Stabilizing mast cells improves acute lung injury after orthotopic liver transplantation via promotion of apoptosis in polymorphonuclear neutrophils

2020 ◽  
Author(s):  
Chaojin Chen ◽  
Zheng Zhang ◽  
Fang Tan ◽  
Fanbing Meng ◽  
Lifei Lai ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Acute Lung Injury ◽  
Mast Cells ◽  
Lung Injury ◽  
Orthotopic Liver Transplantation ◽  
Inflammatory Cells ◽  
Pulmonary Complications ◽  
Polymorphonuclear Neutrophils ◽  
Inflammatory Factor ◽  
Tnf Α

Aims: Postoperative pulmonary complications including acute lung injury (ALI) and acute respiratory distress syndrome have contributed to the mortality and morbidity of orthotopic liver transplantation (OLT) with unclear mechanisms. Mast cells (MCs) and polymorphonuclear neutrophils (PMNs) are the main inflammatory cells and participants in the process of ALI. The present study was designed to investigate the role of MCs and PMNs and their potential relation to ALI following OLT. Main Methods: Rat orthotopic autologous liver transplantation (OALT) model was designed to determine lung injury at different time points after liver reperfusion. We also evaluated the function of MCs and the effect of TNF-α and tryptase on ALI and PMN apoptosis in rats subjected to OALT. Histological scores and inflammatory factor levels as well as PMN apoptosis were measured. Key findings: Rats suffered from ALI after OALT, which was demonstrated with collapse of pulmonary architecture, pulmonary edema, and infiltration of inflammatory cells in alveolar and interstitial spaces, as well as increased levels of pro-inflammatory cytokines. ALI maximized at 8 h after OALT. However, PMN apoptosis lagged behind the pulmonary injury and maximized at 16 h after OALT, when the acute inflammation resolution initiated. MC stabilization, and tryptase and TNF-α inhibitors could significantly decrease the lung pathophysiologic scores accompanied with an increase in PMN apoptosis. Significance: ALI after OLT was associated with MC activation and PMN apoptosis. The ALI progression might be affected by delayed PMN apoptosis, which was related to MC activation. Induction of PMN apoptosis might alleviate ALI after OALT.

scholarly journals Protective Effect of the Fruit Hull ofGleditsia sinensison LPS-Induced Acute Lung Injury Is Associated with Nrf2 Activation

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Jun-Young Choi ◽  
Min Jung Kwun ◽  
Kyun Ha Kim ◽  
Ji Hyo Lyu ◽  
Chang Woo Han ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Inflammation ◽  
Therapeutic Option ◽  
Raw 264.7 Cells ◽  
Inflammatory Factor ◽  
Tnf Α ◽  
Reporter Assays ◽  
Anti Inflammatory ◽  
Underlying Mechanisms

The fruit hull ofGleditsia sinensis(FGS) has been prescribed as a traditional eastern Asian medicinal remedy for the treatment of various respiratory diseases, but the efficacy and underlying mechanisms remain poorly characterized. Here, we explored a potential usage of FGS for the treatment of acute lung injury (ALI), a highly fatal inflammatory lung disease that urgently needs effective therapeutics, and investigated a mechanism for the anti-inflammatory activity of FGS. Pretreatment of C57BL/6 mice with FGS significantly attenuated LPS-induced neutrophilic lung inflammation compared to sham-treated, inflamed mice. Reporter assays, semiquantitative RT-PCR, and Western blot analyses show that while not affecting NF-κB, FGS activated Nrf2 and expressed Nrf2-regulated genes including GCLC, NQO-1, and HO-1 in RAW 264.7 cells. Furthermore, pretreatment of mice with FGS enhanced the expression of GCLC and HO-1 but suppressed that of proinflammatory cytokines in including TNF-α and IL-1β in the inflamed lungs. These results suggest that FGS effectively suppresses neutrophilic lung inflammation, which can be associated with, at least in part, FGS-activating anti-inflammatory factor Nrf2. Our results suggest that FGS can be developed as a therapeutic option for the treatment of ALI.

