scholarly journals Role of neutrophils and α1-antitrypsin in coal- and silica-induced connective tissue breakdown

1999 ◽  
Vol 276 (2) ◽  
pp. L269-L279 ◽  
Author(s):  
K. Zay ◽  
S. Loo ◽  
C. Xie ◽  
D. V. Devine ◽  
J. Wright ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Hplc Analysis ◽  
Lavage Fluid ◽  
Dust Exposure ◽  
Mineral Dusts ◽  
Methionine Residues ◽  
Over Time ◽  
Rapid Appearance

Mineral dusts produce emphysema, and administration of dust to rats results in the rapid appearance of desmosine and hydroxyproline in lavage fluid, confirming that dusts directly induce connective tissue breakdown. To examine the role of neutrophils and α1-antitrypsin (α1-AT) in this process, we instilled silica or coal into normal rats or rats that had been pretreated with antiserum against neutrophils. One day after dust exposure, lavage fluid neutrophils and desmosine and hydroxyproline levels were all elevated; treatment with antiserum against neutrophils reduced neutrophils by 75%, desmosine by 40–50%, and hydroxyproline by 25%. By 7 days, lavage fluid neutrophils and desmosine level had decreased, whereas macrophages and hydroxyproline level had increased. By ELISA analysis, lavage fluid α1-AT levels were increased four- to eightfold at both times. On Western blot, some of the α1-AT appeared as degraded fragments, and by HPLC analysis, 5–10% of the methionine residues were oxidized. At both times, lavage fluid exhibited considerably elevated serine elastase inhibitory capacity and also showed elevations in metalloelastase activity. We conclude that, in this model, connective tissue breakdown is initially driven largely by neutrophil-derived proteases and that markedly elevated levels of functional α1-AT do not prevent breakdown, thus providing in vivo support for the concept of quantum proteolysis proposed by Liou and Campbell (T. G. Liou and E. J. Campbell. Biochemistry 34: 16171–16177, 1995). Macrophage-derived proteases may be of increasing importance over time, especially in coal-treated animals.

The Role of Mechanical Tension in Neurons

2010 ◽  
Vol 1274 ◽  
Author(s):  
Taher Saif ◽  
Jagannathan Rajagopalan ◽  
Alireza Tofangchi
Keyword(s):  
Mechanical Response ◽  
Mechanical Forces ◽  
Active Tension ◽  
Mechanical Tension ◽  
Deformation Response ◽  
Linear Force ◽  
Tension Regulation ◽  
Over Time

AbstractWe used high resolution micromechanical force sensors to study the in vivo mechanical response of embryonic Drosophila neurons. Our experiments show that Drosophila axons have a rest tension of a few nN and respond to mechanical forces in a manner characteristic of viscoelastic solids. In response to fast externally applied stretch they show a linear force-deformation response and when the applied stretch is held constant the force in the axons relaxes to a steady state value over time. More importantly, when the tension in the axons is suddenly reduced by releasing the external force the neurons actively restore the tension, sometimes close to their resting value. Along with the recent findings of Siechen et al (Proc. Natl. Acad. Sci. USA 106, 12611 (2009)) showing a link between mechanical tension and synaptic plasticity, our observation of active tension regulation in neurons suggest an important role for mechanical forces in the functioning of neurons in vivo.

scholarly journals Role of Mouse Cytochrome P450 Enzymes of the Cyp2abfgs Subfamilies in the Induction of Lung Inflammation by Cigarette Smoke Exposure

2019 ◽  
Vol 172 (1) ◽  
pp. 123-131
Author(s):  
Matthew Hartog ◽  
Qing-Yu Zhang ◽  
Xinxin Ding
Keyword(s):  
Cytochrome P450 ◽  
Tobacco Smoke ◽  
Lung Inflammation ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Cigarette Smoke Exposure ◽  
Histopathological Analysis ◽  
Cytochrome P450 Enzymes

