Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact

Pulmonology

  • 155 Articles
  • 2 Posts
  • ← Previous
  • 1
  • 2
  • …
  • 12
  • 13
  • 14
  • 15
  • 16
  • Next →
Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice
Tianju Liu, … , Fuyuki Ishikawa, Sem H. Phan
Tianju Liu, … , Fuyuki Ishikawa, Sem H. Phan
Published November 15, 2007
Citation Information: J Clin Invest. 2007. https://doi.org/10.1172/JCI32369.
View: Text | PDF

Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice

  • Text
  • PDF
Abstract

In addition to its well-known expression in the germline and in cells of certain cancers, telomerase activity is induced in lung fibrosis, although its role in this process is unknown. To identify the pathogenetic importance of telomerase in lung fibrosis, we examined the effects of telomerase reverse transcriptase (TERT) deficiency in a murine model of pulmonary injury. TERT-deficient mice showed significantly reduced lung fibrosis following bleomycin (BLM) insult. This was accompanied by a significant reduction in expression of lung α-SMA, a marker of myofibroblast differentiation. Furthermore, lung fibroblasts isolated from BLM-treated TERT-deficient mice showed significantly decreased proliferation and increased apoptosis rates compared with cells isolated from control mice. Transplantation of WT BM into TERT-deficient mice restored BLM-induced lung telomerase activity and fibrosis to WT levels. Conversely, transplantation of BM from TERT-deficient mice into WT recipients resulted in reduced telomerase activity and fibrosis. These findings suggest that induction of telomerase in injured lungs may be caused by BM-derived cells, which appear to play an important role in pulmonary fibrosis. Moreover, TERT induction is associated with increased survival of lung fibroblasts, which favors the development of fibrosis instead of injury resolution.

Authors

Tianju Liu, Myoung Ja Chung, Matthew Ullenbruch, Hongfeng Yu, Hong Jin, Biao Hu, Yoon Young Choi, Fuyuki Ishikawa, Sem H. Phan

×

IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice
Pamela Gasse, … , Bernhard Ryffel, Isabelle Couillin
Pamela Gasse, … , Bernhard Ryffel, Isabelle Couillin
Published November 8, 2007
Citation Information: J Clin Invest. 2007. https://doi.org/10.1172/JCI32285.
View: Text | PDF

IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice

  • Text
  • PDF
Abstract

The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1– and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1β recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1β production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis.

Authors

Pamela Gasse, Caroline Mary, Isabelle Guenon, Nicolas Noulin, Sabine Charron, Silvia Schnyder-Candrian, Bruno Schnyder, Shizuo Akira, Valérie F.J. Quesniaux, Vincent Lagente, Bernhard Ryffel, Isabelle Couillin

×

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients
Jun Araya, … , David J. Erle, Stephen L. Nishimura
Jun Araya, … , David J. Erle, Stephen L. Nishimura
Published October 25, 2007
Citation Information: J Clin Invest. 2007. https://doi.org/10.1172/JCI32526.
View: Text | PDF

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

  • Text
  • PDF
Abstract

Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1β, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-β activation in amplifying SM and driving IL-1β–dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin αvβ8, which is the major mediator of airway fibroblast TGF-β activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-β as a potential therapeutic target for COPD.

Authors

Jun Araya, Stephanie Cambier, Jennifer A. Markovics, Paul Wolters, David Jablons, Arthur Hill, Walter Finkbeiner, Kirk Jones, V. Courtney Broaddus, Dean Sheppard, Andrea Barzcak, Yuanyuan Xiao, David J. Erle, Stephen L. Nishimura

×

Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis
Jae Young Choi, … , John W. Hanrahan, Jeffrey J. Wine
Jae Young Choi, … , John W. Hanrahan, Jeffrey J. Wine
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):3118-3127. https://doi.org/10.1172/JCI31992.
View: Text | PDF

Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis

  • Text
  • PDF
Abstract

Cystic fibrosis (CF) is caused by dysfunction of the CF transmembrane conductance regulator (CFTR), an anion channel whose dysfunction leads to chronic bacterial and fungal airway infections via a pathophysiological cascade that is incompletely understood. Airway glands, which produce most airway mucus, do so in response to both acetylcholine (ACh) and vasoactive intestinal peptide (VIP). CF glands fail to secrete mucus in response to VIP, but do so in response to ACh. Because vagal cholinergic pathways still elicit strong gland mucus secretion in CF subjects, it is unclear whether VIP-stimulated, CFTR-dependent gland secretion participates in innate defense. It was recently hypothesized that airway intrinsic neurons, which express abundant VIP and ACh, are normally active and stimulate low-level gland mucus secretion that is a component of innate mucosal defenses. Here we show that low levels of VIP and ACh produced significant mucus secretion in human glands via strong synergistic interactions; synergy was lost in glands of CF patients. VIP/ACh synergy also existed in pig glands, where it was CFTR dependent, mediated by both Cl– and HCO3–, and clotrimazole sensitive. Loss of “housekeeping” gland mucus secretion in CF, in combination with demonstrated defects in surface epithelia, may play a role in the vulnerability of CF airways to bacterial infections.

Authors

Jae Young Choi, Nam Soo Joo, Mauri E. Krouse, Jin V. Wu, Robert C. Robbins, Juan P. Ianowski, John W. Hanrahan, Jeffrey J. Wine

×

Crosstalk between Gi and Gq/Gs pathways in airway smooth muscle regulates bronchial contractility and relaxation
Dennis W. McGraw, … , Marc E. Rothenberg, Stephen B. Liggett
Dennis W. McGraw, … , Marc E. Rothenberg, Stephen B. Liggett
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1391-1398. https://doi.org/10.1172/JCI30489.
View: Text | PDF

Crosstalk between Gi and Gq/Gs pathways in airway smooth muscle regulates bronchial contractility and relaxation

  • Text
  • PDF
Abstract

Receptor-mediated airway smooth muscle (ASM) contraction via Gαq, and relaxation via Gαs, underlie the bronchospastic features of asthma and its treatment. Asthma models show increased ASM Gαi expression, considered the basis for the proasthmatic phenotypes of enhanced bronchial hyperreactivity to contraction mediated by M3-muscarinic receptors and diminished relaxation mediated by β2-adrenergic receptors (β2ARs). A causal effect between Gi expression and phenotype has not been established, nor have mechanisms whereby Gi modulates Gq/Gs signaling. To delineate isolated effects of altered Gi, transgenic mice were generated overexpressing Gαi2 or a Gαi2 peptide inhibitor in ASM. Unexpectedly, Gαi2 overexpression decreased contractility to methacholine, while Gαi2 inhibition enhanced contraction. These opposite phenotypes resulted from different crosstalk loci within the Gq signaling network: decreased phospholipase C and increased PKCα, respectively. Gαi2 overexpression decreased β2AR-mediated airway relaxation, while Gαi2 inhibition increased this response, consistent with physiologically relevant coupling of this receptor to both Gs and Gi. IL-13 transgenic mice (a model of asthma), which developed increased ASM Gαi, displayed marked increases in airway hyperresponsiveness when Gαi function was inhibited. Increased Gαi in asthma is therefore a double-edged sword: a compensatory event mitigating against bronchial hyperreactivity, but a mechanism that evokes β-agonist resistance. By selective intervention within these multipronged signaling modules, advantageous Gs/Gq activities could provide new asthma therapies.

Authors

Dennis W. McGraw, Jean M. Elwing, Kevin M. Fogel, Wayne C.H. Wang, Clare B. Glinka, Kathryn A. Mihlbachler, Marc E. Rothenberg, Stephen B. Liggett

×

SPDEF regulates goblet cell hyperplasia in the airway epithelium
Kwon-Sik Park, … , Gang Chen, Jeffrey A. Whitsett
Kwon-Sik Park, … , Gang Chen, Jeffrey A. Whitsett
Published April 2, 2007
Citation Information: J Clin Invest. 2007;117(4):978-988. https://doi.org/10.1172/JCI29176.
View: Text | PDF

SPDEF regulates goblet cell hyperplasia in the airway epithelium

  • Text
  • PDF
Abstract

Goblet cell hyperplasia and mucous hypersecretion contribute to the pathogenesis of chronic pulmonary diseases including cystic fibrosis, asthma, and chronic obstructive pulmonary disease. In the present work, mouse SAM pointed domain-containing ETS transcription factor (SPDEF) mRNA and protein were detected in subsets of epithelial cells lining the trachea, bronchi, and tracheal glands. SPDEF interacted with the C-terminal domain of thyroid transcription factor 1, activating transcription of genes expressed selectively in airway epithelial cells, including Sftpa, Scgb1a1, Foxj1, and Sox17. Expression of Spdef in the respiratory epithelium of adult transgenic mice caused goblet cell hyperplasia, inducing both acidic and neutral mucins in vivo, and stainined for both acidic and neutral mucins in vivo. SPDEF expression was increased at sites of goblet cell hyperplasia caused by IL-13 and dust mite allergen in a process that was dependent upon STAT-6. SPDEF was induced following intratracheal allergen exposure and after Th2 cytokine stimulation and was sufficient to cause goblet cell differentiation of Clara cells in vivo.