Two indole-2-carboxamide derivatives attenuate lipopolysaccharide-induced acute lung injury by inhibiting inflammatory response

2018 ◽  
Vol 96 (12) ◽  
pp. 1261-1267
Author(s):  
Wei Dai ◽  
Xiangting Ge ◽  
Tingting Xu ◽  
Chun Lu ◽  
Wangfeng Zhou ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Tissue ◽  
Inflammatory Diseases ◽  
Inflammatory Cells ◽  
Genes Expression ◽  
Tnf Α ◽  
Induced Changes

Acute lung injury (ALI) is the leading cause of mortality in the intensive care unit. Currently, there is no effective pharmacological treatment for ALI. In our previous study, we reported that Lg25 and Lg26, two indole-2-carboxamide derivatives, inhibited the lipopolysaccharide (LPS)-induced inflammatory cytokines in vitro and attenuated LPS-induced sepsis in vivo. In the present study, we confirmed data from previous studies that LPS significantly induced pulmonary edema and pathological changes in lung tissue, increased protein concentration and number of inflammatory cells in bronchoalveolar lavage fluids (BALF), and increased inflammatory cytokine TNF-α expression in serum and BALF, pro-inflammatory genes expression, and macrophages infiltration in lung tissue. However, pretreatment with Lg25 and Lg26 significantly attenuated the LPS-induced changes in mice. Taken together, these data indicate that the newly discovered indole-2-carboxamide derivatives could be particularly useful in the treatment of inflammatory diseases such as ALI.

scholarly journals Protective Effects of Pterostilbene on Lipopolysaccharide-Induced Acute Lung Injury in Mice by Inhibiting NF-κB and Activating Nrf2/HO-1 Signaling Pathways

2021 ◽  
Vol 11 ◽  
Author(s):  
Yong Zhang ◽  
Zhen Han ◽  
Aimin Jiang ◽  
Di Wu ◽  
Shuangqiu Li ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protective Effect ◽  
Weight Ratio ◽  
Inflammatory Cells ◽  
Underlying Mechanism ◽  
Wall Thickening ◽  
Alveolar Wall ◽  
Tnf Α ◽  
Cox 2

Pterostilbene (PTER) is a kind of stilbene compound with biological activity isolated from plants such as red sandalwood, blueberry and grape. It has anti-tumor, anti-bacterial, anti-oxidation and other pharmacological activities. However, the underlying mechanism of the protective effect of PTER on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remained not clarified. In this study, LPS was used to establish a mouse model of ALI. Bronchoalveolar lavage fluid (BALF) was collected for inflammatory cells, and the wet-to-dry weight ratio of the lungs was measured. The activities of myeloperoxidase (MPO), antioxidant indexes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and oxidation index such as malondialdehyde (MDA) in lung tissues of mice were measured by the corresponding kits. The levels of Cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), TNF-α, IL-6 and IL-1β in lung tissues of mice were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The activities of Nrf2, HO-1, p-p65 and p-IκB were determined by western blotting. The results showed that the model of LPS-induced ALI was successfully replicated, and it was found that PTER could significantly improve the pathological degree of ALI such as sustained the integrity of the lung tissue structure, alleviated pulmonary interstitial edema and alveolar wall thickening, reduced infiltrated inflammatory cells. PTER could decrease the number of inflammatory cells and obviously inhibit the increase of W/D ratio caused by LPS. PTER could also significantly reduce LPS-induced MPO and MDA, and increase LPS-decreased SOD, CAT and GSH-Px in the lungs. In addition, it was also found that PTER has the ability to decrease LPS-induced production of COX-2, iNOS, TNF-α, IL-6 and IL-1β. The underlying mechanism involved in the protective effect of PTER on ALI were via activating Nrf2 and HO-1, and inhibiting the phosphorylation of p65 and IκB. These results suggested that PTER can protect LPS-induced ALI in mice by inhibiting inflammatory response and oxidative stress, which provided evidence that PTER may be a potential therapeutic candidate for LPS-induced ALI intervention.