Abstract Many constituents of tobacco smoke (TS) require bioactivation to exert toxic effects; however, few studies have examined the role of bioactivation enzymes in the adverse effects of TS exposure. This knowledge gap is a major source of uncertainty for risk assessment and chemoprevention efforts. Our aim is to test the hypothesis that cytochrome P450 (P450) enzyme-mediated bioactivation is essential to the development of TS exposure-induced lung toxicity, by determining the contributions of P450 enzymes in the mouse Cyp2abfgs gene subfamilies to environmental tobacco smoke (ETS)-induced lung inflammation. Adult female wildtype (WT) and Cyp2abfgs-null mice (both on C57BL/6J background) were exposed to filtered air or ETS, intermittently, for 1 or 2 weeks. Lung inflammation was assessed by quantification of inflammatory cells, cytokines, chemokines, and proteins in bronchoalveolar lavage fluid (BALF) and histopathological analysis. Glutathione (GSH) conjugates of 2 ETS constituents, naphthalene (NA), and 3-methylindole (3MI), were measured in mice exposed to ETS for 4 h. Persistent macrophagic and neutrophilic lung inflammation was observed in ETS-exposed WT mice; the extent of which was significantly reduced in ETS-exposed Cyp2abfgs-null mice. Levels of proinflammatory cytokines and chemokines, along with the total protein concentration, were increased in cell-free BALF from ETS-exposed WT mice, but not Cyp2abfgs-null mice. Additionally, GSH conjugates of NA and 3MI were detected in the lungs of WT, but not Cyp2abfgs-null, mice following ETS exposure. These results provide the first in vivo evidence that the mouse Cyp2abfgs gene cluster plays an important role in ETS-induced lung inflammation.

Strength Retention of a New Microbial Cellulose Scaffold and Existing Collagen-Based Scaffolds After In Vivo Implantation in a Rabbit Model

2009 ◽  
Author(s):  
Michael I. Dishowitz ◽  
Miltiadis H. Zgonis ◽  
Jeremy J. Harris ◽  
Constance Ace ◽  
Louis J. Soslowsky
Keyword(s):  
Mechanical Behavior ◽  
Healing Process ◽  
Rabbit Model ◽  
In Vivo Model ◽  
Microbial Cellulose ◽  
Poor Outcomes ◽  
Over Time ◽  
Pullout Loads

Rotator cuff tendon tears often require large tensions for repair [1] and these tensions are associated with poor outcomes including rerupture [2]. To address this, repairs are often augmented with collagen-based scaffolds. Microbial cellulose, produced by A. xylinum as a laminar non-woven matrix, is another candidate for repair augmentation [3]. An ideal augmentation scaffold would shield the repair site from damaging loads as they change throughout the healing process. Although the initial mechanical properties of clinically used scaffolds have been well characterized [4–6], their mechanical behavior following implantation is not known. As a result, the role of these scaffolds throughout the healing process remains unknown. Therefore, the objective of this study is to characterize the mechanical behavior of existing collagen-based scaffolds and a new, microbial cellulose scaffold over time using an in vivo model. We hypothesize that: 1) collagen-based scaffolds will show decreased stiffness (1a) and suture pullout loads (1b) over time when compared to initial values while the microbial cellulose scaffold will not; and 2) the collagen-based scaffolds will have decreased stiffness (2a) and suture pullout loads (2b) when compared to the new, microbial cellulose scaffold at all timepoints.

scholarly journals Immunomodulatory Role of Endogenous Interleukin-18 in Gamma Interferon-Mediated Resolution of Replicative Legionella pneumophila Lung Infection

2000 ◽  
Vol 68 (12) ◽  
pp. 6567-6573 ◽  
Author(s):  
Joan K. Brieland ◽  
Craig Jackson ◽  
Steve Hurst ◽  
David Loebenberg ◽  
Tony Muchamuel ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Lavage Fluid ◽  
Lung Infection ◽  
Gamma Interferon ◽  
Pcr Analysis ◽  
Interleukin 18 ◽  
Legionnaires Disease ◽  
Ifn Γ

ABSTRACT The in vivo role of endogenous interleukin-18 (IL-18) in modulating gamma interferon (IFN-γ)-mediated resolution of replicativeLegionella pneumophila lung infection was assessed using a murine model of Legionnaires' disease. Intratracheal inoculation of A/J mice with virulent bacteria (106 L. pneumophila organisms per mouse) resulted in induction of IL-18 protein in bronchoalveolar lavage fluid (BALF) and intrapulmonary expression of IL-18 mRNA. Real-time quantitative RT-PCR analysis of infected lung tissue demonstrated that induction of IL-18 in BALF preceded induction of IL-12 and IFN-γ mRNAs in the lung. Blocking intrapulmonary IL-18 activity by administration of a monoclonal antibody (MAb) to the IL-18 receptor (anti-IL-18R MAb) prior toL. pneumophila infection inhibited induction of intrapulmonary IFN-γ production but did not significantly alter resolution of replicative L. pneumophila lung infection. In contrast, blocking endogenous IL-12 activity by administration of anti-IL-12 MAb) alone or in combination with anti-IL-18R MAb inhibited induction of intrapulmonary IFN-γ and resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection. Taken together, these results demonstrate that IL-18 plays a key role in modulating induction of IFN-γ in the lung in response to L. pneumophila and that together with IL-12, IL-18 regulates intrapulmonary growth of the bacteria.

scholarly journals The role of echocardiography in the assessment of hemodynamics in patients with connective tissue dysplasia

