scholarly journals Syndecan-4 Inhibits the Development of Pulmonary Fibrosis by Attenuating TGF-β Signaling

2019 ◽  
Vol 20 (20) ◽  
pp. 4989 ◽  
Author(s):  
Yoshinori Tanino ◽  
Xintao Wang ◽  
Takefumi Nikaido ◽  
Kenichi Misa ◽  
Yuki Sato ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Heparan Sulfate ◽  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Lavage Fluid ◽  
Lung Fibroblasts ◽  
Fibrosis Score ◽  
Wild Type ◽  
Deficient Mice

Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4′s critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and α-smooth muscle action (α-SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-β expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-β-induced Smad3 activation, collagen and α-SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-β-induced Smad3 activation and upregulated collagen and α-SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-β signaling.

scholarly journals Effect of antigen sensitization and challenge on oscillatory mechanics of the lung and pulmonary inflammation in obese carboxypeptidase E-deficient mice

2014 ◽  
Vol 307 (6) ◽  
pp. R621-R633 ◽  
Author(s):  
Paul H. Dahm ◽  
Jeremy B. Richards ◽  
Harry Karmouty-Quintana ◽  
Kevin R. Cromar ◽  
Sanjiv Sur ◽  
...  
Keyword(s):  
Airway Obstruction ◽  
Genetic Basis ◽  
Bronchoalveolar Lavage Fluid ◽  
Leptin Receptor ◽  
Pulmonary Inflammation ◽  
Lavage Fluid ◽  
Wild Type ◽  
Carboxypeptidase E ◽  
Genetic Deficiency ◽  
Deficient Mice

Atopic, obese asthmatics exhibit airway obstruction with variable degrees of eosinophilic airway inflammation. We previously reported that mice obese as a result of a genetic deficiency in either leptin ( ob/ ob mice) or the long isoform of the leptin receptor ( db/ db mice) exhibit enhanced airway obstruction in the presence of decreased numbers of bronchoalveolar lavage fluid (BALF) eosinophils compared with lean, wild-type mice following antigen (ovalbumin; OVA) sensitization and challenge. To determine whether the genetic modality of obesity induction influences the development of OVA-induced airway obstruction and OVA-induced pulmonary inflammation, we examined indices of these sequelae in mice obese as a result of a genetic deficiency in carboxypeptidase E, an enzyme that processes prohormones and proneuropeptides involved in satiety and energy expenditure ( Cpe fat mice). Accordingly, Cpe fat and lean, wild-type (C57BL/6) mice were sensitized to OVA and then challenged with either aerosolized PBS or OVA. Compared with genotype-matched, OVA-sensitized and PBS-challenged mice, OVA sensitization and challenge elicited airway obstruction and increased BALF eosinophils, macrophages, neutrophils, IL-4, IL-13, IL-18, and chemerin. However, OVA challenge enhanced airway obstruction and pulmonary inflammation in Cpe fat compared with wild-type mice. These results demonstrate that OVA sensitization and challenge enhance airway obstruction in obese mice regardless of the genetic basis of obesity, whereas the degree of OVA-induced pulmonary inflammation is dependent on the genetic modality of obesity induction. These results have important implications for animal models of asthma, as modeling the pulmonary phenotypes for subpopulations of atopic, obese asthmatics critically depends on selecting the appropriate mouse model.

scholarly journals Onset of obesity in carboxypeptidase E-deficient mice and effect on airway responsiveness and pulmonary responses to ozone

2010 ◽  
Vol 108 (6) ◽  
pp. 1812-1819 ◽  
Author(s):  
Richard A. Johnston ◽  
Ming Zhu ◽  
Christopher B. Hernandez ◽  
Erin S. Williams ◽  
Stephanie A. Shore
Keyword(s):  
Bronchoalveolar Lavage Fluid ◽  
Forced Oscillation ◽  
Pulmonary Inflammation ◽  
Age Groups ◽  
Serum Levels ◽  
Lavage Fluid ◽  
Airway Responsiveness ◽  
Wild Type ◽  
Satiety Hormone ◽  
Deficient Mice

