Role of MUC1 in Repair of Injured Airways

Summary

Principal Investigator: Erik P Lillehoj
Abstract: [unreadable] DESCRIPTION (provided by applicant): Airway epithelia are major targets of environmental toxicants. Airway injury due to inhalation of deleterious environmental agents contributes to the etiology of many pulmonary diseases including asthma, cystic fibrosis, acute lung injury, and acute respiratory distress syndrome. Normally following injury, airway epithelia rapidly undergo a series of progressive and cumulative changes to repair the wounded area. First, a provisional matrix mostly derived from fibrin and fibronectin accumulates at the denuded region. Second, airway epithelial cells at the margins of the injured area dedifferentiate and detach from their neighboring cells and migrate across the matrix to restore epithelial integrity. Third, the newly arrived cells proliferate to fill the injured area resulting in a dedifferentiated epithelium. Finally, the cells loose their proliferative capacity, reestablish contacts with neighboring cells, and redifferentiate to restore normal epithelial architecture and barrier function. Although this process has been well-characterized in a variety of different experimental and clinical settings, the exact cellular and molecular mechanisms mediating the repair process remain to be elucidated. Recently, our laboratory developed an in vitro system to study airway repair. Using this system, we made the interesting observation that expression of the MUC1 epithelial membrane protein was initially down-regulated followed by an abrupt and dramatic up-regulation during repair. Based upon these observations, we hypothesize that some of the steps of post-injury repair are mediated by transient alteration of MUC1 expression. In particular, through its interactions with other cellular proteins (beta-catenin, ICAM-1), we suggest that decreased MUC1 expression at an early stage of repair is responsible for cell detachment and proliferation while increased MUC1 at later stages of repair mediates the opposite effects. Successful completion of this study will lay the foundation for our future projects to identify the role of MUC1 in repair using in vivo animal models and clinical samples from patients with environmentally-injured airways. We expect that future therapies for respiratory diseases, particularly those related to toxicant inhalation, will be developed based upon clinical modulation of MUC1 expression. [unreadable] [unreadable]
Funding Period: 2005-01-01 - 2007-12-31
more information: NIH RePORT

Top Publications

  1. ncbi Biochemical interactions among intercellular adhesion molecules expressed by airway epithelial cells
    Keena E Molock
    Division of Pulmonology Allergy, Department of Pediatrics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
    Biochem Biophys Res Commun 343:513-9. 2006
  2. ncbi Neutrophil elastase induces IL-8 gene transcription and protein release through p38/NF-{kappa}B activation via EGFR transactivation in a lung epithelial cell line
    Ippei Kuwahara
    Respiratory Immunology and Asthma Program, Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA
    Am J Physiol Lung Cell Mol Physiol 291:L407-16. 2006
  3. pmc MUC1 inhibits cell proliferation by a beta-catenin-dependent mechanism
    Erik P Lillehoj
    Department of Pediatrics, University of Maryland School of Medicine, 655 West Baltimore Street, BRB 13 029, Baltimore, MD 21201, USA
    Biochim Biophys Acta 1773:1028-38. 2007
  4. ncbi TNF-alpha induces MUC1 gene transcription in lung epithelial cells: its signaling pathway and biological implication
    Takeshi Koga
    Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA
    Am J Physiol Lung Cell Mol Physiol 293:L693-701. 2007
  5. pmc The signaling pathway involved in neutrophil elastase stimulated MUC1 transcription
    Ippei Kuwahara
    Immunology Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 5127, USA
    Am J Respir Cell Mol Biol 37:691-8. 2007
  6. pmc MUC1 mucin interacts with calcium-modulating cyclophilin ligand
    Wei Guang
    Department of Pediatrics, University of Maryland School of Medicine, 655 W Baltimore St, BRB 13 029, Baltimore, MD 21201, United States
    Int J Biochem Cell Biol 41:1354-60. 2009

Scientific Experts

  • Erik P Lillehoj
  • Ippei Kuwahara
  • K Chul Kim
  • Takeshi Koga
  • Yoichiro Isohama
  • Takeshi Miyata
  • Wei Guang
  • Wenju Lu
  • Keena E Molock
  • Ishwar S Singh

Detail Information

Publications6

  1. ncbi Biochemical interactions among intercellular adhesion molecules expressed by airway epithelial cells
    Keena E Molock
    Division of Pulmonology Allergy, Department of Pediatrics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
    Biochem Biophys Res Commun 343:513-9. 2006
    ..We conclude that airway epithelial cell-cell adhesion involves a complex network of protein-protein interactions mediated by a diverse array of membrane-bound and cytosolic protein partners...
  2. ncbi Neutrophil elastase induces IL-8 gene transcription and protein release through p38/NF-{kappa}B activation via EGFR transactivation in a lung epithelial cell line
    Ippei Kuwahara
    Respiratory Immunology and Asthma Program, Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA
    Am J Physiol Lung Cell Mol Physiol 291:L407-16. 2006
    ..We conclude that NE increases IL-8 transcription through p38/NF-kappaB activation via EGFR transactivation...
  3. pmc MUC1 inhibits cell proliferation by a beta-catenin-dependent mechanism
    Erik P Lillehoj
    Department of Pediatrics, University of Maryland School of Medicine, 655 West Baltimore Street, BRB 13 029, Baltimore, MD 21201, USA
    Biochim Biophys Acta 1773:1028-38. 2007
    ..knockout (Muc1(-/-)) mouse primary tracheal epithelial cells. We conclude that MUC1 inhibits cell proliferation through a beta-catenin/LEF-1/cyclin D1/c-Myc pathway...
  4. ncbi TNF-alpha induces MUC1 gene transcription in lung epithelial cells: its signaling pathway and biological implication
    Takeshi Koga
    Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA
    Am J Physiol Lung Cell Mol Physiol 293:L693-701. 2007
    ..We conclude that TNF-alpha induces MUC1 gene transcription through a TNFR1 --> MEK1/2 --> ERK1 --> Sp1 pathway...
  5. pmc The signaling pathway involved in neutrophil elastase stimulated MUC1 transcription
    Ippei Kuwahara
    Immunology Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 5127, USA
    Am J Respir Cell Mol Biol 37:691-8. 2007
    ....
  6. pmc MUC1 mucin interacts with calcium-modulating cyclophilin ligand
    Wei Guang
    Department of Pediatrics, University of Maryland School of Medicine, 655 W Baltimore St, BRB 13 029, Baltimore, MD 21201, United States
    Int J Biochem Cell Biol 41:1354-60. 2009
    ....