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Pulmonology

  • 154 Articles
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Toll-like receptor 4 deficiency causes pulmonary emphysema
Xuchen Zhang, … , Lauren Cohn, Patty J. Lee
Xuchen Zhang, … , Lauren Cohn, Patty J. Lee
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):3050-3059. https://doi.org/10.1172/JCI28139.
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Toll-like receptor 4 deficiency causes pulmonary emphysema

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Abstract

TLRs have been studied extensively in the context of pathogen challenges, yet their role in the unchallenged lung is unknown. Given their direct interface with the external environment, TLRs in the lungs are prime candidates to respond to air constituents, namely particulates and oxygen. The mechanism whereby the lung maintains structural integrity in the face of constant ambient exposures is essential to our understanding of lung disease. Emphysema is characterized by gradual loss of lung elasticity and irreversible airspace enlargement, usually in the later decades of life and after years of insult, most commonly cigarette smoke. Here we show Tlr4–/– mice exhibited emphysema as they aged. Adoptive transfer experiments revealed that TLR4 expression in lung structural cells was required for maintaining normal lung architecture. TLR4 deficiency led to the upregulation of what we believe to be a novel NADPH oxidase (Nox), Nox3, in lungs and endothelial cells, resulting in increased oxidant generation and elastolytic activity. Treatment of Tlr4–/– mice or endothelial cells with chemical NADPH inhibitors or Nox3 siRNA reversed the observed phenotype. Our data identify a role for TLR4 in maintaining constitutive lung integrity by modulating oxidant generation and provide insights into the development of emphysema.

Authors

Xuchen Zhang, Peiying Shan, Ge Jiang, Lauren Cohn, Patty J. Lee

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Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function
Marco Idzko, … , Henk C. Hoogsteden, Bart N. Lambrecht
Marco Idzko, … , Henk C. Hoogsteden, Bart N. Lambrecht
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):2935-2944. https://doi.org/10.1172/JCI28295.
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Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function

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Abstract

Airway DCs play a crucial role in the pathogenesis of allergic asthma, and interfering with their function could constitute a novel form of therapy. The sphingosine 1–phosphate receptor agonist FTY720 is an oral immunosuppressant that retains lymphocytes in lymph nodes and spleen, thus preventing lymphocyte migration to inflammatory sites. The accompanying lymphopenia could be a serious side effect that would preclude the use of FTY720 as an antiasthmatic drug. Here we show in a murine asthma model that local application of FTY720 via inhalation prior to or during ongoing allergen challenge suppresses Th2-dependent eosinophilic airway inflammation and bronchial hyperresponsiveness without causing lymphopenia and T cell retention in the lymph nodes. Effectiveness of local treatment was achieved by inhibition of the migration of lung DCs to the mediastinal lymph nodes, which in turn inhibited the formation of allergen-specific Th2 cells in lymph nodes. Also, FTY720-treated DCs were intrinsically less potent in activating naive and effector Th2 cells due to a reduced capacity to form stable interactions with T cells and thus to form an immunological synapse. These data support the concept that targeting the function of airway DCs with locally acting drugs is a powerful new strategy in the treatment of asthma.

Authors

Marco Idzko, Hamida Hammad, Menno van Nimwegen, Mirjam Kool, Tobias Müller, Thomas Soullié, Monique A.M. Willart, Daniëlle Hijdra, Henk C. Hoogsteden, Bart N. Lambrecht

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Calcineurin/Nfat signaling is required for perinatal lung maturation and function
Vrushank Davé, … , Gerald R. Crabtree, Jeffrey A. Whitsett
Vrushank Davé, … , Gerald R. Crabtree, Jeffrey A. Whitsett
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2597-2609. https://doi.org/10.1172/JCI27331.
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Calcineurin/Nfat signaling is required for perinatal lung maturation and function

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Abstract

Pulmonary surfactant proteins and lipids are required for lung function after birth. Lung immaturity and resultant surfactant deficiency cause respiratory distress syndrome, a common disorder contributing to morbidity and mortality in preterm infants. Surfactant synthesis increases prior to birth in association with formation of the alveoli that mediate efficient gas exchange. To identify mechanisms controlling perinatal lung maturation, the Calcineurin b1 (Cnb1) gene was deleted in the respiratory epithelium of the fetal mouse. Deletion of Cnb1 caused respiratory failure after birth and inhibited the structural maturation of the peripheral lung. Synthesis of surfactant and a lamellar body–associated protein, ABC transporter A3 (ABCA3), was decreased prior to birth. Nuclear factor of activated T cells (Nfat) calcineurin-dependent 3 (Nfatc3), a transcription factor modulated by calcineurin, was identified as a direct activator of Sftpa, Sftpb, Sftpc, Abca3, Foxa1, and Foxa2 genes. The calcineurin/Nfat pathway controls the morphologic maturation of lungs prior to birth and regulates expression of genes involved in surfactant homeostasis that are critical for adaptation to air breathing.