When compared with lean, wild-type mice, obese Cpe fat mice, 14 wk of age and older, manifest innate airway hyperresponsiveness (AHR) to intravenous methacholine and enhanced pulmonary inflammation following acute exposure to ozone (O3). The purpose of this study was to examine the onset of these augmented pulmonary responses during the onset of obesity. Thus airway responsiveness and O3-induced pulmonary inflammation and injury were examined in 7- and 10-wk-old Cpe fat and age-matched, wild-type, C57BL/6 mice. Compared with age-matched controls, 7- and 10-wk-old Cpe fat mice were approximately 25 and 61% heavier, respectively. Airway responsiveness to intravenous methacholine was assessed via forced oscillation in unexposed Cpe fat and wild-type mice. The 10- but not 7-wk-old Cpe fat mice exhibited innate AHR. O3 exposure (2 ppm for 3 h) increased markers of pulmonary inflammation and injury in the bronchoalveolar lavage fluid of all mice. However, most markers were greater in Cpe fat vs. wild-type mice, regardless of age. Serum levels of leptin, a satiety hormone and proinflammatory cytokine, were increased in Cpe fat vs. wild-type mice of both age groups, but the serum levels of other systemic inflammatory markers were greater only in 10-wk-old Cpe fat vs. wild-type mice. These results demonstrate that a 25% increase in body weight is sufficient to augment pulmonary responses to O3, but innate AHR is not manifest until the mice become much heavier. These results suggest that the mechanistic bases for these responses are different and may develop according to the nature and degree of the chronic systemic inflammation that is present.

scholarly journals Lung Neutrophilia in Myeloperoxidase Deficient Mice during the Course of Acute Pulmonary Inflammation

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Silvie Kremserova ◽  
Tomas Perecko ◽  
Karel Soucek ◽  
Anna Klinke ◽  
Stephan Baldus ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Bronchoalveolar Lavage Fluid ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Lavage Fluid ◽  
Surface Expression ◽  
Wild Type ◽  
Inflammatory Site ◽  
Chemotactic Factors ◽  
Deficient Mice

Systemic inflammation accompanying diseases such as sepsis affects primarily lungs and induces their failure. This remains the most common cause of sepsis induced mortality. While neutrophils play a key role in pulmonary failure, the mechanisms remain incompletely characterized. We report that myeloperoxidase (MPO), abundant enzyme in neutrophil granules, modulates the course of acute pulmonary inflammatory responses induced by intranasal application of lipopolysaccharide. MPO deficient mice had significantly increased numbers of airway infiltrated neutrophils compared to wild-type mice during the whole course of lung inflammation. This was accompanied by higher levels of RANTES in bronchoalveolar lavage fluid from the MPO deficient mice. Other markers of lung injury and inflammation, which contribute to recruitment of neutrophils into the inflamed lungs, including total protein and other selected proinflammatory cytokines did not significantly differ in bronchoalveolar lavage fluid from the wild-type and the MPO deficient mice. Interestingly, MPO deficient neutrophils revealed a decreased rate of cell death characterized by phosphatidylserine surface expression. Collectively, the importance of MPO in regulation of pulmonary inflammation, independent of its putative microbicidal functions, can be potentially linked to MPO ability to modulate the life span of neutrophils and to affect accumulation of chemotactic factors at the inflammatory site.

scholarly journals Role of TNFR1 in the innate airway hyperresponsiveness of obese mice

2012 ◽  
Vol 113 (9) ◽  
pp. 1476-1485 ◽  
Author(s):  
Ming Zhu ◽  
Alison S. Williams ◽  
Lucas Chen ◽  
Allison P. Wurmbrand ◽  
Erin S. Williams ◽  
...  
Keyword(s):  
Airway Hyperresponsiveness ◽  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Tumor Necrosis Factor Receptor ◽  
Lavage Fluid ◽  
Forced Oscillation Technique ◽  
Obese Mice ◽  
Wild Type ◽  
Necrosis Factor

