A murine model of acute lung injury identifies growth factors to promote tissue repair and their biomarkers

Genes Cells. 2019 Feb;24(2):112-125. doi: 10.1111/gtc.12659. Epub 2018 Dec 18.


Type II alveolar epithelial cells (AEC2s) play a crucial role in the regeneration of type I AECs after acute lung injury. The mechanisms underlying the regeneration of AEC2s are not fully understood. To address this issue, here, we investigated a murine model of acute lung injury using mice expressing human Diphtheria Toxin Receptor (DTR) under the control of Lysozyme M promoter (LysM-DTR). DT injection induced the depletion of AEC2s, alveolar macrophages, and bone marrow (BM)-derived myeloid cells in LysM-DTR mice, and the mice died within 6 days after DT injection. Apoptotic AEC2s and bronchiolar epithelial cells appeared at 24 hr, whereas Ki67-positive proliferating cells appeared in the alveoli and bronchioles in the lung of LysM-DTR mice at 72-96 hr after DT injection. Transfer of wild-type BM cells into LysM-DTR mice accelerated the regeneration of AEC2s along with the up-regulation of several growth factors. Moreover, several metabolites were significantly decreased in the sera of LysM-DTR mice compared with WT mice after DT injection, suggesting that these metabolites might be biomarkers to predict AEC2s injury. Together, LysM-DTR mice might be useful to identify growth factors to promote lung repair and the metabolites to predict the severity of lung injury.

Keywords: Diphtheria toxin receptor; apoptosis; biomarker; bronchiolar epithelial cell; growth factors; interleukin 11; lung injury; tissue repair; type II alveolar epithelial cell (AEC).

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / metabolism
  • Acute Lung Injury / pathology
  • Acute Lung Injury / prevention & control*
  • Alveolar Epithelial Cells / cytology*
  • Animals
  • Biomarkers / metabolism*
  • Bone Marrow Transplantation*
  • Diphtheria Toxin / toxicity
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Heparin-binding EGF-like Growth Factor / physiology*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Metabolome*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muramidase / genetics
  • Promoter Regions, Genetic
  • Wound Healing


  • Biomarkers
  • Diphtheria Toxin
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Muramidase
  • lysozyme M, mouse