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.

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.

scholarly journals No effect of metformin on the innate airway hyperresponsiveness and increased responses to ozone observed in obese mice

2008 ◽  
Vol 105 (4) ◽  
pp. 1127-1133 ◽  
Author(s):  
Stephanie A. Shore ◽  
Erin S. Williams ◽  
Ming Zhu
Keyword(s):  
Airway Hyperresponsiveness ◽  
Bronchoalveolar Lavage Fluid ◽  
Forced Oscillation ◽  
Inflammatory Responses ◽  
Fasting Blood Glucose ◽  
Lavage Fluid ◽  
Airway Responsiveness ◽  
Air Pollutant ◽  
Obese Mice ◽  
Wild Type

We have previously reported that obese db/db mice exhibit innate airway hyperresponsiveness. These mice also have enhanced inflammatory responses to ozone, a common air pollutant that exacerbates asthma. Since db/db mice are diabetic as well as obese, the purpose of the present study was to determine whether metformin, an antihyperglycemic agent, alters the pulmonary phenotype of db/db mice. Lean wild-type (C57BL/6J) and obese db/db mice were treated by gavage with water or metformin (300 μg/g) once a day for 2 wk. Twenty-four hours after the last treatment, in mice of both genotypes, we either measured airway responsiveness to methacholine by forced oscillation, or we exposed the mice to ozone (2 parts per million for 3 h) and examined the ensuing inflammatory response. Compared with water, treatment with metformin caused a significant decrease in fasting blood glucose in obese mice. Airway responsiveness was increased in db/db versus wild-type mice, but metformin did not affect responsiveness in either group. Four hours after exposure to ozone, there was a significant increase in bronchoalveolar lavage fluid neutrophils and chemokines in mice of both genotypes, but the magnitude of these changes was greater in db/db than wild-type mice. Metformin did not affect ozone-induced inflammation in mice of either genotype. The results indicate that hyperglycemia is unlikely to account for the pulmonary phenotype of obese mice.

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 Less Airway Inflammation and Goblet Cell Metaplasia in an IL-33-Induced Asthma Model of Leptin-Deficient Obese Mice

2020 ◽  
Author(s):  
Atsushi Kurokawa ◽  
Mitsuko Kondo ◽  
Ken Arimura ◽  
Shigeru Ashino ◽  
Etsuko Tagaya
Keyword(s):  
Goblet Cell ◽  
In Vitro Study ◽  
Lavage Fluid ◽  
Forced Oscillation Technique ◽  
Wild Type ◽  
Asthma Model ◽  
Goblet Cell Metaplasia

Abstract BackgroundAsthma with obesity is a phenotype of severe asthma. Leptin exerts an immunomodulatory effect and its level is increased in obesity. IL-33 is associated with innate immunity and induces type 2 inflammation, and is present in adipose tissue. However, the role of IL-33 and leptin in obesity-associated asthma is not fully understood. We examined the effect of IL-33 on eosinophilic inflammation, goblet cell metaplasia, and airway responsiveness in leptin-deficient obese (ob/ob) and wild-type mice, and examined the effect of exogenous leptin pretreatment. MethodsIn ob/ob and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the animals, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine and resistance of the respiratory system (Rrs) was measured using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, KC in bronchoalveolar lavage fluid (BALF), and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin, and MUC5AC levels were measured by ELISA. ResultsOb/ob mice showed greater baseline Rrs than wild-type mice. IL-33 and IL-33 with leptin did not enhance Rrs challenged with methacholine compared to non-treatment in ob/ob mice, whereas IL-33 with leptin enhanced Rrs in wild-type mice. Ob/ob mice showed less IL-33-induced eosinophil numbers, IL-5, IL-13, eotaxin, and KC levels in BALF and eosinophilic infiltration around bronchi and goblet cell metaplasia than wild-type mice, but leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro . ConclusionsLeptin plays an important role in IL-33-induced inflammation and goblet cell metaplasia in the airway, but obesity per se increases airway hyperresponsiveness independent of inflammation. These results explain some aspects of the pathogenesis of obesity-related asthma.

