Conditional depletion of airway progenitor cells induces peribronchiolar fibrosis

Am J Respir Crit Care Med. 2011 Feb 15;183(4):511-21. doi: 10.1164/rccm.201005-0744OC. Epub 2010 Sep 24.

Abstract

Rationale: The respiratory epithelium has a remarkable capacity to respond to acute injury. In contrast, repeated epithelial injury is often associated with abnormal repair, inflammation, and fibrosis. There is increasing evidence that nonciliated epithelial cells play important roles in the repair of the bronchiolar epithelium after acute injury. Cellular processes underlying the repair and remodeling of the lung after chronic epithelial injury are poorly understood.

Objectives: To identify cell processes mediating epithelial regeneration and remodeling after acute and chronic Clara cell depletion.

Methods: A transgenic mouse model was generated to conditionally express diphtheria toxin A to ablate Clara cells in the adult lung. Epithelial regeneration and peribronchiolar fibrosis were assessed after acute and chronic Clara cell depletion.

Measurements and main results: Acute Clara cell ablation caused squamous metaplasia of ciliated cells and induced proliferation of residual progenitor cells. Ciliated cells in the bronchioles and pro-surfactant protein C-expressing cells in the bronchiolar alveolar duct junctions did not proliferate. Epithelial cell proliferation occurred at multiple sites along the airways and was not selectively associated with regions around neuroepithelial bodies. Chronic Clara cell depletion resulted in ineffective repair and caused peribronchiolar fibrosis.

Conclusions: Colocalization of proliferation and cell type-specific markers demonstrate that Clara cells are critical airway progenitor cells. Continuous depletion of Clara cells resulted in persistent squamous metaplasia, lack of normal reepithelialization, and peribronchiolar fibrosis. Induction of proliferation in subepithelial fibroblasts supports the concept that chronic epithelial depletion caused peribronchiolar fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchi / cytology
  • Bronchi / metabolism*
  • Bronchi / pathology*
  • Cells, Cultured
  • Diphtheria Toxin
  • Disease Models, Animal
  • Fibrosis
  • Lung / cytology
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Transgenic
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / metabolism*
  • Respiratory Mucosa / pathology*
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • Stem Cells / pathology*

Substances

  • Diphtheria Toxin