Authors

Vrushank Davé, Tawanna Childs, Yan Xu, Machiko Ikegami, Valérie Besnard, Yutaka Maeda, Susan E. Wert, Joel R. Neilson, Gerald R. Crabtree, Jeffrey A. Whitsett

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Connexin 43 mediates spread of Ca2+-dependent proinflammatory responses in lung capillaries
Kaushik Parthasarathi, … , Andrew Issekutz, Jahar Bhattacharya
Kaushik Parthasarathi, … , Andrew Issekutz, Jahar Bhattacharya
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2562-2562. https://doi.org/10.1172/JCI26605C1.
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Connexin 43 mediates spread of Ca2+-dependent proinflammatory responses in lung capillaries

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Abstract

Authors

Kaushik Parthasarathi, Hideo Ichimura, Eiji Monma, Jens Lindert, Sadiqa Quadri, Andrew Issekutz, Jahar Bhattacharya

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Connexin 43 mediates spread of Ca2+ -dependent proinflammatory responses in lung capillaries
Kaushik Parthasarathi, … , Andrew Issekutz, Jahar Bhattacharya
Kaushik Parthasarathi, … , Andrew Issekutz, Jahar Bhattacharya
Published August 1, 2006
Citation Information: J Clin Invest. 2006;116(8):2193-2200. https://doi.org/10.1172/JCI26605.
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Connexin 43 mediates spread of Ca2+ -dependent proinflammatory responses in lung capillaries

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Abstract

Acute lung injury (ALI), which is associated with a mortality of 30–40%, is attributable to inflammation that develops rapidly across the lung’s vast vascular surface, involving an entire lung or even both lungs. No specific mechanism explains this extensive inflammatory spread, probably because of the lack of approaches for detecting signal conduction in lung capillaries. Here, we addressed this question by applying the photolytic uncaging approach to induce focal increases in Ca2+ levels in targeted endothelial cells of alveolar capillaries. Uncaging caused Ca2+ levels to increase not only in the targeted cell, but also in vascular locations up to 150 μm from the target site, indicating that Ca2+ was conducted from the capillary to adjacent vessels. No such conduction was evident in mouse lungs lacking endothelial connexin 43 (Cx43), or in rat lungs in which we pretreated vessels with peptide inhibitors of Cx43. These findings provide the first direct evidence to our knowledge that interendothelial Ca2+ conduction occurs in the lung capillary bed and that Cx43-containing gap junctions mediate the conduction. A proinflammatory effect was evident in that induction of increases in Ca2+ levels in the capillary activated expression of the leukocyte adherence receptor P-selectin in venules. Further, peptide inhibitors of Cx43 completely blocked thrombin-induced microvascular permeability increases. Together, our findings reveal a novel role for Cx43-mediated gap junctions, namely as conduits for the spread of proinflammatory signals in the lung capillary bed. Gap junctional mechanisms require further consideration in the understanding of ALI.

Authors

Kaushik Parthasarathi, Hideo Ichimura, Eiji Monma, Jens Lindert, Sadiqa Quadri, Andrew Issekutz, Jahar Bhattacharya

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Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury
Chun-Xiao Sun, … , Dewan Zeng, Michael R. Blackburn
Chun-Xiao Sun, … , Dewan Zeng, Michael R. Blackburn
Published August 1, 2006
Citation Information: J Clin Invest. 2006;116(8):2173-2182. https://doi.org/10.1172/JCI27303.
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Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury

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Abstract

Adenosine has been implicated in the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. In vitro studies suggest that activation of the A2B adenosine receptor (A2BAR) results in proinflammatory and profibrotic effects relevant to the progression of lung diseases; however, in vivo data supporting these observations are lacking. Adenosine deaminase–deficient (ADA-deficient) mice develop pulmonary inflammation and injury that are dependent on increased lung adenosine levels. To investigate the role of the A2BAR in vivo, ADA-deficient mice were treated with the selective A2BAR antagonist CVT-6883, and pulmonary inflammation, fibrosis, and airspace integrity were assessed. Untreated and vehicle-treated ADA-deficient mice developed pulmonary inflammation, fibrosis, and enlargement of alveolar airspaces; conversely, CVT-6883–treated ADA-deficient mice showed less pulmonary inflammation, fibrosis, and alveolar airspace enlargement. A2BAR antagonism significantly reduced elevations in proinflammatory cytokines and chemokines as well as mediators of fibrosis and airway destruction. In addition, treatment with CVT-6883 attenuated pulmonary inflammation and fibrosis in wild-type mice subjected to bleomycin-induced lung injury. These findings suggest that A2BAR signaling influences pathways critical for pulmonary inflammation and injury in vivo. Thus in chronic lung diseases associated with increased adenosine, antagonism of A2BAR-mediated responses may prove to be a beneficial therapy.

Authors

Chun-Xiao Sun, Hongyan Zhong, Amir Mohsenin, Eva Morschl, Janci L. Chunn, Jose G. Molina, Luiz Belardinelli, Dewan Zeng, Michael R. Blackburn

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Mast cells can promote the development of multiple features of chronic asthma in mice
Mang Yu, … , James Zehnder, Stephen J. Galli
Mang Yu, … , James Zehnder, Stephen J. Galli
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1633-1641. https://doi.org/10.1172/JCI25702.
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Mast cells can promote the development of multiple features of chronic asthma in mice

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Abstract

Bronchial asthma, the most prevalent cause of significant respiratory morbidity in the developed world, typically is a chronic disorder associated with long-term changes in the airways. We developed a mouse model of chronic asthma that results in markedly increased numbers of airway mast cells, enhanced airway responses to methacholine or antigen, chronic inflammation including infiltration with eosinophils and lymphocytes, airway epithelial goblet cell hyperplasia, enhanced expression of the mucin genes Muc5ac and Muc5b, and increased levels of lung collagen. Using mast cell–deficient (KitW-sh/W-sh and/or KitW/W-v) mice engrafted with FcRγ+/+ or FcRγ–/– mast cells, we found that mast cells were required for the full development of each of these features of the model. However, some features also were expressed, although usually at less than wild-type levels, in mice whose mast cells lacked FcRγ and therefore could not be activated by either antigen- and IgE-dependent aggregation of FcεRI or the binding of antigen-IgG1 immune complexes to FcγRIII. These findings demonstrate that mast cells can contribute to the development of multiple features of chronic asthma in mice and identify both FcRγ-dependent and FcRγ-independent pathways of mast cell activation as important for the expression of key features of this asthma model.

Authors

Mang Yu, Mindy Tsai, See-Ying Tam, Carol Jones, James Zehnder, Stephen J. Galli

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Ligation of protease-activated receptor 1 enhances αv β6 integrin–dependent TGF-β activation and promotes acute lung injury
R. Gisli Jenkins, … , Michael A. Matthay, Dean Sheppard
R. Gisli Jenkins, … , Michael A. Matthay, Dean Sheppard
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1606-1614. https://doi.org/10.1172/JCI27183.
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Ligation of protease-activated receptor 1 enhances αv β6 integrin–dependent TGF-β activation and promotes acute lung injury

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Abstract

Activation of latent TGF-β by the αvβ6 integrin is a critical step in the development of acute lung injury. However, the mechanism by which αvβ6-mediated TGF-β activation is regulated has not been identified. We show that thrombin, and other agonists of protease-activated receptor 1 (PAR1), activate TGF-β in an αvβ6 integrin–specific manner. This effect is PAR1 specific and is mediated by RhoA and Rho kinase. Intratracheal instillation of the PAR1-specific peptide TFLLRN increases lung edema during high-tidal-volume ventilation, and this effect is completely inhibited by a blocking antibody against the αvβ6 integrin. Instillation of TFLLRN during high-tidal-volume ventilation is associated with increased pulmonary TGF-β activation; however, this is not observed in Itgb6–/– mice. Furthermore, Itgb6–/– mice are also protected from ventilator-induced lung edema. We also demonstrate that pulmonary edema and TGF-β activity are similarly reduced in Par1–/– mice following bleomycin-induced lung injury. These results suggest that PAR1-mediated enhancement of αvβ6-dependent TGF-β activation could be one mechanism by which activation of the coagulation cascade contributes to the development of acute lung injury, and they identify PAR1 and the αvβ6 integrin as potential therapeutic targets in this condition.

Authors

R. Gisli Jenkins, Xiao Su, George Su, Christopher J. Scotton, Eric Camerer, Geoffrey J. Laurent, George E. Davis, Rachel C. Chambers, Michael A. Matthay, Dean Sheppard

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Neutrophils and their Fcγ receptors are essential in a mouse model of transfusion-related acute lung injury
Mark R. Looney, … , Clifford A. Lowell, Michael A. Matthay
Mark R. Looney, … , Clifford A. Lowell, Michael A. Matthay
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1615-1623. https://doi.org/10.1172/JCI27238.
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Neutrophils and their Fcγ receptors are essential in a mouse model of transfusion-related acute lung injury

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Abstract

Transfusion-related acute lung injury (TRALI) is the most common cause of transfusion-related mortality. To explore the pathogenesis of TRALI, we developed an in vivo mouse model based on the passive transfusion of an MHC class I (MHC I) mAb (H2Kd) to mice with the cognate antigen. Transfusion of the MHC I mAb to BALB/c mice produced acute lung injury with increased excess lung water, increased lung vascular and lung epithelial permeability to protein, and decreased alveolar fluid clearance. There was 50% mortality at a 2-hour time point after Ab administration. Pulmonary histology and immunohistochemistry revealed prominent neutrophil sequestration in the lung microvasculature that occurred concomitantly with acute peripheral blood neutropenia, all within 2 hours of administration of the mAb. Depletion of neutrophils by injection of anti-granulocyte mAb Gr-1 protected mice from lung injury following MHC I mAb challenge. FcRγ–/– mice were resistant to MHC I mAb–induced lung injury, while adoptive transfer of wild-type neutrophils into the FcRγ–/– animals restored lung injury following MHC I mAb challenge. In conclusion, in a clinically relevant in vivo mouse model of TRALI using an MHC I mAb, the mechanism of lung injury was dependent on neutrophils and their Fcγ receptors.

Authors

Mark R. Looney, Xiao Su, Jessica A. Van Ziffle, Clifford A. Lowell, Michael A. Matthay

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Adenosine metabolism and murine strain–specific IL-4–induced inflammation, emphysema, and fibrosis
Bing Ma, … , Hays W. Young, Jack A. Elias
Bing Ma, … , Hays W. Young, Jack A. Elias
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1274-1283. https://doi.org/10.1172/JCI26372.
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Adenosine metabolism and murine strain–specific IL-4–induced inflammation, emphysema, and fibrosis

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Abstract

To define the factors that control the tissue effects of IL-4, we compared the effects of Tg IL-4 in Balb/c and C57BL/6 mice. In the former, IL-4 caused modest eosinophilic inflammation and mild airway fibrosis and did not shorten survival. In C57BL/6 mice, IL-4 caused profound eosinophilic inflammation, airway fibrosis, emphysematous alveolar destruction, and premature death. These differences could not be accounted for by changes in Th2 or Th1 cytokines, receptor components, STAT6 activation, MMPs, or cathepsins. In contrast, in C57BL/6 mice, alveolar remodeling was associated with decreased levels of tissue inhibitors of metalloproteinase 2, -3, and -4 and α1-antitrypsin, and fibrosis was associated with increased levels of total and bioactive TGF-β1. Impressive differences in adenosine metabolism were also appreciated, with increased tissue adenosine levels and A1, A2B, and A3 adenosine receptor expression and decreased adenosine deaminase (ADA) activity in C57BL/6 animals. Treatment with ADA also reduced the inflammation, fibrosis, and emphysematous destruction and improved the survival of C57BL/6 Tg animals. These studies demonstrate that genetic influences control IL-4 effector pathways in the murine lung. They also demonstrate that IL-4 has different effects on adenosine metabolism in Balb/c and C57BL/6 mice and that these differences contribute to the different responses that IL-4 induces in these inbred animals.

Authors

Bing Ma, Michael R. Blackburn, Chun Geun Lee, Robert J. Homer, Wei Liu, Richard A. Flavell, Lynn Boyden, Richard P. Lifton, Chun-Xiao Sun, Hays W. Young, Jack A. Elias

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Mucus tethering in asthma
Luke Bonser and colleagues characterize the composition and transport of pathogenic, asthma-associated mucus…
Published May 16, 2016
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Translating mechanical stress to fibrogenesis
Shaik Rahaman and colleagues reveal that TRPV4 channel activity links mechanical stress and pulmonary fibrosis…
Published November 3, 2014
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