Authors

Kwon-Sik Park, Thomas R. Korfhagen, Michael D. Bruno, Joseph A. Kitzmiller, Huajing Wan, Susan E. Wert, Gurjit K. Khurana Hershey, Gang Chen, Jeffrey A. Whitsett

×

Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts
Vibha N. Lama, … , Fernando J. Martinez, Victor J. Thannickal
Vibha N. Lama, … , Fernando J. Martinez, Victor J. Thannickal
Published April 2, 2007
Citation Information: J Clin Invest. 2007;117(4):989-996. https://doi.org/10.1172/JCI29713.
View: Text | PDF

Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts

  • Text
  • PDF
Abstract

The origin and turnover of connective tissue cells in adult human organs, including the lung, are not well understood. Here, studies of cells derived from human lung allografts demonstrate the presence of a multipotent mesenchymal cell population, which is locally resident in the human adult lung and has extended life span in vivo. Examination of plastic-adherent cell populations in bronchoalveolar lavage samples obtained from 76 human lung transplant recipients revealed clonal proliferation of fibroblast-like cells in 62% (106 of 172) of samples. Immunophenotyping of these isolated cells demonstrated expression of vimentin and prolyl-4-hydroxylase, indicating a mesenchymal phenotype. Multiparametric flow cytometric analyses revealed expression of cell-surface proteins, CD73, CD90, and CD105, commonly found on mesenchymal stem cells (MSCs). Hematopoietic lineage markers CD14, CD34, and CD45 were absent. Multipotency of these cells was demonstrated by their capacity to differentiate into adipocytes, chondrocytes, and osteocytes. Cytogenetic analysis of cells from 7 sex-mismatched lung transplant recipients harvested up to 11 years after transplant revealed that 97.2% ± 2.1% expressed the sex genotype of the donor. The presence of MSCs of donor sex identity in lung allografts even years after transplantation provides what we believe to be the first evidence for connective tissue cell progenitors that reside locally within a postnatal, nonhematopoietic organ.

Authors

Vibha N. Lama, Lisa Smith, Linda Badri, Andrew Flint, Adin-Cristian Andrei, Susan Murray, Zhuo Wang, Hui Liao, Galen B. Toews, Paul H. Krebsbach, Marc Peters-Golden, David J. Pinsky, Fernando J. Martinez, Victor J. Thannickal

×

Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin
Liat Linde, … , Eitan Kerem, Batsheva Kerem
Liat Linde, … , Eitan Kerem, Batsheva Kerem
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):683-692. https://doi.org/10.1172/JCI28523.
View: Text | PDF

Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin

  • Text
  • PDF
Abstract

Aminoglycosides can readthrough premature termination codons (PTCs), permitting translation of full-length proteins. Previously we have found variable efficiency of readthrough in response to the aminoglycoside gentamicin among cystic fibrosis (CF) patients, all carrying the W1282X nonsense mutation. Here we demonstrate that there are patients in whom the level of CF transmembrane conductance regulator (CFTR) nonsense transcripts is markedly reduced, while in others it is significantly higher. Response to gentamicin was found only in patients with the higher level. We further investigated the possibility that the nonsense-mediated mRNA decay (NMD) might vary among cells and hence governs the level of nonsense transcripts available for readthrough. Our results demonstrate differences in NMD efficiency of CFTR transcripts carrying the W1282X mutation among different epithelial cell lines derived from the same tissue. Variability was also found for 5 physiologic NMD substrates, RPL3, SC35 1.6 kb, SC35 1.7 kb, ASNS, and CARS. Importantly, our results demonstrate the existence of cells in which NMD of all transcripts was efficient and others in which the NMD was less efficient. Downregulation of NMD in cells carrying the W1282X mutation increased the level of CFTR nonsense transcripts and enhanced the CFTR chloride channel activity in response to gentamicin. Together our results suggest that the efficiency of NMD might vary and hence have an important role in governing the response to treatments aiming to promote readthrough of PTCs in many genetic diseases.

