STAT3-dependent CXC chemokine formation and neutrophil migration in streptococcal M1 protein-induced acute lung inflammation

2015 ◽  
Vol 308 (11) ◽  
pp. L1159-L1167 ◽  
Author(s):  
Songen Zhang ◽  
Rundk Hwaiz ◽  
Lingtao Luo ◽  
Heiko Herwald ◽  
Henrik Thorlacius
Keyword(s):  
Streptococcus Pyogenes ◽  
Lung Inflammation ◽  
Neutrophil Migration ◽  
Neutrophil Recruitment ◽  
Acute Lung Inflammation ◽  
Chemokine Production ◽  
Stat3 Signaling ◽  
M1 Protein ◽  
Cxc Chemokine

Streptococcus pyogenes cause infections ranging from mild pharyngitis to severe streptococcal toxic shock syndrome (STSS). The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, it was hypothesized that STAT3 signaling might be involved in M1 protein-evoked lung inflammation. The STAT3 inhibitor, S3I-201, was administered to male C57Bl/6 mice before iv challenge with M1 protein. Bronchoalveolar fluid and lung tissue were harvested for quantification of STAT3 activity, neutrophil recruitment, edema, and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Levels of IL-6 and HMGB1 were determined in plasma. CXCL2-induced neutrophil chemotaxis was studied in vitro. Administration of S3I-201 markedly reduced M1 protein-provoked STAT3 activity, neutrophil recruitment, edema formation, and inflammatory changes in the lung. In addition, M1 protein significantly increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Treatment with S3I-201 had no effect on M1 protein-induced expression of Mac-1 on neutrophils. In contrast, inhibition of STAT3 activity greatly reduced M1 protein-induced formation of CXC chemokines in the lung. Interestingly, STAT3 inhibition markedly decreased plasma levels of IL-6 and HMGB1 in animals exposed to M1 protein. Moreover, we found that S3I-201 abolished CXCL2-induced neutrophil migration in vitro. In conclusion, these novel findings indicate that STAT3 signaling plays a key role in mediating CXC chemokine production and neutrophil infiltration in M1 protein-induced acute lung inflammation.

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.

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.

scholarly journals Leukocyte-specific protein 1 regulates neutrophil recruitment in acute lung inflammation

2015 ◽  
Vol 309 (9) ◽  
pp. L995-L1008 ◽  
Author(s):  
Nguyen Phuong Khanh Le ◽  
Shankaramurthy Channabasappa ◽  
Mokarram Hossain ◽  
Lixin Liu ◽  
Baljit Singh
Keyword(s):  
Lung Inflammation ◽  
Neutrophil Migration ◽  
Specific Protein ◽  
Neutrophil Recruitment ◽  
Acute Lung Inflammation ◽  
Western Blots ◽  
Monocyte Chemoattractant Protein 1 ◽  
Murine Bone Marrow ◽  
Human Lungs ◽  
Activated Neutrophils

The mechanisms of excessive migration of activated neutrophils into inflamed lungs, credited with tissue damage, are not fully understood. We explored the hitherto unknown expression of leukocyte-specific protein 1 (LSP1) in human and mouse lungs and neutrophils and examined its role in neutrophil migration in acute lung inflammation. Autopsied septic human lungs showed increased LSP1 labeling in epithelium, endothelium, and leukocytes, including in their nuclei compared with normal lungs. We induced acute lung inflammation through intranasal administration of E. coli lipopolysaccharide (LPS) (80 μg) in LSP1-deficient ( Lsp1−/−) and wild-type (WT) 129/SvJ mice. Immunocytochemistry and Western blots showed increased expression of LSP1 and phosphorylated LSP1 in lungs of LPS-treated WT mice. Histology showed more congestion, inflammation, and Gr-1+neutrophils in lung of WT mice than Lsp1−/−mice. LPS-treated WT mice had significantly more neutrophils in bronchoalveolar lavage (BAL) and myeloperoxidase levels in lungs compared with Lsp1−/−mice. However, there were no differences in lung tissue and BAL concentrations of keratinocyte-derived chemokine, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α and -1β, vascular permeability, and phosphorylated p38 MAPK between LPS-treated WT and Lsp1−/−mice, whereas TNF-α concentration was higher in BAL fluid from LPS-treated WT. Immunoelectron microscopy showed increased LSP1 in the nuclei of LPS-treated neutrophils. We also found increased levels of phosphorylated LSP1 associated with plasma membrane, nucleus, and cytosol at various times after LPS treatment of murine bone marrow-derived neutrophils, suggesting its role in modulation of neutrophil cytoskeleton and the membrane. These data collectively show increased expression of LSP1 in inflamed mouse and human lungs and its role in neutrophil recruitment and lung inflammation.