2015 ◽  
Vol 14 (2) ◽  
pp. 16-25
Author(s):  
E. V. Fomenko ◽  
S. B. Tkachenko ◽  
N. F. Beresten ◽  
E. S. Pavochkina
Keyword(s):  
Connective Tissue ◽  
Central Hemodynamics ◽  
Cardiac Pathology ◽  
Ultrasound Diagnostics ◽  
Connective Tissue Dysplasia ◽  
Clinically Significant

The article describes the features of ultrasound diagnostics and central hemodynamics in patients with minor heart anomalies. In vivo visualization of these anomalies has become possible after the introduction of echocardiography. The working classification of minor heart anomalies, as well as the description of clinically significant syndromes and abnormalities are considered. The role of connective tissue dysplasia in the development of cardiac pathology is highlighted, and its place in the structure of connective tissue dysplasia syndrome of the heart and heritable disorders of connective tissue is described.

Upregulated miR-29c suppresses silica-induced lung fibrosis through the Wnt/β-catenin pathway in mice

2017 ◽  
Vol 37 (9) ◽  
pp. 944-952 ◽  
Author(s):  
X Wang ◽  
K Xu ◽  
XY Yang ◽  
J Liu ◽  
Q Zeng ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Lentiviral Vector ◽  
Lavage Fluid ◽  
Candidate Target ◽  
Tgf Β1

Silicosis is an irreversible lung disease resulting from long-term inhalation of occupational dust containing silicon dioxide. However, the pathogenesis of silicosis has not been clearly understood yet. Accumulating evidence suggests that miR-29 may have a significant anti-fibrotic capacity, meanwhile it may relate to Wnt/β-catenin pathway. The purpose of this study was to discuss the role of miR-29 in the progression of silicosis. A lentiviral vector was constructed, named Lv-miR-29c, which was overexpressing miR-29c. In vivo, intratracheal treatment with Lv-miR-29c significantly increased expression of miR-29c, and reduced expression of β-catenin, matrix metalloproteinase (MMP)-2, and MMP-9 in the lung and levels of transforming growth factor-beta 1 (TGF-β1) and interleukin-6 (IL-6) in bronchoalveolar lavage fluid, and notably attenuated pulmonary fibrosis as evidenced by hydroxyproline content in silica-administered mice. These results indicated that miR-29c inhibited the development of silica-induced lung fibrosis. Thus, miR-29c may be a candidate target for silicosis treatment via its regulation of the Wnt/β-catenin pathway.

scholarly journals Mir-21 Suppression Promotes Mouse Hepatocarcinogenesis

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4983
Author(s):  
Marta Correia de Sousa ◽  
Nicolas Calo ◽  
Cyril Sobolewski ◽  
Monika Gjorgjieva ◽  
Sophie Clément ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mouse Liver ◽  
Potential Therapeutic Target ◽  
Stat3 Signaling ◽  
Gene And Protein Expression ◽  
Genetic Deletion ◽  
Almost All ◽  
Over Time

The microRNA 21 (miR-21) is upregulated in almost all known human cancers and is considered a highly potent oncogene and potential therapeutic target for cancer treatment. In the liver, miR-21 was reported to promote hepatic steatosis and inflammation, but whether miR-21 also drives hepatocarcinogenesis remains poorly investigated in vivo. Here we show using both carcinogen (Diethylnitrosamine, DEN) or genetically (PTEN deficiency)-induced mouse models of hepatocellular carcinoma (HCC), total or hepatocyte-specific genetic deletion of this microRNA fosters HCC development—contrasting the expected oncogenic role of miR-21. Gene and protein expression analyses of mouse liver tissues further indicate that total or hepatocyte-specific miR-21 deficiency is associated with an increased expression of oncogenes such as Cdc25a, subtle deregulations of the MAPK, HiPPO, and STAT3 signaling pathways, as well as alterations of the inflammatory/immune anti-tumoral responses in the liver. Together, our data show that miR-21 deficiency promotes a pro-tumoral microenvironment, which over time fosters HCC development via pleiotropic and complex mechanisms. These results question the current dogma of miR-21 being a potent oncomiR in the liver and call for cautiousness when considering miR-21 inhibition for therapeutic purposes in HCC.

