Zinc supplementation ameliorates lung injury by reducing neutrophil recruitment and activity

Thorax ◽  
2020 ◽  
Vol 75 (3) ◽  
pp. 253-261 ◽  
Author(s):  
Inga Wessels ◽  
Johanna Theresa Pupke ◽  
Klaus-Thilo von Trotha ◽  
Alexander Gombert ◽  
Anika Himmelsbach ◽  
...  
Keyword(s):  
Lung Injury ◽  
Zinc Supplementation ◽  
Inflammatory Diseases ◽  
Risk Groups ◽  
Lavage Fluid ◽  
Neutrophil Recruitment ◽  
Polymorphonuclear Neutrophils ◽  
Lung Damage ◽  
Inflammatory Status

IntroductionZinc is well known for its anti-inflammatory effects, including regulation of migration and activity of polymorphonuclear neutrophils (PMN). Zinc deficiency is associated with inflammatory diseases such as acute lung injury (ALI). As deregulated neutrophil recruitment and their hyper-activation are hallmarks of ALI, benefits of zinc supplementation on the development of lipopolysaccharides (LPS)-induced ALI were tested.Methods64 C57Bl/6 mice, split into eight groups, were injected with 30 µg zinc 24 hours before exposure to aerosolised LPS for 4 hours. Zinc homoeostasis was characterised measuring serum and lung zinc concentrations as well as metallothionein-1 expression. Recruitment of neutrophils to alveolar, interstitial and intravascular space was assessed using flow cytometry. To determine the extent of lung damage, permeability and histological changes and the influx of protein into the bronchoalveolar lavage fluid were measured. Inflammatory status and PMN activity were evaluated via tumour necrosis factor α levels and formation of neutrophil extracellular traps. The effects of zinc supplementation prior to LPS stimulation on activation of primary human granulocytes and integrity of human lung cell monolayers were assessed as well.ResultsInjecting zinc 24 hours prior to LPS-induced ALI indeed significantly decreased the recruitment of neutrophils to the lungs and prevented their hyperactivity and thus lung damage was decreased. Results from in vitro investigations using human cells suggest the transferability of the finding to human disease, which remains to be tested in more detail.ConclusionZinc supplementation attenuated LPS-induced lung injury in a murine ALI model. Thus, the usage of zinc-based strategies should be considered to prevent detrimental consequences of respiratory infection and lung damage in risk groups.

scholarly journals TLR4-dependent GM-CSF protects against lung injury in Gram-negative bacterial pneumonia

2012 ◽  
Vol 302 (5) ◽  
pp. L447-L454 ◽  
Author(s):  
Louis R. Standiford ◽  
Theodore J. Standiford ◽  
Michael J. Newstead ◽  
Xianying Zeng ◽  
Megan N. Ballinger ◽  
...  
Keyword(s):  
Lung Injury ◽  
Bacterial Pneumonia ◽  
Lavage Fluid ◽  
Alveolar Epithelial Cells ◽  
Intratracheal Administration ◽  
Bacterial Colony ◽  
Gram Negative ◽  
Gm Csf

Toll-like receptors (TLRs) are required for protective host defense against bacterial pathogens. However, the role of TLRs in regulating lung injury during Gram-negative bacterial pneumonia has not been thoroughly investigated. In this study, experiments were performed to evaluate the role of TLR4 in pulmonary responses against Klebsiella pneumoniae (Kp). Compared with wild-type (WT) (Balb/c) mice, mice with defective TLR4 signaling (TLR4lps-d mice) had substantially higher lung bacterial colony-forming units after intratracheal challenge with Kp, which was associated with considerably greater lung permeability and lung cell death. Reduced expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA and protein was noted in lungs and bronchoalveolar lavage fluid of TLR4 mutant mice postintratracheal Kp compared with WT mice, and primary alveolar epithelial cells (AEC) harvested from TLR4lps-d mice produced significantly less GM-CSF in vitro in response to heat-killed Kp compared with WT AEC. TLR4lps-d AEC underwent significantly more apoptosis in response to heat-killed Kp in vitro, and treatment with GM-CSF protected these cells from apoptosis in response to Kp. Finally, intratracheal administration of GM-CSF in TLR4lps-d mice significantly decreased albumin leak, lung cell apoptosis, and bacteremia in Kp-infected mice. Based on these observations, we conclude that TLR4 plays a protective role on lung epithelium during Gram-negative bacterial pneumonia, an effect that is partially mediated by GM-CSF.

