Conditional depletion of airway progenitor cells induces peribronchiolar fibrosis

Anne Karina T. Perl, Dieter Riethmacher, Jeffrey A. Whitsett

Research output: Contribution to journalArticle

47 Citations (Scopus)

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-expressingcells 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.

Original languageEnglish
Pages (from-to)511-521
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume183
Issue number4
DOIs
Publication statusPublished - Feb 15 2011

Keywords

  • Bronchiolitis obliterans syndrome
  • Chronic obstructive pulmonary disease
  • Diphtheria toxin
  • Progenitor cells
  • Squamous metaplasia

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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