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.

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 A role for bronchial epithelial autotaxin in ventilator-induced lung injury

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Ioanna Nikitopoulou ◽  
Ioanna Ninou ◽  
Nikolaos Manitsopoulos ◽  
Ioanna Dimopoulou ◽  
Stylianos E. Orfanos ◽  
...  
Keyword(s):  
Lung Injury ◽  
Protein Concentration ◽  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Small Animal ◽  
Lavage Fluid ◽  
Bronchial Epithelial ◽  
Ventilator Induced Lung Injury ◽  
Lung Histopathology ◽  
Genetic Deletion

Abstract Background The pathophysiology of acute respiratory distress syndrome (ARDS) may eventually result in heterogeneous lung collapse and edema-flooded airways, predisposing the lung to progressive tissue damage known as ventilator-induced lung injury (VILI). Autotaxin (ATX; ENPP2), the enzyme largely responsible for extracellular lysophosphatidic acid (LPA) production, has been suggested to play a pathogenic role in, among others, pulmonary inflammation and fibrosis. Methods C57BL/6 mice were subjected to low and high tidal volume mechanical ventilation using a small animal ventilator: respiratory mechanics were evaluated, and plasma and bronchoalveolar lavage fluid (BALF) samples were obtained. Total protein concentration was determined, and lung histopathology was further performed Results Injurious ventilation resulted in increased BALF levels of ATX. Genetic deletion of ATX from bronchial epithelial cells attenuated VILI-induced pulmonary edema. Conclusion ATX participates in VILI pathogenesis.

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 Mucus accumulation in the lungs precedes structural changes and infection in children with cystic fibrosis

2019 ◽  
Vol 11 (486) ◽  
pp. eaav3488 ◽  
Author(s):  
Charles R. Esther ◽  
Marianne S. Muhlebach ◽  
Camille Ehre ◽  
David B. Hill ◽  
Matthew C. Wolfgang ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Inflammatory Markers ◽  
Structural Changes ◽  
Bronchoalveolar Lavage Fluid ◽  
Airway Disease ◽  
Lavage Fluid ◽  
Preventive Therapy ◽  
Molecular Analyses ◽  
And Oxidative Stress

Although destructive airway disease is evident in young children with cystic fibrosis (CF), little is known about the nature of the early CF lung environment triggering the disease. To elucidate early CF pulmonary pathophysiology, we performed mucus, inflammation, metabolomic, and microbiome analyses on bronchoalveolar lavage fluid (BALF) from 46 preschool children with CF enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program and 16 non-CF disease controls. Total airway mucins were elevated in CF compared to non-CF BALF irrespective of infection, and higher densities of mucus flakes containing mucin 5B and mucin 5AC were observed in samples from CF patients. Total mucins and mucus flakes correlated with inflammation, hypoxia, and oxidative stress. Many CF BALFs appeared sterile by culture and molecular analyses, whereas other samples exhibiting bacterial taxa associated with the oral cavity. Children without computed tomography–defined structural lung disease exhibited elevated BALF mucus flakes and neutrophils, but little/no bacterial infection. Although CF mucus flakes appeared “permanent” because they did not dissolve in dilute BALF matrix, they could be solubilized by a previously unidentified reducing agent (P2062), but notN-acetylcysteine or deoxyribonuclease. These findings indicate that early CF lung disease is characterized by an increased mucus burden and inflammatory markers without infection or structural lung disease and suggest that mucolytic and anti-inflammatory agents should be explored as preventive therapy.

Curcumin attenuates elastase- and cigarette smoke-induced pulmonary emphysema in mice

2009 ◽  
Vol 296 (4) ◽  
pp. L614-L623 ◽  
Author(s):  
Masaru Suzuki ◽  
Tomoko Betsuyaku ◽  
Yoko Ito ◽  
Katsura Nagai ◽  
Nao Odajima ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Cigarette Smoke ◽  
Pulmonary Emphysema ◽  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Antioxidant Properties ◽  
Lavage Fluid ◽  
Curcumin Treatment ◽  
Air Space ◽  
Antioxidant Gene Expression

Curcumin, a yellow pigment obtained from turmeric ( Curcumina longa), is a dietary polyphenol that has been reported to possess anti-inflammatory and antioxidant properties. The effect of curcumin against the development of pulmonary emphysema in animal models is unknown. The aim of this study was to determine whether curcumin is able to attenuate the development of pulmonary emphysema in mice. Nine-week-old male C57BL/6J mice were treated with intratracheal porcine pancreatic elastase (PPE) or exposed to mainstream cigarette smoke (CS) (60 min/day for 10 consecutive days or 5 days/wk for 12 wk) to induce pulmonary inflammation and emphysema. Curcumin (100 mg/kg) or vehicle was administrated daily by oral gavage 1 h and 24 h before intratracheal PPE treatment and daily thereafter throughout a 21-day period in PPE-exposed mice and 1 h before each CS exposure in CS-exposed mice. As a result, curcumin treatment significantly inhibited PPE-induced increase of neutrophils in bronchoalveolar lavage fluid at 6 h and on day 1 after PPE administration, with an increase in antioxidant gene expression at 6 h and significantly attenuated PPE-induced air space enlargement on day 21. It was also found that curcumin treatment significantly inhibited CS-induced increase of neutrophils and macrophages in bronchoalveolar lavage fluid after 10 consecutive days of CS exposure and significantly attenuated CS-induced air space enlargement after 12 wk of CS exposure. In conclusion, oral curcumin administration attenuated PPE- and CS-induced pulmonary inflammation and emphysema in mice.

scholarly journals Herbal Formula, PM014, Attenuates Lung Inflammation in a Murine Model of Chronic Obstructive Pulmonary Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Hyojung Lee ◽  
Youngeun Kim ◽  
Hye Jin Kim ◽  
Soojin Park ◽  
Young Pyo Jang ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Murine Model ◽  
Lung Inflammation ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Chronic Obstructive ◽  
Herbal Formula ◽  
Obstructive Pulmonary Disease ◽  
Beneficial Effects

Chronic obstructive pulmonary disease (COPD), which is characterized by airway obstruction, leads to, as the two major forms of COPD, chronic bronchitis and emphysema. This study was conducted to evaluate the effects of herbal formula, PM014, in a murine model of COPD. Balb/c mice were treated once with each herb extract in PM014 or PM014 mixture via an oral injection. Lipopolysaccharide (LPS) or elastase/LPS were administrated to the mice to induce a disease that resembles COPD. PM014 treatment significantly attenuated the increased accumulation of immune cells in bronchoalveolar lavage fluid (BALF) compared to control mice. In addition, the TNF-αand IL-6 levels in BALF were decreased in the PM014 mice. Furthermore, histological analysis demonstrated that PM014 attenuated the hazardous effects of lung inflammation. These data suggest that PM014 exerts beneficial effects against forms of COPD such as lung inflammation.

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