scholarly journals Apparently Normal Tumor Necrosis Factor Receptor 1 Signaling in the Absence of the Silencer of Death Domains

2003 ◽  
Vol 23 (18) ◽  
pp. 6609-6617 ◽  
Author(s):  
Robert Endres ◽  
Georg Häcker ◽  
Inge Brosch ◽  
Klaus Pfeffer
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Death Receptor ◽  
High Dose ◽  
Wild Type ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT The silencer of death domains (SODD) has been proposed to prevent constitutive signaling of tumor necrosis factor receptor 1 (TNFR1) in the absence of ligand. Besides TNFR1, death receptor 3 (DR3), Hsp70/Hsc70, and Bcl-2 have been characterized as binding partners of SODD. In order to investigate the in vivo role of SODD, we generated mice congenitally deficient in expression of the sodd gene. No spontaneous inflammatory infiltrations were observed in any organ of these mice. Consistent with this finding, in the absence of SODD no alteration in the activation patterns of nuclear factor κB (NF-κB), stress kinases, or ERK1 or -2 was observed after stimulation with tumor necrosis factor (TNF). Activation of NF-κB by DR3 was also unchanged. The extents of DR3- and TNF-induced apoptosis were comparable in gene-deficient and wild-type cells. Protection of cells against heat shock as mediated by the Hsp70 system and against staurosporine-induced apoptosis was independent of SODD. Furthermore, resistance to high-dose lipopolysaccharide (LPS) injections, LPS-d-GalN injections, and infection with listeriae was similar in wild-type and gene-deficient mice. In conclusion, our data do not support the concept of a unique, nonredundant role of SODD for the functions of TNFR1, Hsp70, and DR3.

scholarly journals Role of Flagellin and the Two-Component CheA/CheY System of Listeria monocytogenes in Host Cell Invasion and Virulence

2004 ◽  
Vol 72 (6) ◽  
pp. 3237-3244 ◽  
Author(s):  
Lone Dons ◽  
Emma Eriksson ◽  
Yuxuan Jin ◽  
Martin E. Rottenberg ◽  
Krister Kristensson ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Wild Type Strain ◽  
Tumor Necrosis Factor Receptor ◽  
Soft Agar ◽  
Initial Contact ◽  
Wild Type ◽  
Chemotaxis Proteins ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT The flagellum protein flagellin of Listeria monocytogenes is encoded by the flaA gene. Immediately downstream of flaA, two genes, cheY and cheA, encoding products with homology to chemotaxis proteins of other bacteria, are located. In this study we constructed deletion mutants with mutations in flaA. cheY, and cheA to elucidate their role in the biology of infection with L. monocytogenes. The ΔcheY, ΔcheA, and double-mutant ΔcheYA mutants, but not ΔflaA mutant, were motile in liquid media. However, the ΔcheA mutant had impaired swarming and the ΔcheY and ΔcheYA mutants were unable to swarm on soft agar plates, suggesting that cheY and cheA genes encode proteins involved in chemotaxis. The ΔflaA, ΔcheY, ΔcheA, and ΔcheYA mutants (grown at 24°C) showed reduced association with and invasion of Caco-2 cells compared to the wild-type strain. However, spleens from intragastrically infected BALB/c and C57BL/6 mice showed larger and similar numbers of the ΔflaA and ΔcheYA mutants, respectively, compared to the wild-type controls. Such a discrepancy could be explained by the fact that tumor necrosis factor receptor p55 deficient mice showed dramatically exacerbated susceptibility to the wild-type but unchanged or only slightly increased levels of the ΔflaA or ΔcheYA mutant. In summary, we show that listerial flaA. cheY, and cheA gene products facilitate the initial contact with epithelial cells and contribute to effective invasion but that flaA could also be involved in the triggering of immune responses.