scholarly journals Down-regulation of SNHG16 alleviates the acute lung injury in sepsis rats through miR-128-3p/HMGB3 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Junli Sun ◽  
Keke Xin ◽  
Chenghui Leng ◽  
Jianlin Ge
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Western Blot ◽  
Cell Viability ◽  
Inflammatory Diseases ◽  
Cecal Ligation ◽  
Inflammatory Factors ◽  
Lung Epithelial

Abstract Background Long noncoding RNAs contribute to various inflammatory diseases, including sepsis. We explore the role of small nucleolar RNA host gene 16 (SNHG16) in sepsis-mediated acute lung injury (ALI) and inflammation. Methods A sepsis-induced ALI rat model was constructed by the cecal ligation and perforation method. The profiles of SNHG16, miR-128-3p, and high-mobility group box 3 (HMGB3) were monitored by quantitative reverse transcription PCR and Western blot. The pathologic changes of lung tissues were evaluated by Hematoxylin–Eosin staining, immunohistochemistry, and dry and wet method. Meanwhile, the pro-inflammatory factors and proteins were determined by ELISA and Western blot. In contrast, a sepsis model in BEAS-2B was induced with lipopolysaccharide (LPS) to verify the effects of SNHG16/miR-128-3p/HMGB3 on lung epithelial cell viability and apoptosis. Results As a result, SNHG16 and HMGB3 were up-regulated, while miR-128-3p was down-regulated in sepsis-induced ALI both in vivo and in vitro. Inhibiting SNHG16 reduced the apoptosis and inflammation in the sepsis-induced ALI model. Overexpressing SNHG16 promoted LPS-mediated lung epithelial apoptosis and inhibited cell viability and inflammation, while miR-128-3p had the opposite effects. Mechanistically, SNHG16 targeted miR-128-3p and attenuated its expression, while miR-128-3p targeted the 3′ untranslated region of HMGB3. Conclusions Overall, down-regulating SNHG16 alleviated the sepsis-mediated ALI by regulating miR-128-3p/HMGB3.

Class B Scavenger Receptors BI and BII Protect Against LPS-induced Acute Lung Injury in Mice by Mediating LPS Clearance

2021 ◽  
Author(s):  
Irina N. Baranova ◽  
Alexander V. Bocharov ◽  
Tatyana G. Vishnyakova ◽  
Zhigang Chen ◽  
Anna A. Birukova ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Transgenic Mice ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Protective Role ◽  
Lung Damage ◽  
Wild Type ◽  
Class B ◽  
Anti Inflammatory

Recent studies suggest an anti-inflammatory protective role for class B scavenger receptor BI (SR-BI) in endotoxin-induced inflammation and sepsis. Other data, including ours, provide evidence for an alternative role of SR-BI, facilitating bacterial and endotoxin uptake, and contributing to inflammation and bacterial infection. Enhanced endotoxin susceptibility of SR-BI deficient mice due to their anti-inflammatory glucocorticoid deficiency complicates understanding SR-BI’s role in endotoxemia/sepsis, calling for use of alternative models. In this study, using hSR-BI and hSR-BII transgenic mice, we found that SR-BI and to a lesser extent its splicing variant SR-BII, protects against LPS-induced lung damage. At 20 hours after intratracheal LPS instillation the extent of pulmonary inflammation and vascular leakage was significantly lower in hSR-BI and hSR-BII transgenic mice compared to wild type mice. Higher bronchoalveolar lavage fluid (BALF) inflammatory cell count and protein content as well as lung tissue neutrophil infiltration found in wild type mice was associated with markedly (2-3 times) increased pro-inflammatory cytokine production as compared to transgenic mice following LPS administration. Markedly lower endotoxin levels detected in BALF of transgenic vs. wild type mice along with the significantly increased BODIPY-LPS uptake observed in lungs of hSR-BI and hSR-BII mice 20 hours after the IT LPS injection suggest that hSR-BI and hSR-BII-mediated enhanced LPS clearance in the airways could represent the mechanism of their protective role against LPS-induced acute lung injury.