The purpose of this study was to examine the role of tumor necrosis factor receptor 1 (TNFR1) in the airway hyperresponsiveness characteristic of obese mice. Airway responsiveness to intravenous methacholine was measured using the forced oscillation technique in obese Cpe fat mice that were either sufficient or genetically deficient in TNFR1 ( Cpe fat and Cpe fat/TNFR1−/− mice) and in lean mice that were either sufficient or genetically deficient in TNFR1 [wild-type (WT) and TNFR1−/− mice]. Compared with lean WT mice, Cpe fat mice exhibited airway hyperresponsiveness. Airway hyperresponsives was also greater in Cpe fat/TNFR1−/− than in Cpe fat mice. Compared with WT mice, Cpe fat mice had increases in bronchoalveolar lavage fluid concentrations of several inflammatory moieties including eotaxin, IL-9, IP-10, KC, MIG, and VEGF. These factors were also significantly elevated in Cpe fat/TNFR1−/− vs. TNFR1−/− mice. Additional moieties including IL-13 were also elevated in Cpe fat/TNFR1−/− vs. TNFR1−/− mice but not in Cpe fat vs. WT mice. IL-17A mRNA expression was greater in Cpe fat/TNFR1−/− vs. Cpe fat mice and in TNFR1−/− vs. WT mice. Analysis of serum indicated that obesity resulted in systemic as well as pulmonary inflammation, but TNFR1 deficiency had little effect on this systemic inflammation. Our results indicate that TNFR1 is protective against the airway hyperresponsiveness associated with obesity and suggest that effects on pulmonary inflammation may be contributing to this protection.

C-type natriuretic peptide attenuates bleomycin-induced pulmonary fibrosis in mice

2004 ◽  
Vol 287 (6) ◽  
pp. L1172-L1177 ◽  
Author(s):  
Shinsuke Murakami ◽  
Noritoshi Nagaya ◽  
Takefumi Itoh ◽  
Takafumi Fujii ◽  
Takashi Iwase ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Bronchoalveolar Lavage ◽  
Continuous Infusion ◽  
Natriuretic Peptide ◽  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Physiological Role ◽  
Immunohistochemical Analysis ◽  
Lavage Fluid ◽  
Ki 67

C-type natriuretic peptide (CNP) has been shown to play an important role in the regulation of vascular tone and remodeling. However, the physiological role of CNP in the lung remains unknown. Accordingly, we investigated whether CNP infusion attenuates bleomycin (BLM)-induced pulmonary fibrosis in mice. After intratracheal injection of BLM or saline, mice were randomized to receive continuous infusion of CNP or vehicle for 14 days. CNP infusion significantly reduced the total number of cells and the numbers of macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid. Interestingly, CNP markedly reduced bronchoalveolar lavage fluid IL-1β levels. Immunohistochemical analysis demonstrated that CNP significantly inhibited infiltration of macrophages into the alveolar and interstitial regions. CNP infusion significantly attenuated BLM-induced pulmonary fibrosis, as indicated by significant decreases in Ashcroft score and lung hydroxyproline content. CNP markedly decreased the number of Ki-67-positive cells in fibrotic lesions of the lung, suggesting antiproliferative effects of CNP on pulmonary fibrosis. Kaplan-Meier survival curves demonstrated that BLM mice treated with CNP had a significantly higher survival rate than those given vehicle. These results suggest that continuous infusion of CNP attenuates BLM-induced pulmonary fibrosis and improves survival in BLM mice, at least in part by inhibition of pulmonary inflammation and cell proliferation.

scholarly journals Endogenous osteopontin promotes ozone-induced neutrophil recruitment to the lungs and airway hyperresponsiveness to methacholine

2013 ◽  
Vol 305 (2) ◽  
pp. L118-L129 ◽  
Author(s):  
Ramon X. Barreno ◽  
Jeremy B. Richards ◽  
Daniel J. Schneider ◽  
Kevin R. Cromar ◽  
Arthur J. Nadas ◽  
...  
Keyword(s):  
Airway Hyperresponsiveness ◽  
Pulmonary Inflammation ◽  
Immunohistochemical Analysis ◽  
Lung Parenchyma ◽  
Lavage Fluid ◽  
Environmental Pollutant ◽  
Forced Oscillation Technique ◽  
Pulmonary Injury ◽  
Wild Type ◽  
Deficient Mice