Matrix metalloproteinase and elastase activities in LPS-induced acute lung injury in guinea pigs

1994 ◽  
Vol 266 (3) ◽  
pp. L209-L216 ◽  
Author(s):  
M. P. D'Ortho ◽  
P. H. Jarreau ◽  
C. Delacourt ◽  
I. Macquin-Mavier ◽  
M. Levame ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Guinea Pigs ◽  
Culture Media ◽  
Proteolytic Enzymes ◽  
Intratracheal Instillation ◽  
Inflammatory Cells ◽  
Polymorphonuclear Neutrophils ◽  
Control Group ◽  
Gelatinase Activity

Matrix metalloproteinases (MMPs) and elastase are proteolytic enzymes specifically directed against extracellular matrix (ECM) components. They are secreted by inflammatory cells and may consequently contribute to the lesions of the ECM observed during acute pulmonary edema. We therefore evaluated the MMP and elastase activities, which are secreted by cultured alveolar macrophages (AMACs) and polymorphonuclear neutrophils (PMNs) and present in the bronchoalveolar lavage (BAL) fluid in a guinea pig model of acute lung injury induced by intratracheal instillation of lipopolysaccharide (LPS). The control group was given 0.9% NaCl. 24 h after instillation, a BAL was performed, the BAL fluid was separated from the cells by centrifugation, and AMACs and PMNs were separately cultured for 24 h. In BAL fluid from LPS-treated guinea pigs, we found 1) an increase in free gelatinase activity, tested on [3H]gelatin (0.7 +/- 0.2 micrograms.200 microliters BAL fluid-1.48 h-1 vs. 0.2 +/- 0.1 in controls, P < 0.05), and 2) increased total gelatinase activities, as assessed by zymography. The molecular masses of the major gelatinase species found in BAL fluid by zymography were 92 and 68 kDa. The 92-kDa gelatinase was secreted by both AMACs and PMNs, as demonstrated by zymography of their respective culture media. When tested on [3H]elastin, the elastase activity of BAL fluid of LPS-treated animals exhibited no increase, but when tested on a synthetic peptidic substrate [N-succinyl-(L-alanine)3-p-nitro anilide (SLAPN)], increased elastase-like activity was observed (from 17 +/- 4 nmol of SLAPN.200 microliters BAL fluid-1.24 h-1 in control group to 34 +/- 8 in LPS group, P < 0.05). This increase was attributable to the activity of a metalloendopeptidase that was inhibited by the metal chelator EDTA but not by the specific tissue inhibitor of MMPs.

Ethanolic extract of Achillea wilhelmsii C. Koch improves pulmonary function and inflammation in LPS-induced acute lung injury mice

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Niloofar Honari ◽  
Parastoo Shaban ◽  
Saeed Nasseri ◽  
Mehran Hosseini
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Cell ◽  
Ethanolic Extract ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Lps Challenge ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Achillea Wilhelmsii

Abstract Objectives Acute lung injury (ALI) is a life-threatening pulmonary dysfunction associated with severe inflammation. There are still no effective pharmacological therapies for the treatment of ALI. In this concern, several anti-inflammatory agents could be used as add-on therapy to inhibit inflammation. Achillea wilhelmsii (AW) C. Koch is a well-known medicinal plant in the Iranian ethnomedical practices with anti-inflammatory activity. This study was aimed to evaluate the efficacy of ethanolic extract of AW on lipopolysaccharide (LPS)-induced ALI in mice. Methods The ALI model was established via the intra-tracheal (i.t.) administration of LPS (2 mg/kg) to male BALB/c mice. The ALI mice were divided into four groups (n=8 each) which intra-peritoneally (i.p.) treated with repeated doses of saline (model), dexamethasone (2 mg/kg), and AW (150–300 mg/kg) 1, 11 and 23 h post LPS administration. Twenty-four hours after the LPS challenge, bronchoalveolar lavage fluid (BALF) and lung tissue were evaluated for inflammatory cell influx, level of tumor necrosis factor-α (TNF-α) and histopathological changes. Results The AW (150–300 mg/kg) treated mice showed lower inflammatory cells infiltration in BALF and TNF-α level when compared to the model group. In addition, LPS induced several pathological alterations such as edema, alveolar hemorrhage and inflammatory cell infiltration into the interstitium and alveolar spaces. Treatment with AW significantly reduced LPS-induced pathological injury. Conclusions Taken together, the data here indicated that AW may be considered as a promising add-on therapy for ALI.

