Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury

2013 ◽  
Vol 305 (10) ◽  
pp. L756-L763 ◽  
Author(s):  
Songen Zhang ◽  
Lei Song ◽  
Yongzhi Wang ◽  
Heiko Herwald ◽  
Henrik Thorlacius
Keyword(s):  
Lung Injury ◽  
Leukocyte Adhesion ◽  
Neutrophil Infiltration ◽  
Neutrophil Recruitment ◽  
Lung Damage ◽  
Streptococcal Toxic Shock Syndrome ◽  
Leukocyte Rolling ◽  
Inflammatory Reactions ◽  
Capillary Trapping ◽  
M1 Protein

Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung damage. CD162 is an adhesion molecule that has been reported to mediate neutrophil recruitment in acute inflammatory reactions. In this study, the purpose was to investigate the role of CD162 in M1 protein-provoked lung injury. Male C57BL/6 mice were treated with monoclonal antibody directed against CD162 or a control antibody before M1 protein challenge. Edema, neutrophil infiltration, and CXC chemokines were determined in the lung, 4 h after M1 protein administration. Fluorescence intravital microscopy was used to analyze leukocyte-endothelium interactions in the pulmonary microcirculation. Inhibition of CD162 reduced M1 protein-provoked accumulation of neutrophils, edema, and CXC chemokine formation in the lung by >54%. Moreover, immunoneutralization of CD162 abolished leukocyte rolling and firm adhesion in pulmonary venules of M1 protein-treated animals. In addition, inhibition of CD162 decreased M1 protein-induced capillary trapping of leukocytes in the lung microvasculature and improved microvascular perfusion in the lungs of M1 protein-treated animals. Our findings suggest that CD162 plays an important role in M1 protein-induced lung damage by regulating leukocyte rolling in pulmonary venules. Consequently, inhibition of CD162 attenuates M1 protein-evoked leukocyte adhesion and extravasation in the lung. Thus, our results suggest that targeting the CD162 might pave the way for novel opportunities to protect against pulmonary damage in streptococcal infections.

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 Simvastatin regulates CXC chemokine formation in streptococcal M1 protein-induced neutrophil infiltration in the lung

2011 ◽  
Vol 300 (6) ◽  
pp. L930-L939 ◽  
Author(s):  
Songen Zhang ◽  
Milladur Rahman ◽  
Su Zhang ◽  
Zhongquan Qi ◽  
Heiko Herwald ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophages ◽  
Tissue Injury ◽  
Neutrophil Infiltration ◽  
Streptococcal Toxic Shock Syndrome ◽  
Edema Formation ◽  
M1 Protein ◽  
Cxcr2 Antagonist

Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung injury. Statins exert beneficial effects in septic patients although the mechanisms remain elusive. This study examined effects of simvastatin on M1 protein-provoked pulmonary inflammation and tissue injury. Male C57BL/6 mice were pretreated with simvastatin or a CXCR2 antagonist before M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for determination of neutrophil infiltration, formation of edema, and CXC chemokines. Flow cytometry was used to determine Mac-1 expression on neutrophils. Gene expression of CXC chemokines was determined in alveolar macrophages by using quantitative RT-PCR. M1 protein challenge caused massive infiltration of neutrophils, edema formation, and production of CXC chemokines in the lung as well as upregulation of Mac-1 on circulating neutrophils. Simvastatin reduced M1 protein-induced infiltration of neutrophils and edema in the lung. In addition, M1 protein-induced Mac-1 expression on neutrophils was abolished by simvastatin. Furthermore, simvastatin markedly decreased pulmonary formation of CXC chemokines and gene expression of CXC chemokines in alveolar macrophages. Moreover, the CXCR2 antagonist reduced M1 protein-induced neutrophil expression of Mac-1 and accumulation of neutrophils as well as edema formation in the lung. These novel findings indicate that simvastatin is a powerful inhibitor of neutrophil infiltration in acute lung damage triggered by streptococcal M1 protein. The inhibitory effect of simvastatin on M1 protein-induced neutrophil recruitment appears related to reduced pulmonary generation of CXC chemokines. Thus, simvastatin may be a useful tool to ameliorate acute lung injury in streptococcal infections.

scholarly journals Targeting Rac1 Signaling Inhibits Streptococcal M1 Protein-Induced CXC Chemokine Formation, Neutrophil Infiltration and Lung Injury

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e71080 ◽  
Author(s):  
Songen Zhang ◽  
Milladur Rahman ◽  
Su Zhang ◽  
Lei Song ◽  
Heiko Herwald ◽  
...  
Keyword(s):  
Lung Injury ◽  
Neutrophil Infiltration ◽  
M1 Protein ◽  
Cxc Chemokine

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.