Inhalation of ozone (O3), a common environmental pollutant, causes pulmonary injury, pulmonary inflammation, and airway hyperresponsiveness (AHR) in healthy individuals and exacerbates many of these same sequelae in individuals with preexisting lung disease. However, the mechanisms underlying these phenomena are poorly understood. Consequently, we sought to determine the contribution of osteopontin (OPN), a hormone and a pleiotropic cytokine, to the development of O3-induced pulmonary injury, pulmonary inflammation, and AHR. To that end, we examined indices of these aforementioned sequelae in mice genetically deficient in OPN and in wild-type, C57BL/6 mice 24 h following the cessation of an acute (3 h) exposure to filtered room air (air) or O3 (2 parts/million). In wild-type mice, O3 exposure increased bronchoalveolar lavage fluid (BALF) OPN, whereas immunohistochemical analysis demonstrated that there were no differences in the number of OPN-positive alveolar macrophages between air- and O3-exposed wild-type mice. O3 exposure also increased BALF epithelial cells, protein, and neutrophils in wild-type and OPN-deficient mice compared with genotype-matched, air-exposed controls. However, following O3 exposure, BALF neutrophils were significantly reduced in OPN-deficient compared with wild-type mice. When airway responsiveness to inhaled acetyl-β-methylcholine chloride (methacholine) was assessed using the forced oscillation technique, O3 exposure caused hyperresponsiveness to methacholine in the airways and lung parenchyma of wild-type mice, but not OPN-deficient mice. These results demonstrate that OPN is increased in the air spaces following acute exposure to O3 and functionally contributes to the development of O3-induced pulmonary inflammation and airway and lung parenchymal hyperresponsiveness to methacholine.

Immunoregulatory effects of regulated, lung-targeted expression of IL-10 in vivo

2005 ◽  
Vol 288 (2) ◽  
pp. L251-L265 ◽  
Author(s):  
Donn Spight ◽  
Bin Zhao ◽  
Michael Haas ◽  
Susan Wert ◽  
Alvin Denenberg ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Lavage Fluid ◽  
Cytokine Gene Expression ◽  
Cytokine Gene ◽  
Targeted Expression ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine

Regulation of pulmonary inflammation involves an intricate balance of both pro- and anti-inflammatory mediators. Acute lung injury can result from direct pulmonary insults that activate alveolar macrophages to respond with increased cytokine expression. Such cytokine gene expression is mediated in part via NF-κB. IL-10 has been previously identified as an important endogenous anti-inflammatory cytokine in vivo on the basis of inhibiting NF-κB activation; however, the mechanism of this inhibition remains incompletely defined. We hypothesized that IL-10 regulated NF-κB activation in vivo via IκK inhibition. A bitransgenic mouse that allowed for externally regulated, lung-specific human IL-10 overexpression was generated. In the bitransgenic mice, introduction of doxycycline induced lung-specific, human IL-10 overexpression. Acute induction of IL-10 resulted in significant decreases in bronchoalveolar lavage fluid neutrophils (48%, P = 0.03) and TNF (62%, P < 0.01) following intratracheal LPS compared with bitransgenic negative mice. In vitro kinase assays showed this decrease to correlate to diminished lung IκK activity. Furthermore, we also examined the effect of chronic IL-10 overexpression in these transgenic mice. Results show that IL-10 overexpression in lungs of mature mice increased the number of intrapulmonary cells the phenotype of which was skewed toward increased B220+/CD45+ B cells and CD4+ T cells and was associated with increased CC chemokine expression. Thus regulated, lung-specific IL-10 overexpression may have a variety of complex immunologic effects depending on the timing and duration of expression.

scholarly journals Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rosana Banzato ◽  
Nathalia M. Pinheiro ◽  
Clarice R. Olivo ◽  
Fernanda R. Santana ◽  
Fernanda D. T. Q. S. Lopes ◽  
...  
Keyword(s):  
Lung Inflammation ◽  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Lavage Fluid ◽  
Innate Immune ◽  
Matrix Remodeling ◽  
And Oxidative Stress ◽  
Deficient Mice ◽  
Pro Inflammatory Cytokines