scholarly journals EGCG promotes PRKCA expression to alleviate LPS-induced acute lung injury and inflammatory response

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mian Wang ◽  
Hua Zhong ◽  
Xian Zhang ◽  
Xin Huang ◽  
Jing Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Weight Ratio ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Protective Mechanism ◽  
High Morbidity ◽  
Inflammatory Factor ◽  
Egcg Treatment

AbstractAcute lung injury (ALI), which could be induced by multiple factors such as lipopolysaccharide (LPS), refer to clinical symptoms of acute respiratory failure, commonly with high morbidity and mortality. Reportedly, active ingredients from green tea have anti-inflammatory and anticancer properties, including epigallocatechin-3-gallate (EGCG). In the present study, protein kinase C alpha (PRKCA) is involved in EGCG protection against LPS-induced inflammation and ALI. EGCG treatment attenuated LPS-stimulated ALI in mice as manifested as improved lung injury scores, decreased total cell amounts, neutrophil amounts and macrophage amounts, inhibited the activity of MPO, decreased wet-to-dry weight ratio of lung tissues, and inhibited release of inflammatory cytokines TNF-α, IL-1β, and IL-6. PRKCA mRNA and protein expression showed to be dramatically decreased by LPS treatment while reversed by EGCG treatment. Within LPS-stimulated ALI mice, PRKCA silencing further aggravated, while PRKCA overexpression attenuated LPS-stimulated inflammation and ALI through MAPK signaling pathway. PRKCA silencing attenuated EGCG protection. Within LPS-induced RAW 264.7 macrophages, EGCG could induce PRKCA expression. Single EGCG treatment or Lv-PRKCA infection attenuated LPS-induced increases in inflammatory factors; PRKCA silencing could reverse the suppressive effects of EGCG upon LPS-stimulated inflammatory factor release. In conclusion, EGCG pretreatment inhibits LPS-induced ALI in mice. The protective mechanism might be associated with the inhibitory effects of PRKCA on proinflammatory cytokine release via macrophages and MAPK signaling pathway.

scholarly journals Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets

2017 ◽  
Vol 312 (5) ◽  
pp. L625-L637 ◽  
Author(s):  
Mark J. McVey ◽  
Michael Kim ◽  
Arata Tabuchi ◽  
Victoria Srbely ◽  
Lukasz Japtok ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Pulmonary Complications ◽  
Acid Sphingomyelinase ◽  
Blood Products ◽  
Barrier Dysfunction ◽  
Neutrophil Accumulation ◽  
Characteristic Features ◽  
Underlying Mechanisms ◽  
Stored Blood

Pulmonary complications from stored blood products are the leading cause of mortality related to transfusion. Transfusion-related acute lung injury is mediated by antibodies or bioactive mediators, yet underlying mechanisms are incompletely understood. Sphingolipids such as ceramide regulate lung injury, and their composition changes as a function of time in stored blood. Here, we tested the hypothesis that aged platelets may induce lung injury via a sphingolipid-mediated mechanism. To assess this hypothesis, a two-hit mouse model was devised. Recipient mice were treated with 2 mg/kg intraperitoneal lipopolysaccharide (priming) 2 h before transfusion of 10 ml/kg stored (1–5 days) platelets treated with or without addition of acid sphingomyelinase inhibitor ARC39 or platelets from acid sphingomyelinase-deficient mice, which both reduce ceramide formation. Transfused mice were examined for signs of pulmonary neutrophil accumulation, endothelial barrier dysfunction, and histological evidence of lung injury. Sphingolipid profiles in stored platelets were analyzed by mass spectrophotometry. Transfusion of aged platelets into primed mice induced characteristic features of lung injury, which increased in severity as a function of storage time. Ceramide accumulated in platelets during storage, but this was attenuated by ARC39 or in acid sphingomyelinase-deficient platelets. Compared with wild-type platelets, transfusion of ARC39-treated or acid sphingomyelinase-deficient aged platelets alleviated lung injury. Aged platelets elicit lung injury in primed recipient mice, which can be alleviated by pharmacological inhibition or genetic deletion of acid sphingomyelinase. Interventions targeting sphingolipid formation represent a promising strategy to increase the safety and longevity of stored blood products.

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