Authors

Liat Linde, Stephanie Boelz, Malka Nissim-Rafinia, Yifat S. Oren, Michael Wilschanski, Yasmin Yaacov, Dov Virgilis, Gabriele Neu-Yilik, Andreas E. Kulozik, Eitan Kerem, Batsheva Kerem

×

Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR
William R. Thelin, … , M. Jackson Stutts, Sharon L. Milgram
William R. Thelin, … , M. Jackson Stutts, Sharon L. Milgram
Published February 1, 2007
Citation Information: J Clin Invest. 2007;117(2):364-374. https://doi.org/10.1172/JCI30376.
View: Text | PDF

Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR

  • Text
  • PDF
Abstract

The role of the cystic fibrosis transmembrane conductance regulator (CFTR) as a cAMP-dependent chloride channel on the apical membrane of epithelia is well established. However, the processes by which CFTR is regulated on the cell surface are not clear. Here we report the identification of a protein-protein interaction between CFTR and the cytoskeletal filamin proteins. Using proteomic approaches, we identified filamins as proteins that associate with the extreme CFTR N terminus. Furthermore, we identified a disease-causing missense mutation in CFTR, serine 13 to phenylalanine (S13F), which disrupted this interaction. In cells, filamins tethered plasma membrane CFTR to the underlying actin network. This interaction stabilized CFTR at the cell surface and regulated the plasma membrane dynamics and confinement of the channel. In the absence of filamin binding, CFTR was internalized from the cell surface, where it prematurely accumulated in lysosomes and was ultimately degraded. Our data demonstrate what we believe to be a previously unrecognized role for the CFTR N terminus in the regulation of the plasma membrane stability and metabolic stability of CFTR. In addition, we elucidate the molecular defect associated with the S13F mutation.

Authors

William R. Thelin, Yun Chen, Martina Gentzsch, Silvia M. Kreda, Jennifer L. Sallee, Cameron O. Scarlett, Christoph H. Borchers, Ken Jacobson, M. Jackson Stutts, Sharon L. Milgram

×

Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis
Javier Rangel-Moreno, … , Moises Selman, Troy D. Randall
Javier Rangel-Moreno, … , Moises Selman, Troy D. Randall
Published December 1, 2006
Citation Information: J Clin Invest. 2006;116(12):3183-3194. https://doi.org/10.1172/JCI28756.
View: Text | PDF

Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis

  • Text
  • PDF
Abstract

Bronchus-associated lymphoid tissue (BALT) was originally described as a mucosal lymphoid organ in the lungs of some species. However, while the lungs of naive mice and humans typically lack BALT, pulmonary infection in mice leads to the development of inducible BALT (iBALT), which is located in peribronchial, perivascular, and interstitial areas throughout the lung. Here we investigated whether iBALT forms in patients with a variety of interstitial lung diseases. We show that while iBALT can be found in the lungs of patients suffering from multiple diseases, well-developed iBALT is most prevalent in patients with pulmonary complications of RA and Sjögren syndrome. In these patients, iBALT consisted of numerous B cell follicles containing germinal centers and follicular dendritic cells. A loosely defined T cell area surrounded the B cell follicles while lymphatics and high endothelial venules were found at the B cell/T cell interface. Increased expression of lymphoid-organizing chemokines, such as CXCL13 and CCL21, as well as molecules involved in the immunopathology of RA, such as B cell–activating factor of the TNF family (BAFF), ICOS ligand, and lymphotoxin, correlated with more well-developed iBALT. Finally, the presence of iBALT correlated with tissue damage in the lungs of RA patients, suggesting that iBALT participates in local RA pathogenesis.

Authors

Javier Rangel-Moreno, Louise Hartson, Carmen Navarro, Miguel Gaxiola, Moises Selman, Troy D. Randall

×
  • ← Previous
  • 1
  • 2
  • …
  • 12
  • 13
  • 14
  • 15
  • 16
  • Next →
Mucus tethering in asthma
Luke Bonser and colleagues characterize the composition and transport of pathogenic, asthma-associated mucus…
Published May 16, 2016
Scientific Show StopperPulmonology

Translating mechanical stress to fibrogenesis
Shaik Rahaman and colleagues reveal that TRPV4 channel activity links mechanical stress and pulmonary fibrosis…
Published November 3, 2014
Scientific Show StopperPulmonology
Advertisement
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts