Mucociliary Function in Chronic Bronchitis

Summary

Principal Investigator: MATTHIAS A SALATHE
Abstract: DESCRIPTION (provided by applicant): In chronic bronchitis, mucociliary clearance is dysfunctional, especially during disease exacerbation. Chronic bronchitis exacerbations are commonly associated with increased production of reactive oxygen species (ROS) and airway acidification. This project will examine how ROS and intracellular acidification may regulate and/or dysregulate mucociliary function. At least two endogenous and paracrine mediators control key components of the mucociliary transport system: extracellular ATP and hyaluronan fragments. We propose that pannexins, proteins related to but different from connexins, form channels to the outside of cells (called pannexons) and are responsible, at least in part, for the release of apical ATP in the airway epithelium. We hypothesize that early in disease exacerbation, the production of ROS not only increases intracellular calcium concentrations ([Ca2+]i) to stimulate ciliary beat frequency (CBF) and apical ATP release through pannexons but also degrades apical hyaluronan which in turn stimulates CBF and increases airway surface liquid (ASL) volume. Subsequent intracellular acidification, possibly mediated by cytokine-mediated upregulation of an NADPH oxidase activity expressed in the airway (Duox), leads to mucociliary dysfunction by inhibiting ciliary activity and pannexins. This hypothesis will be tested with three specific aims. Specific Aim 1 will test the hypothesis that exogenous ROS activate a signaling cascade that includes an initial [Ca2+]i increase to stimulate CBF, despite a mild and temporary intracellular acidification due to H+ production by Duox;in addition, direct apical hyaluronan degradation activates RHAMM and RON to stimulate CBF and possibly increase ASL volume. Specific Aim 2 will test the hypothesis that pannexins are responsible for releasing ATP to the apical surface of airway epithelial cells where ATP plays an important role in regulating mucociliary functions including CBF and ASL volume. Specific Aim 3 will test the hypothesis that persistent intracellular acidification inhibits mucociliary clearance by a direct action on ciliary beating as well as by preventing ATP release through pannexons. The results of the proposed experiments, using novel and state-of-the-art methods, will provide new and important mechanistic insights into the regulation of mucociliary clearance in chronic bronchitis.
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Epithelial organic cation transporters ensure pH-dependent drug absorption in the airway
    Gabor Horvath
    Division of Pulmonary and Critical Care Medicine, University of Miami Miler School of Medicine, Miami, FL 33101, USA
    Am J Respir Cell Mol Biol 36:53-60. 2007
  2. pmc H2O2 stimulates cystic fibrosis transmembrane conductance regulator through an autocrine prostaglandin pathway, using multidrug-resistant protein-4
    Gregory E Conner
    1 Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, and
    Am J Respir Cell Mol Biol 49:672-9. 2013
  3. pmc IFN-γ-mediated reduction of large-conductance, Ca2+-activated, voltage-dependent K+ (BK) channel activity in airway epithelial cells leads to mucociliary dysfunction
    Dahis Manzanares
    1600 NW 10 Ave, RMSB 7063, Miami, FL 33136
    Am J Physiol Lung Cell Mol Physiol 306:L453-62. 2014
  4. pmc Soluble adenylyl cyclase is localized to cilia and contributes to ciliary beat frequency regulation via production of cAMP
    Andreas Schmid
    Division of Pulmonary and Critical Care, University of Miami, Miami, FL 33136, USA
    J Gen Physiol 130:99-109. 2007
  5. pmc Calcium-mediated, purinergic stimulation and polarized localization of calcium-sensitive adenylyl cyclase isoforms in human airway epithelia
    Marie Christine Nlend
    Division of Pulmonary and Critical Care Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
    FEBS Lett 581:3241-6. 2007
  6. pmc Apical oxidative hyaluronan degradation stimulates airway ciliary beating via RHAMM and RON
    Dahis Manzanares
    Division of Pulmonary and Critical Care Medicine, University of Miami Miller School of Medicine, 1600 NW 10th Ave, RMSB 7063A R 47, Miami, FL 33136, USA
    Am J Respir Cell Mol Biol 37:160-8. 2007
  7. pmc The lactoperoxidase system links anion transport to host defense in cystic fibrosis
    Gregory E Conner
    Division of Pulmonary and Critical Care Medicine, University of Miami School of Medicine, Miami, FL 33136, United States
    FEBS Lett 581:271-8. 2007
  8. pmc Pannexin 1 contributes to ATP release in airway epithelia
    George A Ransford
    Division of Pulmonary and Critical Care Medicine R 47, University of Miami Miller School of Medicine, 1600 NW 10th Ave, RMSB 7058, Miami, FL 33136, USA
    Am J Respir Cell Mol Biol 41:525-34. 2009
  9. pmc Decreased soluble adenylyl cyclase activity in cystic fibrosis is related to defective apical bicarbonate exchange and affects ciliary beat frequency regulation
    Andreas Schmid
    Division of Pulmonary and Critical Care, University of Miami, Miami, Florida 33136, USA
    J Biol Chem 285:29998-30007. 2010
  10. pmc Functional apical large conductance, Ca2+-activated, and voltage-dependent K+ channels are required for maintenance of airway surface liquid volume
    Dahis Manzanares
    Division of Pulmonary and Critical Care, University of Miami, Miami, Florida 33136, USA
    J Biol Chem 286:19830-9. 2011