Geranylgeranyl transferase regulates CXC chemokine formation in alveolar macrophages and neutrophil recruitment in septic lung injury

2013 ◽  
Vol 304 (4) ◽  
pp. L221-L229 ◽  
Author(s):  
Zirak Hasan ◽  
Milladur Rahman ◽  
Karzan Palani ◽  
Ingvar Syk ◽  
Bengt Jeppsson ◽  
...  
Keyword(s):  
Lung Injury ◽  
Alveolar Macrophages ◽  
Neutrophil Infiltration ◽  
Abdominal Sepsis ◽  
Neutrophil Recruitment ◽  
Chemokine Production ◽  
Tnf Α ◽  
Cxc Chemokine ◽  
Geranylgeranyl Transferase

Overwhelming accumulation of neutrophils is a significant component in septic lung damage, although the signaling mechanisms behind neutrophil infiltration in the lung remain elusive. In the present study, we hypothesized that geranylgeranylation might regulate the inflammatory response in abdominal sepsis. Male C57BL/6 mice received the geranylgeranyl transferase inhibitor, GGTI-2133, before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 on neutrophils and CD40L on platelets. Gene expression of CXC chemokines, tumor necrosis factor-α (TNF-α), and CCL2 chemokine was determined by quantitative RT-PCR in isolated alveolar macrophages. Administration of GGTI-2133 markedly decreased CLP-induced infiltration of neutrophils, edema, and tissue injury in the lung. CLP triggered clear-cut upregulation of Mac-1 on neutrophils. Inhibition of geranylgeranyl transferase reduced CLP-evoked upregulation of Mac-1 on neutrophils in vivo but had no effect on chemokine-induced expression of Mac-1 on isolated neutrophils in vitro. Notably, GGTI-2133 abolished CLP-induced formation of CXC chemokines, TNF-α, and CCL2 in alveolar macrophages in the lung. Geranylgeranyl transferase inhibition had no effect on sepsis-induced platelet shedding of CD40L. In addition, inhibition of geranylgeranyl transferase markedly decreased CXC chemokine-triggered neutrophil chemotaxis in vitro. Taken together, our findings suggest that geranylgeranyl transferase is an important regulator of CXC chemokine production and neutrophil recruitment in the lung. We conclude that inhibition of geranylgeranyl transferase might be a potent way to attenuate acute lung injury in abdominal sepsis.

Protective Role of Urinary Trypsin Inhibitor in Acute Lung Injury Induced by Lipopolysaccharide

2005 ◽  
Vol 230 (4) ◽  
pp. 281-287 ◽  
Author(s):  
Ken-ichiro Inoue ◽  
Hirohisa Takano ◽  
Rie Yanagisawa ◽  
Miho Sakurai ◽  
Akinori Shimada ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Trypsin Inhibitor ◽  
Inflammatory Diseases ◽  
Lavage Fluid ◽  
Intercellular Adhesion Molecule ◽  
Urinary Trypsin Inhibitor ◽  
Intercellular Adhesion Molecule 1 ◽  
Lung Water ◽  
Lps Challenge

Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used as a drug for patients with acute inflammatory disorders such as disseminated intravascular coagulation, shock, and pancreatitis. However, direct contribution of UTI to inflammatory diseases has not been established. The present study analyzed acute inflammatory lung injury induced by lipopolysaccharide (LPS) in UTI-deficient (–/–) mice and corresponding wild-type (WT) mice. UTI (–/–) and WT mice were treated intratracheally with vehicle or LPS (125 μg/kg). The cellular profile of bronchoalveolar lavage fluid, lung water content, histology, and expression of proinflammatory molecules in the lung were evaluated. After LPS challenge, both genotypes of mice revealed neutrophilic lung inflammation and pulmonary edema. UTI (–/–) mice, however, showed more prominent infiltration of inflammatory cells and edema than WT mice. After LPS challenge in both genotypes of mice, the lung levels of mRNA and/or protein expression of interleukin-1β, macrophage inflammatory protein-1α, macrophage chemoattractant protein-1, keratinocyte chemoattractant, and intercellular adhesion molecule-1 (ICAM-1) were elevated in both groups, but to a greater extent in UTI (–/–) mice than in WT mice. These results suggest that UTI protects against acute lung injury induced by bacterial endotoxin, at least partly, through the inhibition of the enhanced local expression of proinflammatory cytokines, chemokines, and ICAM-1.

scholarly journals Bcl-2 overexpression in type II epithelial cells does not prevent hyperoxia-induced acute lung injury in mice

2010 ◽  
Vol 299 (3) ◽  
pp. L312-L322 ◽  
Author(s):  
Isabelle Métrailler-Ruchonnet ◽  
Alessandra Pagano ◽  
Stéphanie Carnesecchi ◽  
Karim Khatib ◽  
Pedro Herrera ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Ex Vivo ◽  
Lung Damage ◽  
Type Ii Cells ◽  
Type Ii ◽  
Lung Weight

