scholarly journals G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling

2016 ◽  
Vol 213 (10) ◽  
pp. 1999-2018 ◽  
Author(s):  
Besnik Bajrami ◽  
Haiyan Zhu ◽  
Hyun-Jeong Kwak ◽  
Subhanjan Mondal ◽  
Qingming Hou ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Acute Inflammation ◽  
Early Stage ◽  
Pulmonary Inflammation ◽  
Lung Damage ◽  
Critical Event ◽  
Neutrophil Accumulation ◽  
Peripheral Blood Neutrophil ◽  
Lung Injury Model

Cytokine-induced neutrophil mobilization from the bone marrow to circulation is a critical event in acute inflammation, but how it is accurately controlled remains poorly understood. In this study, we report that CXCR2 ligands are responsible for rapid neutrophil mobilization during early-stage acute inflammation. Nevertheless, although serum CXCR2 ligand concentrations increased during inflammation, neutrophil mobilization slowed after an initial acute fast phase, suggesting a suppression of neutrophil response to CXCR2 ligands after the acute phase. We demonstrate that granulocyte colony-stimulating factor (G-CSF), usually considered a prototypical neutrophil-mobilizing cytokine, was expressed later in the acute inflammatory response and unexpectedly impeded CXCR2-induced neutrophil mobilization by negatively regulating CXCR2-mediated intracellular signaling. Blocking G-CSF in vivo paradoxically elevated peripheral blood neutrophil counts in mice injected intraperitoneally with Escherichia coli and sequestered large numbers of neutrophils in the lungs, leading to sterile pulmonary inflammation. In a lipopolysaccharide-induced acute lung injury model, the homeostatic imbalance caused by G-CSF blockade enhanced neutrophil accumulation, edema, and inflammation in the lungs and ultimately led to significant lung damage. Thus, physiologically produced G-CSF not only acts as a neutrophil mobilizer at the relatively late stage of acute inflammation, but also prevents exaggerated neutrophil mobilization and the associated inflammation-induced tissue damage during early-phase infection and inflammation.

scholarly journals ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 964 ◽  
Author(s):  
Izabela Galvão ◽  
Rayssa M. Athayde ◽  
Denise A. Perez ◽  
Alesandra C. Reis ◽  
Luisa Rezende ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Pleural Cavity ◽  
Inflammatory Diseases ◽  
Human Neutrophils ◽  
Neutrophil Accumulation ◽  
Resolution Of Inflammation ◽  
Induced Apoptosis ◽  
Rock Inhibition ◽  
Rock Activity

Uncontrolled inflammation leads to tissue damage and it is central for the development of chronic inflammatory diseases and autoimmunity. An acute inflammatory response is finely regulated by the action of anti-inflammatory and pro-resolutive mediators, culminating in the resolution of inflammation and restoration of homeostasis. There are few studies investigating intracellular signaling pathways associated with the resolution of inflammation. Here, we investigate the role of Rho-associated kinase (ROCK), a serine/threonine kinase, in a model of self-resolving neutrophilic inflammatory. We show that ROCK activity, evaluated by P-MYPT-1 kinetics, was higher during the peak of lipopolysaccharide-induced neutrophil influx in the pleural cavity of mice. ROCK inhibition by treatment with Y-27632 decreased the accumulation of neutrophils in the pleural cavity and was associated with an increase in apoptotic events and efferocytosis, as evaluated by an in vivo assay. In a model of gout, treatment with Y-27632 reduced neutrophil accumulation, IL-1β levels and hypernociception in the joint. These were associated with reduced MYPT and IκBα phosphorylation levels and increased apoptosis. Finally, inhibition of ROCK activity also induced apoptosis in human neutrophils and destabilized cytoskeleton, extending the observed effects to human cells. Taken together, these data show that inhibition of the ROCK pathway might represent a potential therapeutic target for neutrophilic inflammatory diseases.

scholarly journals In Vivo Activation of STAT3 Signaling in Satellite Cells and Myofibers in Regenerating Rat Skeletal Muscles

2002 ◽  
Vol 50 (12) ◽  
pp. 1579-1589 ◽  
Author(s):  
Katsuya Kami ◽  
Emiko Senba
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Intracellular Signaling ◽  
Skeletal Muscles ◽  
Early Stage ◽  
Skeletal Muscle Regeneration ◽  
Stat3 Signaling