scholarly journals Lack of CD34 delays bacterial endotoxin-induced lung inflammation

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Gurpreet K. Aulakh ◽  
Sushmita Maltare ◽  
Baljit Singh
Keyword(s):  
Lung Inflammation ◽  
Neutrophil Migration ◽  
Neutrophil Recruitment ◽  
Multiple Time ◽  
Acute Lung Inflammation ◽  
Knock Out ◽  
Time Points ◽  
Bronchiolar Epithelium ◽  
Alveolar Septa

Abstract Background CD34, a pan-selectin binding protein when glycosylated, has been shown to be involved in leukocyte migration to the site of inflammation. However, only one report is available on the expression and role of CD34 in neutrophil recruitment during acute lung inflammation. Methods We proceeded to study the role of CD34 in lung neutrophil migration using mouse model of endotoxin induced acute lung inflammation and studied over multiple time points, in generic CD34 knock-out (KO) strain. Results While there was no difference in BAL total or differential leukocyte counts, lung MPO content was lower in LPS exposed KO compared to WT group at 3 h time-point (p = 0.0308). The MPO levels in CD34 KO mice begin to rise at 9 h (p = 0.0021), as opposed to an early 3 h rise in WT mice (p = 0.0001), indicating that KO mice display delays in lung neutrophil recruitment kinetics. KO mice do not loose endotoxin induced lung vascular barrier properties as suggested by lower BAL total protein at 3 h (p = 0.0452) and 24 h (p = 0.0113) time-points. Several pro-inflammatory cytokines and chemokines (TNF-α, IL-1β, KC, MIP-1α, IL-6, IL-10 and IL-12 p70 sub-unit; p < 0.05) had higher levels in WT compared to KO group, at 3 h. Lung immunofluorescence in healthy WT mice reveals CD34 expression in the bronchiolar epithelium, in addition to alveolar septa. Conclusion Thus, given CD34′s pan-selectin affinity, and expression in the bronchiolar epithelium as well as alveolar septa, our study points towards a role of CD34 in lung neutrophil recruitment but not alveolar migration, cytokine expression and lung inflammation.

scholarly journals Combined In Vitro and In Vivo Approaches to Propose a Putative Adverse Outcome Pathway for Acute Lung Inflammation Induced by Nanoparticles: A Study on Carbon Dots

Nanomaterials ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 180
Author(s):  
Maud Weiss ◽  
Jiahui Fan ◽  
Mickaël Claudel ◽  
Luc Lebeau ◽  
Françoise Pons ◽  
...  
Keyword(s):  
Carbon Dots ◽  
Lung Inflammation ◽  
Adverse Outcome ◽  
Cellular Responses ◽  
Target Cells ◽  
Inflammasome Activation ◽  
Adverse Outcome Pathway ◽  
Acute Lung Inflammation