Diet-induced obesity causes innate airway hyperresponsiveness to methacholine and enhances ozone-induced pulmonary inflammation

2008 ◽  
Vol 104 (6) ◽  
pp. 1727-1735 ◽  
Author(s):  
Richard A. Johnston ◽  
Todd A. Theman ◽  
Frank L. Lu ◽  
Raya D. Terry ◽  
Erin S. Williams ◽  
...  
Keyword(s):  
Airway Hyperresponsiveness ◽  
Pulmonary Inflammation ◽  
Extended Period ◽  
Lavage Fluid ◽  
Interferon Γ ◽  
Obese Mice ◽  
Human Obesity ◽  
Diet Induced Obesity ◽  
Inducible Protein ◽  
Fat Diets

We previously reported that genetically obese mice exhibit innate airway hyperresponsiveness (AHR) and enhanced ozone (O3)-induced pulmonary inflammation. Such genetic deficiencies in mice are rare in humans, and they may not be representative of human obesity. Thus the purpose of this study was to determine the pulmonary phenotype of mice with diet-induced obesity (DIO), which more closely mimics the cause of human obesity. Therefore, wild-type C57BL/6 mice were reared from the time of weaning until at least 30 wk of age on diets in which either 10 or 60% of the calories are derived from fat in the form of lard. Body mass was ∼40% greater in mice fed 60 vs. 10% fat diets. Baseline airway responsiveness to intravenous methacholine, measured by forced oscillation, was greater in mice fed 60 vs. 10% fat diets. We also examined lung permeability and inflammation after exposure to room air or O3 (2 parts/million for 3 h), an asthma trigger. Four hours after the exposure ended, O3-induced increases in bronchoalveolar lavage fluid protein, interleukin-6, KC, macrophage inflammatory protein-2, interferon-γ-inducible protein-10, and eotaxin were greater in mice fed 60 vs. 10% fat diets. Innate AHR and augmented responses to O3 were not observed in mice raised from weaning until 20–22 wk of age on a 60% fat diet. These results indicate that mice with DIO exhibit innate AHR and enhanced O3-induced pulmonary inflammation, similar to genetically obese mice. However, mice with DIO must remain obese for an extended period of time before this pulmonary phenotype is observed.

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 Essential Roles of Receptor-Interacting Protein and TRAF2 in Oxidative Stress-Induced Cell Death

2004 ◽  
Vol 24 (13) ◽  
pp. 5914-5922 ◽  
Author(s):  
Han-Ming Shen ◽  
Yong Lin ◽  
Swati Choksi ◽  
Jamie Tran ◽  
Tian Jin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Tumor Necrosis Factor Receptor ◽  
Membrane Lipid ◽  
Critical Event ◽  
Wild Type ◽  
Embryonic Fibroblasts ◽  
Interacting Protein ◽  
Necrosis Factor

ABSTRACT Oxidative stress and reactive oxygen species (ROS) can elicit and modulate various physiological and pathological processes, including cell death. However, the mechanisms controlling ROS-induced cell death are largely unknown. Data from this study suggest that receptor-interacting protein (RIP) and tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2), two key effector molecules of TNF signaling, are essential for ROS-induced cell death. We found that RIP−/− or TRAF2−/− mouse embryonic fibroblasts (MEF) are resistant to ROS-induced cell death when compared to wild-type cells, and reconstitution of RIP and TRAF2 gene expression in their respective deficient MEF cells restored their sensitivity to H2O2-induced cell death. We also found that RIP and TRAF2 form a complex upon H2O2 exposure, but without the participation of TNFR1. The colocalization of RIP with a membrane lipid raft marker revealed a possible role of lipid rafts in the transduction of cell death signal initiated by H2O2. Finally, our results demonstrate that activation of c-Jun NH2-terminal kinase 1 is a critical event downstream of RIP and TRAF2 in mediating ROS-induced cell death. Therefore, our study uncovers a novel signaling pathway regulating oxidative stress-induced cell death.

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