Although growth factors and cytokines play critical roles in skeletal muscle regeneration, intracellular signaling molecules that are activated by these factors in regenerating muscles have been not elucidated. Several lines of evidence suggest that leukemia inhibitory factor (LIF) is an important cytokine for the proliferation and survival of myoblasts in vitro and acceleration of skeletal muscle regeneration. To elucidate the role of LIF signaling in regenerative responses of skeletal muscles, we examined the spatial and temporal activation patterns of an LIF-associated signaling molecule, the signal transducer and activator transcription 3 (STAT3) proteins in regenerating rat skeletal muscles induced by crush injury. At the early stage of regeneration, activated STAT3 proteins were first detected in the nuclei of activated satellite cells and then continued to be activated in proliferating myoblasts expressing both PCNA and MyoD proteins. When muscle regeneration progressed, STAT3 signaling was no longer activated in differentiated myoblasts and myotubes. In addition, activation of STAT3 was also detected in myonuclei within intact sarcolemmas of surviving myofibers that did not show signs of necrosis. These findings suggest that activation of STAT3 signaling is an important molecular event that induces the successful regeneration of injured skeletal muscles.

Identification of a Two-Step Mechanism Responsible for Antibody-Mediated Transfusion Related Acute Lung Injury (TRALI)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 846-846
Author(s):  
Christopher G.J. McKenzie ◽  
Michael Kim ◽  
Tarandeep Singh ◽  
John W. Semple
Keyword(s):  
Reactive Oxygen Species ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Mhc Class I ◽  
Reactive Oxygen ◽  
Lung Damage ◽  
Class I ◽  
Oxygen Species ◽  
Neutrophil Accumulation

Abstract Abstract 846 Transfusion-related acute lung injury (TRALI) is one of the leading causes of transfusion fatalities, and most TRALI reactions are thought to be caused by donor antibodies. It is currently thought that the donor antibodies activate pulmonary neutrophils to produce reactive oxygen species that damage lung tissue. There have been several animal models of TRALI developed including, for example, ex vivo lung models demonstrating the importance of human anti-neutrophil antibodies in TRALI, and in vivo models showing how biological response modifiers can induce recipient lung damage. An in vivo murine model of antibody-mediated TRALI was developed in 2006, and has also shown several similarities with human TRALI induction (Looney MR et al., J Clin Invest 116: 1615, 2006). Specifically, a monoclonal anti-mouse MHC class I antibody (34-1-2s) causes significant increases in excess lung water, lung vascular permeability and mortality within 2 hours after administration. These adverse reactions were found to be due to the antibody's ability to activate pulmonary neutrophils to produce reactive oxygen species (ROS) in an Fc receptor (FcR)-dependent manner. In contrast, however, it was recently shown that 34-1-2s induces pulmonary damage by activating macrophages to generate ROS in a complement (C5a)-dependent process (Strait RT J et al., Exp Med 208: 2525, 2011). In order to better understand this apparent controversy, we attempted to determine the nature of how 34-1-2s mediates its lung damaging properties. 34-1-2s was digested with pepsin or papain to produce F(ab')2 or Fc fragments respectively, and the fragments were tested for their ability to mediate TRALI reactions. In control mice, when intact 34-1-2s antibody was intravenously injected into either CB.17 mice with severe combined immunodeficiency or C5 deficient DBA/2 mice, increased shock, serum MIP-2 (murine equivalent to human IL-8) levels, pulmonary neutrophil accumulation, pulmonary edema and mortality all occurred within 2 hours. In contrast, however, injection with 34-1-2s F(ab')2 fragments was only able to generate MIP-2 production and pulmonary neutrophil accumulation; no lung damage or mortality occurred. Injection of 34-1-2s Fc fragments either alone or together with equal molar concentrations of F(ab')2 fragments failed to induce any lung damage or mortality. These results suggest that 34-1-2s recognition of it's cognate MHC class I antigen may be a priming reaction that stimulates MIP-2 and chemotaxis of neutrophils to the lungs, whereas the Fc portion of the intact molecule is responsible for the second step of exacerbating TRALI symptoms in a complement independent manner. Disclosures: No relevant conflicts of interest to declare.

scholarly journals miR-20b suppresses mitochondrial dysfunction–mediated apoptosis to alleviate hyperoxia-induced acute lung injury by directly targeting MFN1 and MFN2