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.

Pathophysiological patterns of resolution from acute oleic acid lung injury in the dog

1984 ◽  
Vol 56 (2) ◽  
pp. 472-481 ◽  
Author(s):  
R. B. Schoene ◽  
H. T. Robertson ◽  
D. R. Thorning ◽  
S. C. Springmeyer ◽  
M. P. Hlastala ◽  
...  
Keyword(s):  
Oleic Acid ◽  
Gas Exchange ◽  
Lung Injury ◽  
Control Period ◽  
Lung Damage ◽  
Acute Injury ◽  
Saline Control ◽  
Time Interval ◽  
Inflammatory Reactions ◽  
Pulmonary Arterial

Lungs of mongrel dogs with permanent tracheostomies and implanted systemic pulmonary arterial catheters were injured by intravenous infusion of oleic acid (0.09 mg/kg). Injury resulted in extensive, multifocal, and nonrandomly distributed lung damage. Awake dogs were studied during a control period and 1, 4, and 7 days following injection of oleic acid. Standard gas exchange measurements, the inert gas elimination technique, and subsegmental bronchoalveolar lavage (BAL) were used. Five oleic acid dogs and two saline control dogs were killed after each study period for morphological evaluation. Control dogs did not develop significant gas exchange abnormalities but did have localized inflammatory reactions at the lavage site. The oleic acid dogs developed significant shunt at day 1 with resolution of shunt by day 7. The multifocal sites of oleic acid injury were virtually identical in appearance at a given time interval; they consisted of alveolar cell necrosis with varying amounts of hemorrhagic inflammatory exudation at day 1 followed by a proliferative reparative reaction resulting in substantial restoration of alveolar structure at day 7. BAL showed a suppurative inflammatory response with hemorrhage on day 1 and an increased number of macrophages by day 7. The oleic acid model of acute diffuse lung injury demonstrates several pathophysiological alterations that could be compared with pathomorphological changes during the acute injury phase and during the subsequent reparative phase.

scholarly journals Streptococcal M1 protein triggers chemokine formation, neutrophil infiltration, and lung injury in an NFAT-dependent manner

2015 ◽  
Vol 97 (6) ◽  
pp. 1003-1010 ◽  
Author(s):  
Songen Zhang ◽  
Su Zhang ◽  
Eliana Garcia-Vaz ◽  
Heiko Herwald ◽  
Maria F. Gomez ◽  
...  
Keyword(s):  
Lung Injury ◽  
Neutrophil Infiltration ◽  
Dependent Manner ◽  
M1 Protein

scholarly journals Streptococcal M1 Protein-Provoked CXC Chemokine Formation, Neutrophil Recruitment and Lung Damage Are Regulated by Rho-Kinase Signaling

2012 ◽  
Vol 4 (4) ◽  
pp. 399-408 ◽  
Author(s):  
Songen Zhang ◽  
Milladur Rahman ◽  
Su Zhang ◽  
Heiko Herwald ◽  
Zhongquan Qi ◽  
...  
Keyword(s):  
Rho Kinase ◽  
Neutrophil Recruitment ◽  
Lung Damage ◽  
Kinase Signaling ◽  
M1 Protein ◽  
Cxc Chemokine

scholarly journals Targeting S100A9 Reduces Neutrophil Recruitment, Inflammation and Lung Damage in Abdominal Sepsis

2021 ◽  
Vol 22 (23) ◽  
pp. 12923
Author(s):  
Zhiyi Ding ◽  
Feifei Du ◽  
Richard Garland Averitt V ◽  
Gabriel Jakobsson ◽  
Carl-Fredrik Rönnow ◽  
...  
Keyword(s):  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Abdominal Sepsis ◽  
Neutrophil Activation ◽  
Neutrophil Recruitment ◽  
Lung Damage ◽  
Edema Formation ◽  
Chemokine Production ◽  
Activated Complex

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.

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