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Yael G. Alevy, … , Tom J. Brett, Michael J. Holtzman
Published November 26, 2012
Citation Information: J Clin Invest. 2012;122(12):4555-4568. https://doi.org/10.1172/JCI64896.
Citation Information: J Clin Invest. 2012;122(12):4555-4568. https://doi.org/10.1172/JCI64896.
Abstract
Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13–driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases.
Authors
Yael G. Alevy, Anand C. Patel, Arthur G. Romero, Dhara A. Patel, Jennifer Tucker, William T. Roswit, Chantel A. Miller, Richard F. Heier, Derek E. Byers, Tom J. Brett, Michael J. Holtzman
Total citations by year
Citation information
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Expert Review of Respiratory Medicine | 2015 |
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IL13 activates autophagy to regulate secretion in airway epithelial cells
JD Dickinson, Y Alevy, NP Malvin, KK Patel, SP Gunsten, MJ Holtzman, TS Stappenbeck, SL Brody |
Autophagy | 2015 |
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The Goblet Cell Protein Clca1 (Alias mClca3 or Gob-5) Is Not Required for Intestinal Mucus Synthesis, Structure and Barrier Function in Naive or DSS-Challenged Mice
NA Erickson, EE Nyström, L Mundhenk, L Arike, R Glauben, MM Heimesaat, A Fischer, S Bereswill, GM Birchenough, AD Gruber, ME Johansson, B Ryffel |
PloS one | 2015 |
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Novel Roles for Chloride Channels, Exchangers, and Regulators in Chronic Inflammatory Airway Diseases
M Sala-Rabanal, Z Yurtsever, KN Berry, TJ Brett |
Mediators of Inflammation | 2015 |
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Secreted CLCA1 modulates TMEM16A to activate Ca 2+ -dependent chloride currents in human cells: ( A ) GFP-expressing cells were co-cultured with pHLsec- or CLCA1-transfected cells, and assayed for I CaCC by patch clamp electrophysiology. ( B – C ) Whole-cell currents measured in GFP-positive cells from experiments as in ( A ), superfused with standard extracellular solution, and in the absence or presence of 10 μM free Ca 2+ in the pipette (respectively, [0 μM Ca 2+ ] in or [10 μM Ca 2+ ] in ). ( B ) Representative current traces. The pulse protocol is shown at the top left. Outward currents are represented by upward deflections , and dotted lines indicate zero current. Membrane capacitance was similar in all cases at ∼25 pF. ( C ) Current–voltage relationships at the end of the 600-ms voltage steps. Membrane potential values were corrected off-line for the calculated liquid junction potentials, respectively −5.5 mV ([0 μM Ca 2+ ] in ) and −6.0 mV ([10 μM Ca 2+ ] in ). Data are presented as means ± S.E. (n = 5–9). ( D ) Current density at +100 mV, from the same experiments as in ( C ). Symbols represent data from individual patches; bars indicate the means ± S.E. of all experiments. *p < 0.01 (one-way ANOVA, F = 30.3 and p = 1.2 × 10 −7 ; followed by Tukey test)
M Sala-Rabanal, Z Yurtsever, CG Nichols, TJ Brett |
eLife | 2015 |
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A Computational Strategy to Select Optimized Protein Targets for Drug Development toward the Control of Cancer Diseases
N Carels, T Tilli, JA Tuszynski, P Rameshwar |
PloS one | 2015 |
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The crystal structure of phosphorylated MAPK13 reveals common structural features and differences in p38 MAPK family activation
Z Yurtsever, SM Scheaffer, AG Romero, MJ Holtzman, TJ Brett |
Acta crystallographica. Section D, Biological crystallography | 2015 |
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Virus Infection of Airway Epithelial Cells
Alexander-Brett J, Holtzman MJ |
Mucosal Immunology | 2015 |
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Respiratory epithelial cells orchestrate pulmonary innate immunity
JA Whitsett, T Alenghat |
Nature Immunology | 2014 |
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Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion
SJ Dando, A Mackay-Sim, R Norton, BJ Currie, JA st. John, JA Ekberg, M Batzloff, GC Ulett, IR Beacham |
Clinical microbiology reviews | 2014 |
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Cell biology of disease: The cell biology of asthma
DJ Erle, D Sheppard |
The Journal of Cell Biology | 2014 |
