a. Meanwhile, we found that MgSO4 administration significantly reduced the LPS-induced increases in permeability index after LPS administration [Figure 1]b. The MDA levels in lung tissue also markedly decreased in the mice of the LPS + MgSO4 group as compared to LPS-treated group [Figure 1]c. Moreover, the pathological changes in the lung tissue of the mice significantly decreased in the LPS + MgSO4 group as compared to LPS group [Figure 1]d. These results demonstrated that MgSO4 treatment attenuated LPS-induced ALI in vivo.
Figure 1: Effect of magnesium sulfate on lipopolysaccharides-induced acute lung injury in mice lung. Acute lung injury was induced by intravenously administration of lipopolysaccharides via tail vein. 18 h later, bronchoalveolar lavage fluid and serum samples were collected for calculation of permeability index, and the whole lungs were harvested for determination of the lipid peroxidation levels and histological examination as well as lung wet-to-dry weight ratio measurement. (a) Lung wet-to-dry weight ratio. (b) Permeability index. (c) Malondialdehyde levels in lung tissue. (d) The histological patterns of lung (×200, scale bars, 100 μm). Data are expressed as the mean value ± standard deviation from three independent experiments (n = 6). Compared to the control group *P < 0.05; **P < 0.01; ***P < 0.001

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Magnesium sulfate mitigated lipopolysaccharide-induced lung inflammation

ALI is often accompanied by an inflammatory response in the lungs; this response can be identified by the measurements of pro-inflammatory cytokines. To investigate the anti-inflammatory effect of MgSO4 in the lungs, neutrophil counts in BALF and the concentrations of TNF-α and IL-1β in both BALF and serum were determined. The results showed that TNF-α and IL-1β in both BALF and serum were significantly increased in the LPS-treated group, while there were no differences between the control, MgSO4, and LPS + MgSO4 group. Noticeably, both TNF-α and IL-1β in the BALF [Figure 2]a and [Figure 2]b and serum [Figure 2]c and [Figure 2]d were decreased in LPS-treated mice following MgSO4 treatment [Figure 2]a, [Figure 2]b, [Figure 2]c. In addition, the results of neutrophil counts showed that neutrophils in BALF were significantly increased in the LPS-treated group as compared to MgSO4 group. Noticeably, neutrophils in BALF were decreased significantly in LPS + MgSO4 and compared to LPS-treated group [Figure 2]e and [Figure 2]f. These results indicated that MgSO4 could decrease LPS-induced lung inflammatory responses.
Figure 2: Effect of magnesium sulfate on lipopolysaccharides-induced production of inflammatory cytokines in bronchoalveolar lavage fluid and serum. Acute lung injury was induced by intravenously injection of lipopolysaccharides via tail vein. 18 h later, bronchoalveolar lavage fluid and serum samples were collected for neutrophil counts and measurement of cytokines. (a and b) The tumor necrosis factor-α levels in bronchoalveolar lavage fluid and serum. (c and d) The interleukin-1β levels in bronchoalveolar lavage fluid and Serum. (e) Wright-Giemsa stain of bronchoalveolar lavage cells (×1000, scale bars, 50 μm), red arrow-neutrophils, black arrow-macrophages. (f) Neutrophil counts in bronchoalveolar lavage fluid. Data are expressed as the mean value ± standard deviation from three independent experiments (n = 6). Compared to the control group *P < 0.05; **P < 0.01

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Magnesium sulfate alleviated lipopolysaccharide-induced cell apoptosis

To further assess the effect of MgSO4 on LPS-induced alteration of the lung, the lung epithelial cell line A549 was used in this study to investigate the effect of MgSO4 on A549 cell apoptosis. The flow cytometric data showed that cell apoptotic rate was significantly increased after LPS treatment. However, MgSO4 administration could significantly reduce the LPS-induced A549 cell apoptosis after LPS treatment [Figure 3].
Figure 3: Effect of magnesium sulfate on lipopolysaccharides -induced cell apoptosis in A549 cells. A549 cells were pretreated with the indicated dose of magnesium sulfate immediately after lipopolysaccharides. Following 18 h, the A549 cells were harvested and the cell apoptosis was determined by flow cytometry using PI and FITC-conjugated Annexin V staining. Data are expressed as the mean value ± standard deviation from three independent experiments. Compared to the control group **P < 0.01

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In combination, these results suggested that MgSO4 was able to protect against LPS-induced ALI in mice in vitro.

Magnesium sulfate inhibited the expression of apoptosis-inducing factor and Poly(ADP-ribose) polymerase-1 both in vivo and in vitro

The results from the Western blot analysis demonstrated that the expression levels of both AIF and PARP-1 in the lung of the LPS-treated mice were significantly increased compared with mice in the control group. However, the expression of these two proteins was significantly decreased in the LPS-treated mice following MgSO4 treatment [Figure 4]a. Furthermore, the in vitro study indicated that the expression of AIF and PARP-1 were also markedly increased in A549 cells treated with LPS. However, treatment with MgSO4 after LPS injection also could significantly decrease the expression of AIF and PARP-1 in A549 cells [Figure 4]b. This result together with the in vivo study demonstrated that MgSO4 could down-regulate the expression levels of AIF and PARP-1.
Figure 4: Effect of magnesium sulfate on the expression of apoptosis-inducing factor and poly (ADP-ribose) polymerase-1 in vivo and in vitro The total protein from the lung lysates and A549 cells were harvested and then subjected to SDS-PAGE and Western blot analysis using respective antibodies against apoptosis-inducing factor, polymerase-1 and β-actin. (a) Poly (ADP-ribose) polymerase-1 and apoptosis-inducing factor expression in the lung tissue. (b) Poly (ADP-ribose) polymerase-1 and apoptosis-inducing factor expression in A549 cells

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  Discussion Top


LPS is well-known as one of the major causes of Gram-negative bacterium-cased ALI,[18] and hence, LPS has been commonly used to induce animal models of ALI. In the present study, the Kunming mice were treated with LPS to induce an animal ALI model to evaluate the therapeutic effect of MgSO4 in ALI. ALI is characterized by pulmonary edema, activation of pro-inflammatory cytokines and chemokines, infiltration of neutrophils and macrophages and protein-rich exudate in the alveolar space.[1],[19] We found that LPS treatment increased the lung W/D, LW/body weight, MDA levels in lung tissue, pulmonary permeability, and lung histological injury [[Figure 1] and data not shown]. In addition, LPS exposure time-dependently increased the concentration of reactive oxygen species in the lung tissue and nitric oxide (NO) in both BALF and serum (data not shown). Numerous studies have revealed that various inflammatory mediators are involved in the pathogenesis of ALI. According to the results of our study, the expression levels of TNF-α, IL-1β, IL-6, IL-8, and intercellular adhesion molecule-1 were markedly increased in both BALF and serum [[Figure 2] and data not shown]. Our results, taken together, demonstrated that LPS-induced ALI was well established and could be used for further study.

Data from this study demonstrated that MgSO4 treatment significantly reduced the severity of LPS-induced ALI in mice. Pulmonary edema and capillary permeability are the major characters of ALI.[20] To quantify the severity of pulmonary edema, we investigated the lung W/D. We also calculated the lung permeability index. Our results revealed that MgSO4 treatment could decrease the magnitude of pulmonary edema and capillary permeability, an indication that MgSO4 attenuated the LPS-induced lung injury. We also evaluated pulmonary histological changes using H and E staining. Our results showed that the damaged condition of lung tissue induced by LPS was potently alleviated by MgSO4 treatment. In addition, treatment with MgSO4 also effectively decreased the amount of MDA in the lung tissue. MDA is one of the major secondary oxidation products of peroxidized polyunsaturated fatty acids.[21],[22] It can thus be used as a biomarker of oxidative stress. Pro-inflammatory cytokines such as TNF-α and IL-1β, play critical roles in mediating and promoting the process of lung inflammation [1] and can be used to evaluate lung injury and inflammation levels. In the present study, the content of TNF-α and IL-1β in both BALF and serum was significantly decreased by MgSO4 treatment, suggesting that MgSO4 could alleviate the LPS-induced inflammatory response.

Recent studies have indicated that apoptosis plays a key role in the pathogenesis of ALI.[23],[24],[25] PARP-1 and AIF play important roles in apoptosis induction under both physiologic and pathologic conditions.[26] The crucial roles of PARP-1 in ALI has been demonstrated in PARP-1-deficient mice models. Liaudet et al. demonstrated that the absence of the function of PARP-1 by genetic deletion or pharmacological inhibition could reduce LPS-induced increases of cytokines and chemokines, lung hyperpermeability, NO production, and MDA levels in the lung tissue.[27] Another study conducted by Pagano et al. suggested that PARP-1 plays crucial roles in regulating lung cell proliferation and repair after hyperoxia-induced acute injury.[28] AIF is thought to be an essential downstream effector of the cell-death program initiated by PARP-1.[29],[30] In the present work, we identified that LPS treatment significantly increased the expression levels of PARP-1 and AIF in both vivo and vitro study, which prompted the critical roles of PARP-1 and AIF in the development of LPS-induced ALI. Dysregulation of apoptosis pathways could contribute to the endothelial and epithelial injury that is one of the characteristics of ALI in humans.[31] The study further revealed that treatment with MgSO4 significantly decreased the expression of PARP-1 and AIF both in vivo and in vitro. Meanwhile, A549 cell apoptosis induced by LPS also significantly alleviated after MgSO4 treatment. We can thus reasonably conclude that MgSO4 treatment decreased A549 cell apoptosis through inhibiting the expression of PARP-1 and AIF.


  Conclusion Top


The present study demonstrated that MgSO4 has a protective effect on LPS-induced ALI, possibly by attenuating pulmonary edema, down-regulating LPS-induced inflammatory damage, inhibiting the expression of AIF and PARP, and alleviating cell apoptosis. Furthermore, our results demonstrated that MgSO4 is a potential therapeutic agent for ALI taken into consideration that MgSO4 is commonly used in clinical settings.

Financial support and sponsorship

This work was supported by grants from the National Natural Science Foundation of China (Nos. 31560322, 31760324, 31560678).

Conflicts of interest

There are no conflicts of interest.



 
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