ABL kinase inhibition promotes lung regeneration through expansion of an SCGB1A1+ SPC+ cell population following bacterial pneumonia

Aaditya Khatri, Bryan D. Kraft, Purushothama Rao Tata, Scott H. Randell, Claude A. Piantadosi, Ann Marie Pendergast

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Current therapeutic interventions for the treatment of respiratory infections are hampered by the evolution of multidrug resistance in pathogens as well as the lack of effective cellular targets. Despite the identification of multiple region-specific lung progenitor cells, the identity of molecules that might be therapeutically targeted in response to infections to promote activation of progenitor cell types remains elusive. Here, we report that loss of Abl1 specifically in SCGB1A1-expressing cells leads to a significant increase in the proliferation and differentiation of bronchiolar epithelial cells, resulting in dramatic expansion of an SCGB1A1+ airway cell population that coexpresses SPC, a marker for type II alveolar cells that promotes alveolar regeneration following bacterial pneumonia. Furthermore, treatment with an Abl-specific allosteric inhibitor enhanced regeneration of the alveolar epithelium and promoted accelerated recovery of mice following pneumonia. These data reveal a potential actionable target that may be exploited for efficient recovery after pathogen-induced infections.

Original languageEnglish
Pages (from-to)1603-1612
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number5
DOIs
StatePublished - Jan 29 2019

Keywords

  • Abl kinases
  • Alveolar injury
  • Lung regeneration
  • Pneumonia

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