Bcl-2 is an anti-apoptotic molecule preventing oxidative stress damage and cell death. We have previously shown that Bcl-2 is able to prevent hyperoxia-induced cell death when overexpressed in a murine fibrosarcoma cell line L929. We hypothesized that its specific overexpression in pulmonary epithelial type II cells could prevent hyperoxia-induced lung injury by protecting the epithelial side of the alveolo-capillary barrier. In the present work, we first showed that in vitro Bcl-2 can rescue murine pulmonary epithelial cells (MLE12) from oxygen-induced cell apoptosis, as shown by analysis of LDH release, annexin V/propidium staining, and caspase-3 activity. We then generated transgenic mice overexpressing specifically Bcl-2 in lung epithelial type II cells under surfactant protein C (SP-C) promoter (Tg-Bcl-2) and exposed them to hyperoxia. Bcl-2 did not hinder hyperoxia-induced mitochondria and DNA oxidative damage of type II cell in vivo. Accordingly, lung damage was identical in both Tg-Bcl-2 and littermate mice strains, as measured by lung weight, bronchoalveolar lavage, and protein content. Nevertheless, we observed a significant lower number of TUNEL-positive cells in type II cells isolated from Tg-Bcl-2 mice exposed to hyperoxia compared with cells isolated from littermate mice. In summary, these results show that although Bcl-2 overexpression is able to prevent hyperoxia-induced cell death at single cell level in vitro and ex vivo, it is not sufficient to prevent cell death of parenchymal cells and to protect the lung from acute damage in mice.

Scutellaria baicalensis Ameliorates Acute Lung Injury by Suppressing Inflammation In Vitro and In Vivo

2017 ◽  
Vol 45 (01) ◽  
pp. 137-157 ◽  
Author(s):  
Jian-Jung Chen ◽  
Chung-Chun Huang ◽  
Heng-Yuan Chang ◽  
Pei-Ying Li ◽  
Yu-Chia Liang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Water Extract ◽  
Scutellaria Baicalensis ◽  
Raw 264.7 Cells ◽  
Necrosis Factor Alpha ◽  
Anti Inflammatory

Scutellaria baicalensis has been widely used as both a dietary ingredient and traditional herbal medicine in Taiwan to treat inflammation, cancer, and bacterial and viral infections of the respiratory tract and gastrointestinal tract. This paper aims to investigate the in vitro and in vivo anti-inflammatory effects of S. baicalensis. In HPLC analysis, the fingerprint chromatogram of the water extract of S. baicalensis (WSB) was established. The anti-inflammatory effects of WSB were inverstigated using lipopolysaccharide (LPS)-stimulated mouse macrophage (RAW264.7) in vitro and LPS-induced lung injury in vivo. WSB attenuated the production of LPS-induced nitric oxide (NO), tumor necrosis factor-alpha (TNF-[Formula: see text], interleukin-[Formula: see text] (IL-1[Formula: see text], and IL-6 in vitro and in vivo. Pretreatment with WSB markedly reduced the LPS-induced histological alterations in lung tissues. Furthermore, WSB significantly reduced the number of total cells and the protein concentration levels in the BALF. WSB blocked protein expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), phosphorylation of I[Formula: see text]B-[Formula: see text] protein and MAPKs in LPS-stimulated RAW 264.7 cells and LPS-induce lung injury was also blocked. This study suggests that WSB possesses anti-inflammatory effects in vitro and in vivo, and the results suggested that WSB may be a potential therapeutic candidate for the treatment of inflammatory diseases.

scholarly journals A Subanesthetic Dose of Isoflurane during Postconditioning Ameliorates Zymosan-Induced Neutrophil Inflammation Lung Injury and Mortality in Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Hui Wang ◽  
Jing Fan ◽  
Nan-lin Li ◽  
Jun-tang Li ◽  
Shi-fang Yuan ◽  
...  
Keyword(s):  
Lung Injury ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Weight Ratio ◽  
Polymorphonuclear Neutrophils ◽  
Mouse Lung ◽  
Endothelial Adhesion Molecule ◽  
Primary Mouse

Anesthetic isoflurane (ISO) has immunomodulatory effects. In the present study, we investigated whether a subanesthetic dose of ISO (0.7%) protected against zymosan (ZY) induced inflammatory responses in the murine lung and isolated neutrophils. At 1 and 6 hrs after ZY administration intraperitoneally, ISO was inhaled for 1 hr, and 24 hrs later, lung inflammation and injury were assessed. We found that ISO improved the survival rate of mice and mitigated lung injury as characterized by the histopathology, wet-to-dry weight ratio, protein leakage, and lung function index. ISO significantly attenuated ZY-induced lung neutrophil recruitment and inflammation. This was suggested by the downregulation of (a) endothelial adhesion molecule expression and myeloperoxidase (MPO) activity in lung tissue and polymorphonuclear neutrophils (b) chemokines, and (c) proinflammatory cytokines in BALF. Furthermore, ZY-induced nuclear translocation and DNA-binding activity of NF-κB p65 were also reduced by ISO. ISO treatment inhibited iNOS expression and activity, as well as subsequent nitric oxide generation. Consistent with thesein vivoobservations,in vitrostudies confirmed that ISO blocked NF-κB and iNOS activation in primary mouse neutrophils challenged by ZY. These results provide evidence that 0.7% ISO ameliorates inflammatory responses in ZY-treated mouse lung and primary neutrophils.