Scientific Experts

  • Matthias Salathe
  • Gregory E Conner
  • Dahis Manzanares
  • Andreas Schmid
  • Gabor Horvath
  • Nevis Fregien
  • Pedro Ivonnet
  • George A Ransford
  • Zoltan Sutto
  • Nathalie Schmid
  • Marie Christine Nlend
  • Hoshang J Unwalla
  • Rafael Arrojo e Drigo
  • Monica Valencia Gattas
  • Miryam A Fragoso
  • John S Dennis
  • Maria Srinivasan
  • Samuel T Salathe
  • Nathalie Baumlin
  • PHILIP WHITNEY
  • Murline Gelin
  • Felix D Roth
  • H Peter Larsson
  • Balazs Gereben
  • Ren Shiang Chen
  • Carlos Gonzalez
  • Petra Mohácsik
  • Antonio C Bianco
  • Gordana Simovic
  • Melany Castillo
  • Tatiana L Fonseca
  • Monica Valencia-Gattas
  • Gregory Conner
  • Lisa Novak
  • Pedro Salas
  • Feng Qiu
  • Radia Forteza
  • Gerhard Dahl
  • Lonny R Levin
  • Jochen Buck
  • Corinne Wijkstrom-Frei
  • Vania E Fernandez
  • Scott H Randell
  • Rashmin C Savani
  • Maria Elena Monzon
  • Adam Wanner