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Interferon response and respiratory virus control are preserved in bronchial epithelial cells in asthma
DA Patel, Y You, G Huang, DE Byers, HJ Kim, E Agapov, ML Moore, RS Peebles, M Castro, K Sumino, A Shifren, SL Brody, MJ Holtzman |
Journal of Allergy and Clinical Immunology | 2014 |
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The role of airway epithelial cells and innate immune cells in chronic respiratory disease
MJ Holtzman, DE Byers, J Alexander-Brett, X Wang |
Nature Reviews Immunology | 2014 |
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Linking Acute Infection to Chronic Lung Disease. The Role of IL-33–Expressing Epithelial Progenitor Cells
MJ Holtzman, DE Byers, JA Brett, AC Patel, E Agapov, X Jin, K Wu |
Annals of the American Thoracic Society | 2014 |
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p38 δ MAPK: Emerging Roles of a Neglected Isoform
C O’Callaghan, LJ Fanning, OP Barry |
International Journal of Cell Biology | 2014 |
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Chemosensory Functions for Pulmonary Neuroendocrine Cells
X Gu, PH Karp, SL Brody, RA Pierce, MJ Welsh, MJ Holtzman, Y Ben-Shahar |
American journal of respiratory cell and molecular biology | 2014 |
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Myb Permits Multilineage Airway Epithelial Cell Differentiation: Myb Permits Airway Epithelial Differentiation
JH Pan, TL Adair-Kirk, AC Patel, T Huang, NS Yozamp, J Xu, EP Reddy, DE Byers, RA Pierce, MJ Holtzman, SL Brody |
Stem Cells | 2014 |
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Interleukin-17A Promotes MUC5AC Expression and Goblet Cell Hyperplasia in Nasal Polyps via the Act1-Mediated Pathway
W Xia, J Bai, X Wu, Y Wei, S Feng, L Li, J Zhang, G Xiong, Y Fan, J Shi, H Li |
PloS one | 2014 |
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mCLCA3 modulates IL-17 and CXCL-1 induction and leukocyte recruitment in murine Staphylococcus aureus pneumonia
K Dietert, K Reppe, L Mundhenk, M Witzenrath, AD Gruber |
PloS one | 2014 |
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Murine CLCA5 is uniquely expressed in distinct niches of airway epithelial cells
K Dietert, L Mundhenk, NA Erickson, K Reppe, AC Hocke, W Kummer, M Witzenrath, AD Gruber |
Histochemistry and Cell Biology | 2014 |
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Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease
Derek Byers, Jennifer Alexander-Brett, Anand Patel, Eugene Agapov, Geoffrey Dang-Vu, Xiaohua Jin, Kangyun Wu, Yingjian You, Yael Alevy, Jean-Philippe Girard, Thaddeus Stappenbeck, G. Alexander Patterson, Richard Pierce, Steven Brody, Michael Holtzman |
Journal of Clinical Investigation | 2013 |
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High-Throughput Screening Normalized to Biological Response: Application to Antiviral Drug Discovery
DA Patel, AC Patel, WC Nolan, G Huang, AG Romero, N Charlton, E Agapov, Y Zhang, MJ Holtzman |
Journal of biomolecular screening | 2013 |
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Regulated mucin secretion from airway epithelial cells
KB Adler, MJ Tuvim, BF Dickey |
Frontiers in Endocrinology | 2013 |
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Secreted hCLCA1 is a signaling molecule that activates airway macrophages
JC Ching, L Lobanova, ME Loewen |
PloS one | 2013 |
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Identifying core herbal treatments for children with asthma: implication from a chinese herbal medicine database in taiwan
HY Chen, YH Lin, PF Thien, SC Chang, YC Chen, SS Lo, SH Yang, JL Chen |
Evidence-Based Complementary and Alternative Medicine | 2013 |
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Self-cleavage of human CLCA1 protein by a novel internal metalloprotease domain controls calcium-activated chloride channel activation
Z Yurtsever, M Sala-Rabanal, DT Randolph, SM Scheaffer, WT Roswit, YG Alevy, AC Patel, RF Heier, AG Romero, CG Nichols, MJ Holtzman, TJ Brett |
The Journal of biological chemistry | 2012 |
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Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd |
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2009 |
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