scholarly journals Streptococcal M1 Protein Triggers Farnesyltransferase-Dependent Formation of CXC Chemokines in Alveolar Macrophages and Neutrophil Infiltration of the Lungs

2012 ◽  
Vol 80 (11) ◽  
pp. 3952-3959 ◽  
Author(s):  
Songen Zhang ◽  
Milladur Rahman ◽  
Su Zhang ◽  
Bengt Jeppsson ◽  
Heiko Herwald ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alveolar Macrophages ◽  
Neutrophil Migration ◽  
Neutrophil Recruitment ◽  
Lung Damage ◽  
Streptococcal Toxic Shock Syndrome ◽  
Edema Formation ◽  
M1 Protein ◽  
Cxc Chemokine

ABSTRACTThe M1 serotype ofStreptococcus pyogenesplays an important role in streptococcal toxic shock syndrome. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to inhibit streptococcal M1 protein-induced acute lung damage, although downstream mechanisms remain elusive. Protein isoprenylation, such as farnesylation and geranylgeranylation, has been suggested to regulate anti-inflammatory effects exerted by statins. Here, we examined the effect of a farnesyltransferase inhibitor (FTI-277) on M1 protein-triggered lung inflammation. Male C57BL/6 mice were treated with FTI-277 prior to M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema, and CXC chemokine formation. Flow cytometry was used to determine Mac-1 expression on neutrophils. The gene expression of CXC chemokines was determined in alveolar macrophages by using quantitative reverse transcription (RT)-PCR. We found that the administration of FTI-277 markedly decreased M1 protein-induced accumulation of neutrophils, edema formation, and tissue damage in the lung. Notably, inhibition of farnesyltransferase abolished M1 protein-evoked production of CXC chemokines in the lung and gene expression of CXC chemokines in alveolar macrophages. Moreover, FTI-277 completely inhibited chemokine-induced neutrophil migrationin vitro. However, farnesyltransferase inhibition had no effect on M1 protein-induced expression of Mac-1 on neutrophils. Our findings suggest that farnesyltransferase is a potent regulator of CXC chemokine formation in alveolar macrophages and that inhibition of farnesyltransferase not only reduces neutrophil recruitment but also attenuates acute lung injury provoked by streptococcal M1 protein. We conclude that farnesyltransferase activity is a potential target in order to attenuate acute lung damage in streptococcal infections.

scholarly journals TGF-β-R2 is required for HBP induced acute lung injury and vascular leakage for TGF-[beta]/Smad/Rho signaling pathway activation

2022 ◽  
Author(s):  
Zixuan Liu ◽  
Mingming Chen ◽  
Yini Sun ◽  
Xu Li ◽  
Liu Cao ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Vascular Leakage ◽  
Polymorphonuclear Neutrophils ◽  
Heparin Binding

Heparin-binding protein (HBP), as a granule protein secreted by polymorphonuclear neutrophils (PMNs) participates in the pathophysiological process of sepsis. It has been reported that HBP is a biomarker of sepsis, which is related to the severity of septic shock and organ dysfunction. HBP binds to vascular endothelial cells as one of the primary target sites. However, it is still unclear whether HBP-binding protein receptors exist on the surface of ECs. The effect of HBP on vascular permeability in sepsis and its mechanism needs to be explored. We conducted in vivo and in vitro study. We demonstrated that HBP bound to transforming growth factor-β receptor type 2 (TGF-β-R2) as a ligand. GST pull-down analysis reveals that HBP mainly interacts with the extracellular domain of TGF-β-R2. HBP induced acute lung injury (ALI) and vascular leakage via activation of TGF-β/SMAD2/3 signaling pathway. Permeability assay suggests TGF-β-R2 is necessary for HBP-induced increased permeability. We also defined the role of HBP and its potential membrane receptor TGF-β-R2 in the blood-gas barrier in the pathogenesis of HBP-related ALI.

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