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Glycyrrhizic Acid Prevents Sepsis-Induced Acute Lung Injury and Mortality in Rats.

ABSTRACT: Glycyrrhizic acid (GA), an active ingredient in licorice, has multiple pharmacological activities. However, the effects of GA on sepsis-induced acute lung injury (ALI) have not been determined. Tthe aim of this study was to investigate the molecular mechanism involved in the effects of GA against sepsis-induced ALI in rats. We found that GA alleviated sepsis-induced ALI through improvements in various pathological changes, as well as decreases in the lung wet/dry weight ratio and total protein content in bronchoalveolar lavage fluid, and a significant increase in the survival rate of treated rats. Additionally, GA markedly inhibited sepsis-induced pulmonary inflammatory responses. Moreover, we found that treatment with GA inhibited oxidative stress damage and apoptosis in lung tissue induced by ALI. Finally, GA treatment significantly inhibited NF-? B, JNK and P38 MAPK activation. Our data indicate that GA has a protective effect against sepsis-induced ALI by inhibiting the inflammatory response, damage from oxidative stress, and apoptosis via inactivation of NF-?B and MAPK signaling pathways, providing a molecular basis for a new medical treatment for sepsis-induced ALI.

SUBMITTER: Zhao H

PROVIDER: S-EPMC4812678 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Glycyrrhizic Acid Prevents Sepsis-Induced Acute Lung Injury and Mortality in Rats.

Zhao Hongyu H Zhao Min M Wang Yu Y Li Fengchun F Zhang Zhigang Z

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 20150918 2

Glycyrrhizic acid (GA), an active ingredient in licorice, has multiple pharmacological activities. However, the effects of GA on sepsis-induced acute lung injury (ALI) have not been determined. Tthe aim of this study was to investigate the molecular mechanism involved in the effects of GA against sepsis-induced ALI in rats. We found that GA alleviated sepsis-induced ALI through improvements in various pathological changes, as well as decreases in the lung wet/dry weight ratio and total protein c ...[more]

PMID: 26385569

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Project description:Acute lung injury (ALI) is a severe inflammatory process of the lung. The only proven life-saving support is mechanical ventilation (MV) using low tidal volumes (LVT) plus moderate to high levels of positive end-expiratory pressure (PEEP). However, it is currently unknown how they exert the protective effects. To identify the molecular mechanisms modulated by protective MV, this study reports transcriptomic analyses based on microarray and microRNA sequencing in lung tissues from a clinically relevant animal model of sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP) in male Sprague-Dawley rats. At 24 hours post-CLP, septic animals were randomized to three ventilatory strategies: spontaneous breathing, LVT (6 ml/kg) plus 10 cmH2O PEEP and high tidal volume (HVT, 20 ml/kg) plus 2 cmH2O PEEP. Healthy, non-septic, non-ventilated animals served as controls. After 4 hours of ventilation, lung samples were obtained for histological examination and gene expression analysis using microarray and microRNA sequencing. Validations were assessed using parallel analyses on existing publicly available genome-wide association study findings and transcriptomic human data. The catalogue of deregulated processes differed among experimental groups. The 'response to microorganisms' was the most prominent biological process in septic, non-ventilated and in HVT animals. Unexpectedly, the 'neuron projection morphogenesis' process was one of the most significantly deregulated in LVT. Further support for the key role of the latter process was obtained by microRNA studies, as four species targeting many of its genes (Mir-27a, Mir-103, Mir-17-5p and Mir-130a) were found deregulated. Additional analyses revealed 'VEGF signaling' as a central underlying response mechanism to all the septic groups (spontaneously breathing or mechanically ventilated). Based on this data, we conclude that a co-deregulation of 'VEGF signaling' along with 'neuron projection morphogenesis', which have been never anticipated in ALI pathogenesis, promotes lung-protective effects of LVT with high levels of PEEP.

Project description:ObjectiveThe aim of this study was to examine the role of keratinocyte growth factor-2 (KGF-2) in oleic acid-induced acute lung injury (ALI) in rats.Methods Forty-five healthy adult male Sprague Dawley rats were divided into 3 groups. Rat ALI model was established by injection of 0.01 mL/kg oleic acid into the tail vein. Rats in the control group were injected with the same amount of normal saline (NS). In the ALI + KGF-2 group, 5 mg/kg of KGF-2 was instilled into the airway of rats 72 hours before the model preparation, and the control group and the ALI model group were instilled with the same amount of NS. The lung permeability index (LPI) and lung wet/dry weight (W / D) ratios were measured 8 hours after the model preparation. The permeability of pulmonary microvascular endothelium was evaluated by Evans blue leakage test. Histopathological changes were observed under light microscope and the ALI pathology score (LIS) was calculated. Ultrastructural changes of lung tissue were observed under electron microscope. The apoptosis was detected by TUNEL assay. The expression of Claudin-5, ZO-1, and VE Cadherin in lung tissue was qualitatively and quantitatively analyzed by immunohistochemistry, Western Blot, and qRT-PCR, respectively.ResultsThe ALI model group had severe lung injury and obvious pathological changes, including alveolar septal thickening and inflammatory cell infiltration. TUNEL assay showed that the apoptosis of ALI group was significantly increased. The LIS score, lung W/D ratio, LPI, and Evans blue leakage were significantly higher than those in the control group; electron microscopy showed that the alveolar-capillary barrier was severely damaged in the ALI group. Compared with the control group, the expression of Claudin-5, ZO-1, and VE cadherin in the lung tissue of the ALI model group was significantly attenuated. After pretreatment with KGF-2, the degree of lung tissue damage was significantly reduced and the pathological changes were significantly improved. TUNEL assay showed that the apoptosis of ALI group was decreased. Lung W/D ratio, LPI, and Evans blue leakage decreased; electron microscopy showed that the alveolar-capillary barrier of ALI group recovered significantly. Compared with the ALI model group, the expression of Claudin-5, ZO-1, and VE cadherin in the lung tissue of the KGF-2 pretreatment group increased.ConclusionThe results indicate that KGF-2 may attenuate oleic acid-induced ALI in rats by maintaining the pulmonary microvascular endothelial barrier, which is an effective ALI preventive measure.

Project description:Objective: To investigate the mechanism of Tocilizumab (TCZ) in attenuating acute lung injury in rats with sepsis by regulating the S100A12/NLRP3 axis. Methods: A rat model of sepsis was constructed using cecal ligation and puncture (CLP). Rats were treated with TCZ, and their lung tissue was collected. H&E staining was used to detect pathologic damage to lung tissue, and lung wet/dry (W/D) weight ratio was measured to assess pulmonary edema. Lipid oxidation assay and superoxide dismutase (SOD) activity assay kits were used to measure malondialdehyde (MDA) and SOD levels. Primary rat pulmonary microvascular endothelial cells (MPVECs) were treated with lipopolysaccharide (LPS) to construct a rat model of sepsis, which was then treated with TCZ. The mRNA and protein expressions of S100A12/NLRP3 were detected by qRT-PCR and western blot, respectively. S100A12 knockdown and overexpression plasmids, and NLRP3 knockdown plasmids were constructed and transfected into sepsis cells to intervene in the levels of S100A12/NLRP3. The apoptosis rate was detected by apoptosis assay. The levels of IL-6, TNF-α, and IL-10 in cells and tissues were analyzed by ELISA. Results: Compared to the Sham group, the CLP group had increased W/D weight ratio of lung tissue, IL-6, TNF-α, and MDA levels, lowered IL-10 and SOD levels, and more severe tissue damage (all P<0.05). After TCZ treatment, the above indicators were improved. The expressions of S100A12/NLRP3 cells were increased in LPS-induced MPVECs, but decreased after TCZ treatment. LPS induced apoptosis, but TCZ reduced the apoptosis, weakened the secretion levels of IL-6 and TNF-α, and enhanced IL-10 secretion levels. Transfection to cause the overexpression of S100A12 or NLRP3 plasmid partially counteracted the effect of TCZ. Knockdown of S100A12 was transfected on the basis of overexpression of NLRP3, which weakened the countervailing effect of overexpressed NLRP3 on TCZ. Conclusion: TCZ has a therapeutic effect on lung injury in rats with sepsis by reducing the expressions of S100A12/NLRP3.

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Glycyrrhizic Acid Prevents Sepsis-Induced Acute Lung Injury and Mortality in Rats.

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Glycyrrhizic Acid Prevents Sepsis-Induced Acute Lung Injury and Mortality in Rats.

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