With the growth of nanotechnologies, concerns raised regarding the potential adverse effects of nanoparticles (NPs), especially on the respiratory tract. Adverse outcome pathways (AOP) have become recently the subject of intensive studies in order to get a better understanding of the mechanisms of NP toxicity, and hence hopefully predict the health risks associated with NP exposure. Herein, we propose a putative AOP for the lung toxicity of NPs using emerging nanomaterials called carbon dots (CDs), and in vivo and in vitro experimental approaches. We first investigated the effect of a single administration of CDs on mouse airways. We showed that CDs induce an acute lung inflammation and identified airway macrophages as target cells of CDs. Then, we studied the cellular responses induced by CDs in an in vitro model of macrophages. We observed that CDs are internalized by these cells (molecular initial event) and induce a series of key events, including loss of lysosomal integrity and mitochondrial disruption (organelle responses), as well as oxidative stress, inflammasome activation, inflammatory cytokine upregulation and macrophage death (cellular responses). All these effects triggering lung inflammation as tissular response may lead to acute lung injury.

scholarly journals Pulmonary Endothelial Protein Kinase C-Delta (PKCδ) Regulates Neutrophil Migration in Acute Lung Inflammation

2014 ◽  
Vol 184 (1) ◽  
pp. 200-213 ◽  
Author(s):  
Mark J. Mondrinos ◽  
Ting Zhang ◽  
Shuang Sun ◽  
Paul A. Kennedy ◽  
Devon J. King ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Lung Inflammation ◽  
Neutrophil Migration ◽  
Acute Lung Inflammation ◽  
Protein Kinase C Delta ◽  
Kinase C

scholarly journals The Crucial Role of PPARγ-Egr-1-Pro-Inflammatory Mediators Axis in IgG Immune Complex-Induced Acute Lung Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Chunguang Yan ◽  
Jing Chen ◽  
Yue Ding ◽  
Zetian Zhou ◽  
Bingyu Li ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Immune Complex ◽  
Inflammatory Mediators ◽  
Lung Inflammation ◽  
Acute Lung Inflammation ◽  
Pparγ Agonist

BackgroundThe ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR) γ plays crucial roles in diverse biological processes including cellular metabolism, differentiation, development, and immune response. However, during IgG immune complex (IgG-IC)-induced acute lung inflammation, its expression and function in the pulmonary tissue remains unknown.ObjectivesThe study is designed to determine the effect of PPARγ on IgG-IC-triggered acute lung inflammation, and the underlying mechanisms, which might provide theoretical basis for therapy of acute lung inflammation.SettingDepartment of Pathogenic Biology and Immunology, Medical School of Southeast UniversitySubjectsMice with down-regulated/up-regulated PPARγ activity or down-regulation of Early growth response protein 1 (Egr-1) expression, and the corresponding controls.InterventionsAcute lung inflammation is induced in the mice by airway deposition of IgG-IC. Activation of PPARγ is achieved by using its agonist Rosiglitazone or adenoviral vectors that could mediate overexpression of PPARγ. PPARγ activity is suppressed by application of its antagonist GW9662 or shRNA. Egr-1 expression is down-regulated by using the gene specific shRNA.Measures and Main ResultsWe find that during IgG-IC-induced acute lung inflammation, PPARγ expression at both RNA and protein levels is repressed, which is consistent with the results obtained from macrophages treated with IgG-IC. Furthermore, both in vivo and in vitro data show that PPARγ activation reduces IgG-IC-mediated pro-inflammatory mediators’ production, thereby alleviating lung injury. In terms of mechanism, we observe that the generation of Egr-1 elicited by IgG-IC is inhibited by PPARγ. As an important transcription factor, Egr-1 transcription is substantially increased by IgG-IC in both in vivo and in vitro studies, leading to augmented protein expression, thus amplifying IgG-IC-triggered expressions of inflammatory factors via association with their promoters.ConclusionDuring IgG-IC-stimulated acute lung inflammation, PPARγ activation can relieve the inflammatory response by suppressing the expression of its downstream target Egr-1 that directly binds to the promoter regions of several inflammation-associated genes. Therefore, regulation of PPARγ-Egr-1-pro-inflammatory mediators axis by PPARγ agonist Rosiglitazone may represent a novel strategy for blockade of acute lung injury.

scholarly journals 2,4-Dimethoxy-6-Methylbenzene-1,3-diol, a Benzenoid From Antrodia cinnamomea, Mitigates Psoriasiform Inflammation by Suppressing MAPK/NF-κB Phosphorylation and GDAP1L1/Drp1 Translocation

2021 ◽  
Vol 12 ◽  
Author(s):  
Shih-Yi Chuang ◽  
Chi-Yuan Chen ◽  
Shih-Chun Yang ◽  
Ahmed Alalaiwe ◽  
Chih-Hung Lin ◽  
...  
Keyword(s):  
Cell Model ◽  
Mitochondrial Fission ◽  
Neutrophil Migration ◽  
Chemokine Production ◽  
Antrodia Cinnamomea ◽  
Effective Treatment Modality ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory ◽  
Novel Target

Antrodia cinnamomea exhibits anti-inflammatory, antioxidant, and immunomodulatory activities. We aimed to explore the antipsoriatic potential of 2,4-dimethoxy-6-methylbenzene-1,3-diol (DMD) derived from A. cinnamomea. The macrophages activated by imiquimod (IMQ) were used as the cell model for examining the anti-inflammatory effect of DMD in vitro. A significantly high inhibition of IL-23 and IL-6 by DMD was observed in THP-1 macrophages and bone marrow-derived mouse macrophages. The conditioned medium of DMD-treated macrophages could reduce neutrophil migration and keratinocyte overproliferation. DMD could downregulate cytokine/chemokine by suppressing the phosphorylation of mitogen-activated protein kinases (MAPKs) and NF-κB. We also observed inhibition of GDAP1L1/Drp1 translocation from the cytoplasm to mitochondria by DMD intervention. Thus, mitochondrial fission could be a novel target for treating psoriatic inflammation. A psoriasiform mouse model treated by IMQ showed reduced scaling, erythema, and skin thickening after topical application of DMD. Compared to the IMQ stimulation only, the active compound decreased epidermal thickness by about 2-fold. DMD diminished the number of infiltrating macrophages and neutrophils and their related cytokine/chemokine production in the lesional skin. Immunostaining of the IMQ-treated skin demonstrated the inhibition of GDAP1LI and phosphorylated Drp1 by DMD. The present study provides insight regarding the potential use of DMD as an effective treatment modality for psoriatic inflammation.

Role of surface complexed iron in oxidant generation and lung inflammation induced by silicates

1992 ◽  
Vol 263 (5) ◽  
pp. L511-L518 ◽  
Author(s):  
A. J. Ghio ◽  
T. P. Kennedy ◽  
A. R. Whorton ◽  
A. L. Crumbliss ◽  
G. E. Hatch ◽  
...  
Keyword(s):  
Respiratory Burst ◽  
Lung Inflammation ◽  
Important Determinant ◽  
Surface Complexation ◽  
Oxidative Degradation ◽  
Transition Metal Ions ◽  
Leukotriene B4 ◽  
Acute Lung Inflammation

Inhalation of silicates induces a variety of lung diseases in humans. The molecular mechanism(s) by which these dusts cause disease is not known. Because several naturally occurring mineral oxides have large amounts of transition metal ions on their surfaces, we tested the hypothesis that surface complexation of iron may be an important determinant of their ability to induce disease. Silica, crocidolite, kaolinite, and talc complexed considerable concentrations of Fe3+ onto their surfaces from both in vitro and in vivo sources. The potential biological importance of iron complexation was assessed by examining the relationship between surface [Fe3+] and the ability of silicates to mediate oxidative degradation of deoxyribose in vitro, induce a respiratory burst and elicit leukotriene B4 (LTB4) release by alveolar macrophages (AM) in vitro, and cause acute alveolitis after intratracheal insufflation. For these studies, three varieties of silicate dusts were used: iron-loaded, wetted (unmodified), and deferoxamine-treated to remove Fe3+. The ability of silicates to catalyze oxidant generation in an ascorbate/H2O2 system in vitro, to trigger respiratory burst activity and LTB4 release by AM, and to induce acute lung inflammation in the rat all increased with surface complexed Fe3+. The results of these studies suggest that surface complexation of iron may be an important determinant in the pathogenesis of disease after silicate exposure.

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