Detail Information

Publications13

  1. pmc Epithelial organic cation transporters ensure pH-dependent drug absorption in the airway
    Gabor Horvath
    Division of Pulmonary and Critical Care Medicine, University of Miami Miler School of Medicine, Miami, FL 33101, USA
    Am J Respir Cell Mol Biol 36:53-60. 2007
    ..We suggest that epithelial OCTN1/2 are involved in the delivery of inhaled cationic bronchodilators to the airway tissue...
  2. pmc H2O2 stimulates cystic fibrosis transmembrane conductance regulator through an autocrine prostaglandin pathway, using multidrug-resistant protein-4
    Gregory E Conner
    1 Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, and
    Am J Respir Cell Mol Biol 49:672-9. 2013
    ....
  3. pmc IFN-γ-mediated reduction of large-conductance, Ca2+-activated, voltage-dependent K+ (BK) channel activity in airway epithelial cells leads to mucociliary dysfunction
    Dahis Manzanares
    1600 NW 10 Ave, RMSB 7063, Miami, FL 33136
    Am J Physiol Lung Cell Mol Physiol 306:L453-62. 2014
    ..Key experiments were repeated in cystic fibrosis cells and showed the same results. Therefore, IFN-γ induces mucociliary dysfunction through BK inactivation...
  4. pmc Soluble adenylyl cyclase is localized to cilia and contributes to ciliary beat frequency regulation via production of cAMP
    Andreas Schmid
    Division of Pulmonary and Critical Care, University of Miami, Miami, FL 33136, USA
    J Gen Physiol 130:99-109. 2007
    ..Thus, sAC is localized to motile airway cilia and it contributes to the regulation of human airway CBF. In addition, CO(2)/HCO(3)(-) increases indeed reversibly stimulate intracellular cAMP production by sAC in intact cells...
  5. pmc Calcium-mediated, purinergic stimulation and polarized localization of calcium-sensitive adenylyl cyclase isoforms in human airway epithelia
    Marie Christine Nlend
    Division of Pulmonary and Critical Care Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
    FEBS Lett 581:3241-6. 2007
    ..Real-time, ciliated-cell specific cAMP production by tmACs upon apical, purinergic stimulation with UTP was confirmed using fluorescent energy resonance transfer between fluorescently tagged PKA subunits...
  6. pmc Apical oxidative hyaluronan degradation stimulates airway ciliary beating via RHAMM and RON
    Dahis Manzanares
    Division of Pulmonary and Critical Care Medicine, University of Miami Miller School of Medicine, 1600 NW 10th Ave, RMSB 7063A R 47, Miami, FL 33136, USA
    Am J Respir Cell Mol Biol 37:160-8. 2007
    ..These data suggest that high molecular form HA is broken down by reactive oxygen species to form low-molecular-weight fragments that signal via RHAMM and RON to stimulate CBF...
  7. pmc The lactoperoxidase system links anion transport to host defense in cystic fibrosis
    Gregory E Conner
    Division of Pulmonary and Critical Care Medicine, University of Miami School of Medicine, Miami, FL 33136, United States
    FEBS Lett 581:271-8. 2007
    ..The lower CF [SCN-] did not support LPO antibacterial activity. Modeling of airway LPO activity suggested that reduced transport impairs LPO-mediated defense and cannot be compensated by LPO or H2O2 upregulation...
  8. pmc Pannexin 1 contributes to ATP release in airway epithelia
    George A Ransford
    Division of Pulmonary and Critical Care Medicine R 47, University of Miami Miller School of Medicine, 1600 NW 10th Ave, RMSB 7058, Miami, FL 33136, USA
    Am J Respir Cell Mol Biol 41:525-34. 2009
    ..These data not only show that Panx1 is expressed apically in differentiated airway epithelial cells but also that it contributes to ATP release in these cells...
  9. pmc Decreased soluble adenylyl cyclase activity in cystic fibrosis is related to defective apical bicarbonate exchange and affects ciliary beat frequency regulation
    Andreas Schmid
    Division of Pulmonary and Critical Care, University of Miami, Miami, Florida 33136, USA
    J Biol Chem 285:29998-30007. 2010
    ..These results suggest that CBF regulation by sAC-produced cAMP could be impaired in CF, thereby possibly contributing to mucociliary dysfunction in this disease, at least during disease exacerbations when airway acidification is common...
  10. pmc Functional apical large conductance, Ca2+-activated, and voltage-dependent K+ channels are required for maintenance of airway surface liquid volume
    Dahis Manzanares
    Division of Pulmonary and Critical Care, University of Miami, Miami, Florida 33136, USA
    J Biol Chem 286:19830-9. 2011
    ..Thus, apical BK channels play an important, previously unrecognized role in maintaining adequate airway surface hydration...
  11. pmc Endoplasmic reticulum stress decreases intracellular thyroid hormone activation via an eIF2a-mediated decrease in type 2 deiodinase synthesis
    Rafael Arrojo e Drigo
    Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine Miami, Florida 33136, USA
    Mol Endocrinol 25:2065-75. 2011
    ..This explains the lack of D2 activity in primary human airway cells with ER stress resulting from cystic fibrosis...
  12. pmc Albuterol modulates its own transepithelial flux via changes in paracellular permeability
    Hoshang J Unwalla
    Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Miami and Miller School of Medicine, Florida, USA
    Am J Respir Cell Mol Biol 46:551-8. 2012
    ....
  13. pmc Oxidative epithelial host defense is regulated by infectious and inflammatory stimuli
    Monica Valencia Gattas
    Department of Cell Biology and Anatomy, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
    Free Radic Biol Med 47:1450-8. 2009
    ..The data suggest that Duox2 is the major contributor to basal H(2)O(2) synthesis despite the presence of greater amounts of Duox1...