2020 ◽  
Author(s):  
Genhua Mu ◽  
Yijun Deng ◽  
Zhongqian Lu ◽  
Xing Li ◽  
Yanbin Chen
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Cell Apoptosis ◽  
Prolonged Exposure ◽  
Biological Effects ◽  
Pulmonary Inflammation ◽  
Alveolar Epithelial Cells ◽  
Lung Damage

Abstract Supplemental oxygen is commonly used to treat severe respiratory failure, while prolonged exposure to hyperoxia can induce acute lung injury characterized by the accumulation of reactive oxygen species (ROS) and pulmonary inflammation. Dysregulation of microRNAs contributes to multiple diseases, including hyperoxia-induced acute lung injury (HALI). In this study, we explored the roles of miR-20b in mediating the response of type II alveolar epithelial cells (ACE IIs) to hyperoxia and the potential underlying mechanisms. We found that miR-20b was significantly decreased in the lung tissues of HALI models and H2O2-treated ACE IIs. Hyperoxia induced the release of TNF-α, decreased the mitochondrial membrane potential, and led to excessive ROS production and cell apoptosis. Overexpression of miR-20b suppressed the hyperoxia-induced biological effects in ACE IIs. miR-20b negatively regulated the expression levels of Mitofusin 1 (MFN1) and MFN2, the two key proteins of mitochondrial fusion, via complementarily binding to the 3ʹ-untranslated regions of mRNAs. Furthermore, both in vivo and in vitro, upregulation of MFN1 and MFN2 aggravated lung damage and cell apoptosis that were alleviated by miR-20b overexpression. These results provided new insights into the involvement of the miR-20b/MFN1/2 signaling pathway in HALI.

Association between Maturation and Aging and Pulmonary Responses in Animal Models of Lung Injury

2015 ◽  
Vol 123 (2) ◽  
pp. 389-408 ◽  
Author(s):  
Laura R. A. Schouten ◽  
Marcus J. Schultz ◽  
Anton H. van Kaam ◽  
Nicole P. Juffermans ◽  
Albert P. Bos ◽  
...  
Keyword(s):  
Animal Models ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Intracellular Signaling ◽  
Meta Analysis ◽  
Pulmonary Inflammation ◽  
Age Groups ◽  
Qualitative Comparison ◽  
In Vivo Models

Abstract Background: Advanced age is associated with an increased susceptibility and mortality of the acute respiratory distress syndrome. This may be due to the progressive changes in innate immune responses and intrinsic properties of the lung that occur during the process of aging. Therefore, this study assesses the association between maturation and aging and pulmonary responses to injury in animal models of lung injury. Methods: A systematic search was conducted in PubMed, EMBASE (up to June 2014) and in the references of relevant articles to identify the studies using in vivo models of lung injury caused by an acute pulmonary insult, in which at least two age groups were compared. Because methodological diversity precluded combining these studies in a quantitative meta-analysis, data are presented based on the qualitative comparison with the adult group. Results: Of the 2,840 identified studies, 51 were included in this review. Most studies showed that, in response to a pulmonary insult, increasing age is associated with more pulmonary inflammation, edema, alveolar damage, and higher mortality. In addition, results indicate the existence of age-dependent changes in key components of the intracellular signaling pathways involved in the inflammatory response. Conclusions: Increasing age seems to be correlated with exaggerated pulmonary responses to injury, ultimately leading to more severe lung injury. Pulmonary inflammation seems relatively suppressed in infants/juveniles, whereas in the middle aged/elderly, the inflammatory response seems delayed but aggravated. This implies that investigators and clinicians need to use caution about extrapolating results from adolescent or youngadult animals to pediatric or elderly patients in clinical practice.

Does the melatonin supplementation decrease the severity of the outcomes in COVID-19 patients? A mini review of observational data in the in vivo and in vitro studies

2021 ◽  
Vol 4 (2) ◽  
pp. 348-359
Author(s):  
Mohammad Gholizadeh ◽  
Faezeh Abaj ◽  
Hossein Hasani ◽  
Atieh Mirzababaei ◽  
Khadijeh Mirzaei
Keyword(s):  
Molecular Level ◽  
Antioxidant Activities ◽  
Early Stage ◽  
Specific Treatment ◽  
Case Series ◽  
Lung Damage ◽  
In Vivo Studies ◽  
Critical Conditions

The Coronavirus Disease 2019 (COVID-19) is a global pandemic and there is no specific treatment for reducing the severity of this disease up to date. The majority of the treatments remain supportive and empirical. The aim of present study is to assess the relationship between melatonin supplementation and its effect on the severity of the outcomes in covid-19 patients. All published studies up to April 4 of 2021 were searched by using the databases of PubMed, ISI Web of Science, SCOPUS and Google Scholar.  Finally, 201 studies have been acquired.      After screening titles, abstracts and justifying the inclusion criteria, eight studies were finally selected in our study. Four studies were observational and case series with total 216,792 participants. Three studies performed on laboratory in the molecular level and one was carried out in mice. The results have suggested that melatonin decreases the severity of the outcomes of COVID-19 patients in their early stage or even in their critical conditions. Furthermore, the melatonin decreases pneumonia and reduces the ground glass lung damage observed in the image findings. Also, it plays an important role as anti-inflammatory, anti-viral and antioxidant activities. Melatonin inhibits the main protease of sares-cov-2 virus and decreases the viral load in molecular level. Regarding the in vivo studies, melatonin is more effective for reducing acute lung injury than other treatments. Although, further clinical studies are required.

scholarly journals C-reactive protein enhances murine antibody–mediated transfusion-related acute lung injury

Blood ◽  
2015 ◽  
Vol 126 (25) ◽  
pp. 2747-2751 ◽  
Author(s):  
Rick Kapur ◽  
Michael Kim ◽  
Shanjeevan Shanmugabhavananthan ◽  
Jonathan Liu ◽  
Yuan Li ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Damage ◽  
C Reactive Protein ◽  
Neutrophil Accumulation ◽  
Reactive Protein ◽  
Key Points ◽  
Synergistic Increase ◽  
Murine Antibody

Key Points CRP enhances antibody-mediated lung damage when infused into TRALI-resistant mice. CRP and TRALI-inducing antibodies generate a synergistic increase in MIP-2 production and pulmonary neutrophil accumulation in vivo.

scholarly journals Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO

2018 ◽  
Vol 17 ◽  
pp. 153601211879231 ◽  
Author(s):  
Vidya Narayanaswami ◽  
Kenneth Dahl ◽  
Vadim Bernard-Gauthier ◽  
Lee Josephson ◽  
Paul Cumming ◽  
...  
Keyword(s):  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Intracellular Signaling ◽  
Glycogen Synthase ◽  
Early Stage ◽  
Translocator Protein ◽  
Imaging Biomarker ◽  
Cellular Expression ◽  
Pet Radiotracers

The dynamic and multicellular processes of neuroinflammation are mediated by the nonneuronal cells of the central nervous system, which include astrocytes and the brain’s resident macrophages, microglia. Although initiation of an inflammatory response may be beneficial in response to injury of the nervous system, chronic or maladaptive neuroinflammation can have harmful outcomes in many neurological diseases. An acute neuroinflammatory response is protective when activated neuroglia facilitate tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. On the other hand, chronic neuroglial activation is a major pathological mechanism in neurodegenerative diseases, likely contributing to neuronal dysfunction, injury, and disease progression. Therefore, the development of specific and sensitive probes for positron emission tomography (PET) studies of neuroinflammation is attracting immense scientific and clinical interest. An early phase of this research emphasized PET studies of the prototypical imaging biomarker of glial activation, translocator protein-18 kDa (TSPO), which presents difficulties for quantitation and lacks absolute cellular specificity. Many alternate molecular targets present themselves for PET imaging of neuroinflammation in vivo, including enzymes, intracellular signaling molecules as well as ionotropic, G-protein coupled, and immunoglobulin receptors. We now review the lead structures in radiotracer development for PET studies of neuroinflammation targets for neurodegenerative diseases extending beyond TSPO, including glycogen synthase kinase 3, monoamine oxidase-B, reactive oxygen species, imidazoline-2 binding sites, cyclooxygenase, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, cannabinoid-2 receptor, the chemokine receptor CX3CR1, purinergic receptors: P2X7 and P2Y12, the receptor for advanced glycation end products, Mer tyrosine kinase, and triggering receptor expressed on myeloid cells-1. We provide a brief overview of the cellular expression and function of these targets, noting their selectivity for astrocytes and/or microglia, and highlight the classes of PET radiotracers that have been investigated in early-stage preclinical or clinical research studies of neuroinflammation.

IL-10 enhances resolution of pulmonary inflammation in vivo by promoting apoptosis of neutrophils

1996 ◽  
Vol 271 (4) ◽  
pp. L566-L571 ◽  
Author(s):  
G. Cox
Keyword(s):  
Ex Vivo ◽  
Pulmonary Inflammation ◽  
Survival Rates ◽  
Initial Response ◽  
Interleukin 10 ◽  
Human Neutrophils ◽  
Neutrophil Accumulation ◽  
Lps Challenge ◽  
Ex Vivo Culture

Interleukin-10 (IL-10) has been shown to be protective in models of sepsis. This protection is mediated in part by inhibition of monokine-dependent processes. Because IL-10 can act on other cells to regulate inflammatory events, and because we have previously shown that clearance of inflammation is an active process, we examined whether IL-10 could regulate processes of resolution during pulmonary inflammation induced by lipopolysaccharide (LPS) challenge. Administration of 1 microgram of IL-10 with 6 micrograms LPS intratracheally to rats did not alter the time of onset or the magnitude of the initial response, as assessed by bronchoalveolar lavage (BAL) neutrophilia. However, the extent of the neutrophilia was markedly reduced at 18 h, and longer, after challenge. During ex vivo culture of cells obtained by BAL, neutrophils died by apoptosis and were engulfed by macrophages. Clearance of neutrophils was more rapid in the cultured BAL of rats treated with IL-10. In separate experiments, IL-10 did not reduce survival rates of untreated human neutrophils, but did inhibit LPS-induced increases in survival in a dose-dependent fashion. Thus IL-10 did not modulate the onset of, or peak of, neutrophil accumulation in response to LPS but did promote the clearance of recruited neutrophils in vivo. The mechanism of this anti-inflammatory action may be through the prevention of stimulated increases in neutrophil survival.

Endogenous hydrogen sulfide sulfhydrates IKKβ at cysteine 179 to control pulmonary artery endothelial cell inflammation

2019 ◽  
Vol 133 (20) ◽  
pp. 2045-2059 ◽  
Author(s):  
Da Zhang ◽  
Xiuli Wang ◽  
Siyao Chen ◽  
Selena Chen ◽  
Wen Yu ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Endothelial Cell ◽  
Pulmonary Artery ◽  
Cell Model ◽  
Site Directed Mutagenesis ◽  
Critical Event ◽  
Hypertensive Rats ◽  
Pulmonary Artery Endothelial Cell

Abstract Background: Pulmonary artery endothelial cell (PAEC) inflammation is a critical event in the development of pulmonary arterial hypertension (PAH). However, the pathogenesis of PAEC inflammation remains unclear. Methods: Purified recombinant human inhibitor of κB kinase subunit β (IKKβ) protein, human PAECs and monocrotaline-induced pulmonary hypertensive rats were employed in the study. Site-directed mutagenesis, gene knockdown or overexpression were conducted to manipulate the expression or activity of a target protein. Results: We showed that hydrogen sulfide (H2S) inhibited IKKβ activation in the cell model of human PAEC inflammation induced by monocrotaline pyrrole-stimulation or knockdown of cystathionine γ-lyase (CSE), an H2S generating enzyme. Mechanistically, H2S was proved to inhibit IKKβ activity directly via sulfhydrating IKKβ at cysteinyl residue 179 (C179) in purified recombinant IKKβ protein in vitro, whereas thiol reductant dithiothreitol (DTT) reversed H2S-induced IKKβ inactivation. Furthermore, to demonstrate the significance of IKKβ sulfhydration by H2S in the development of PAEC inflammation, we mutated C179 to serine (C179S) in IKKβ. In purified IKKβ protein, C179S mutation of IKKβ abolished H2S-induced IKKβ sulfhydration and the subsequent IKKβ inactivation. In human PAECs, C179S mutation of IKKβ blocked H2S-inhibited IKKβ activation and PAEC inflammatory response. In pulmonary hypertensive rats, C179S mutation of IKKβ abolished the inhibitory effect of H2S on IKKβ activation and pulmonary vascular inflammation and remodeling. Conclusion: Collectively, our in vivo and in vitro findings demonstrated, for the first time, that endogenous H2S directly inactivated IKKβ via sulfhydrating IKKβ at Cys179 to inhibit nuclear factor-κB (NF-κB) pathway activation and thereby control PAEC inflammation in PAH.

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