AbstractAcetylcholine (ACh), the neurotransmitter of the cholinergic system, regulates inflammation in several diseases including pulmonary diseases. ACh is also involved in a non-neuronal mechanism that modulates the innate immune response. Because inflammation and release of pro-inflammatory cytokines are involved in pulmonary emphysema, we hypothesized that vesicular acetylcholine transport protein (VAChT) deficiency, which leads to reduction in ACh release, can modulate lung inflammation in an experimental model of emphysema. Mice with genetical reduced expression of VAChT (VAChT KDHOM 70%) and wild-type mice (WT) received nasal instillation of 50 uL of porcine pancreatic elastase (PPE) or saline on day 0. Twenty-eight days after, animals were evaluated. Elastase instilled VAChT KDHOM mice presented an increase in macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage fluid and MAC2-positive macrophages in lung tissue and peribronchovascular area that was comparable to that observed in WT mice. Conversely, elastase instilled VAChT KDHOM mice showed significantly larger number of NF-κB-positive cells and isoprostane staining in the peribronchovascular area when compared to elastase-instilled WT-mice. Moreover, elastase-instilled VAChT-deficient mice showed increased MCP-1 levels in the lungs. Other cytokines, extracellular matrix remodeling, alveolar enlargement, and lung function were not worse in elastase-instilled VAChT deficiency than in elastase-instilled WT-controls. These data suggest that decreased VAChT expression may contribute to the pathogenesis of emphysema, at least in part, through NF-κB activation, MCP-1, and oxidative stress pathways. This study highlights novel pathways involved in lung inflammation that may contribute to the development of chronic obstrutive lung disease (COPD) in cholinergic deficient individuals such as Alzheimer’s disease patients.

CCR2-positive monocytes recruited to inflamed lungs downregulate local CCL2 chemokine levels

2005 ◽  
Vol 288 (2) ◽  
pp. L350-L358 ◽  
Author(s):  
Ulrich A. Maus ◽  
Sandra Wellmann ◽  
Christine Hampl ◽  
William A. Kuziel ◽  
Mrigank Srivastava ◽  
...  
Keyword(s):  
Lavage Fluid ◽  
Wild Type ◽  
Lps Challenge ◽  
Inflammatory Conditions ◽  
Monocyte Recruitment ◽  
Chemokine Ligand ◽  
Cc Chemokine Ligand 2 ◽  
Deficient Mice ◽  
Monocyte Trafficking

The CC chemokine ligand-2 (CCL2) and its receptor CCR2 are essential for monocyte trafficking under inflammatory conditions. However, the mechanisms that determine the intensity and duration of alveolar monocyte accumulation in response to CCL2 gradients in inflamed lungs have not been resolved. To determine the potential role of CCR2-expressing monocytes in regulating alveolar CCL2 levels, we compared leukocyte recruitment kinetics and alveolar CCL2 levels in wild-type and CCR2-deficient mice in response to intratracheal LPS challenge. In wild-type mice, LPS elicited a dose- and time-dependent alveolar monocyte accumulation accompanied by low CCL2 levels in bronchoalveolar lavage fluid (BALF). In contrast, LPS-treated CCR2-deficient mice lacked alveolar monocyte accumulation, which was accompanied by relatively high CCL2 levels in BALF. Similarly, wild-type mice that were treated systemically with the blocking anti-CCR2 antibody MC21 completely lacked LPS-induced alveolar monocyte trafficking that was associated with high CCL2 levels in BALF. Intratracheal application of anti-CCR2 antibody MC21 to locally block CCR2 on both resident and recruited cells did not affect LPS-induced alveolar monocyte trafficking but led to significantly increased BALF CCL2 levels. Reciprocally bone marrow-transplanted, LPS-treated wild-type and CCR2-deficient mice showed a strict inverse relationship between alveolar monocyte recruitment and BALF CCL2 levels. In addition, freshly isolated human and mouse monocytes were capable of integrating CCL2 in vitro. LPS-induced alveolar monocyte accumulation is accompanied by monocytic CCR2-dependent consumption of CCL2 levels in the lung. This feedback loop may limit the intensity of monocyte recruitment to inflamed lungs and play a role in the maintenance of homeostasis.

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