Thrombomodulin mutant mice with a strongly reduced capacity to generate activated protein C have an unaltered pulmonary immune response to respiratory pathogens and lipopolysaccharide

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1702-1709 ◽  
Author(s):  
Anita W. Rijneveld ◽  
Sebastiaan Weijer ◽  
Sandrine Florquin ◽  
Charles T. Esmon ◽  
Joost C. M. Meijers ◽  
...  
Keyword(s):  
Immune Response ◽  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Lavage Fluid ◽  
Respiratory Pathogens ◽  
Pulmonary Response ◽  
Inflammatory Infiltrates

AbstractThe thrombomodulin–protein C–protein S (TM-PC-PS) pathway exerts anticoagulant and anti-inflammatory effects. We investigated the role of TM in the pulmonary immune response in vivo by the use of mice with a mutation in the TM gene (TMpro/pro) that was earlier found to result in a minimal capacity for activated PC (APC) generation in the circulation. We here demonstrate that TMpro/pro mice also display a strongly reduced capacity to produce APC in the alveolar compartment upon intrapulmonary delivery of PC and thrombin. We monitored procoagulant and inflammatory changes in the lung during Gram-positive (Streptococcus pneumoniae) and Gram-negative (Klebsiella pneumoniae) pneumonia and after local administration of lipopolysaccharide (LPS). Bacterial pneumonia was associated with fibrin(ogen) depositions in the lung that colocalized with inflammatory infiltrates. LPS also induced a rise in thrombin-antithrombin complexes in bronchoalveolar lavage fluid. These pulmonary procoagulant responses were unaltered in TMpro/pro mice, except for enhanced fibrin(ogen) deposition during pneumococcal pneumonia. In addition, TMpro/pro mice displayed unchanged antibacterial defense, neutrophil recruitment, and cytokine/chemokine levels. These data suggest that the capacity of TM to generate APC does not play a role of importance in the pulmonary response to respiratory pathogens or LPS.

Ozone-induced airway hyperresponsiveness: role of superoxide anions, NEP, and BK receptors

1995 ◽  
Vol 78 (3) ◽  
pp. 1015-1022 ◽  
Author(s):  
H. Tsukagoshi ◽  
E. B. Haddad ◽  
J. Sun ◽  
P. J. Barnes ◽  
K. F. Chung
Keyword(s):  
Airway Hyperresponsiveness ◽  
Lavage Fluid ◽  
Airway Responsiveness ◽  
Ozone Exposure ◽  
Brown Norway ◽  
Superoxide Anions ◽  
Norway Rat

We investigated the role of reactive oxygen species in ozone-induced airway hyperresponsiveness (AHR) in Brown Norway rats. Airway responsiveness to inhaled acetylcholine (ACh) and bradykinin (BK) and inflammatory cell recruitment in bronchoalveolar lavage fluid (BALF) were measured in vivo. Neutral endopeptidase (NEP) activity assay and measurement of BK-receptor binding sites in Brown Norway rat lungs were carried out in vitro. Apocynin (5 mg/kg), an inhibitor of superoxide anion-generating NADPH oxidase, was administered perorally 30 min before a 3- or 6-h exposure to 3 ppm of ozone, and the animals were studied 18–24 h postexposure. Ozone induced increases in airway responsiveness to ACh and BK and in neutrophil counts in BALF. Apocynin inhibited the increase in airway responsiveness to BK but not to ACh without affecting the neutrophil counts in BALF. The antioxidants allopurinol and deferoxamine prevented ozone-induced AHR to both ACh and BK but did not reduce neutrophil counts. To further examine the mechanisms of ozone-induced AHR to BK, we measured NEP activity and the density of BK receptors in vitro after ozone exposure. Ozone exposure had no significant effect either on NEP activity or on the affinity and the number of BK receptors in lungs from rats treated with or without apocynin. We conclude that superoxide anions released from inflammatory cells in the airway may be involved in ozone-induced AHR. Inactivation of NEP or upregulation of BK receptors do not appear to be involved, but the possibility of localized changes cannot be excluded.

scholarly journals Animating embryos: thein totorepresentation of life

2017 ◽  
Vol 50 (3) ◽  
pp. 521-535 ◽  
Author(s):  
JANINA WELLMANN
Keyword(s):  
Developmental Biology ◽  
Systems Biology ◽  
Computational Model ◽  
Computer Model ◽  
Live Imaging ◽  
Cellular Resolution ◽  
Visualization Techniques ◽  
Over Time

AbstractWith the recent advent of systems biology, developmental biology is taking a new turn. Attempts to create a ‘digital embryo’ are prominent among systems approaches. At the heart of these systems-based endeavours, variously described as ‘in vivoimaging’, ‘live imaging’ or ‘in totorepresentation’, are visualization techniques that allow researchers to image whole, live embryos at cellular resolution over time. Ultimately, the aim of the visualizations is to build a computer model of embryogenesis. This article examines the role of such visualization techniques in the building of a computational model, focusing, in particular, on the cinematographic character of these representations. It asks how the animated representation of development may change the biological understanding of embryogenesis. By situating the animations of the digital embryo within the iconography of developmental biology, it brings to light the inextricably entwined, yet shifting, borders between the animated, the living and the computational.

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