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Proteomic Profiling of Hypoplastic Lungs Suggests an Underlying Inflammatory Response in the Pathogenesis of Abnormal

Richard Wagner1,2,3,4, Paula Lieckfeldt1,2,3,4, Hadeesha Piyadasa3,5,6

  • 1Departments of Surgery, Division of Pediatric Surgery, Pediatrics & Child Health, University of Manitoba, Winnipeg, MB, Canada.

Annals of Surgery
|August 3, 2022
PubMed

Insights

Congenital diaphragmatic hernia (CDH) causes abnormal lung development. This study found inflammatory pathways, particularly STAT3 signaling, are key to lung hypoplasia in CDH, offering new therapeutic targets.

Area of Science:

  • Developmental Biology
  • Proteomics
  • Neonatal Pathology

Background:

  • Congenital diaphragmatic hernia (CDH) is a severe birth defect characterized by abnormal lung development and high mortality.
  • The precise mechanisms driving lung hypoplasia in CDH remain poorly understood, hindering effective treatment strategies.

Purpose of the Study:

  • To investigate the proteomic differences in fetal lungs affected by CDH compared to controls.
  • To identify key molecular pathways and proteins involved in the pathogenesis of CDH-induced lung hypoplasia.
  • To explore potential therapeutic targets for improving lung development in CDH.

Main Methods:

  • Comparative proteomic analysis of fetal rat lungs exposed to nitrofen (CDH model) versus vehicle controls.
  • Pathway analysis to identify enriched biological processes in CDH lungs.
  • Immunohistochemical analysis of Tenascin C and STAT3 expression in rat and human CDH lungs.
  • Ex vivo experiments using fetal rat lung explants to assess the effect of STAT3 inhibition.
  • Analysis of cytokine levels in fetal tracheal aspirates from CDH patients.

Main Results:

  • Proteomic analysis revealed significant enrichment of inflammatory response proteins, including cytokine signaling and Epstein Barr Virus pathways, in nitrofen-induced CDH lungs.
  • Tenascin C was decreased, while STAT3 was significantly increased in the airway epithelium of CDH lungs.
  • STAT3 inhibition partially rescued the lung hypoplasia phenotype ex vivo, promoting peripheral lung budding.
  • Elevated levels of STAT3-associated cytokines (IL-15, IL-9, IL-2) were observed in CDH survivors' tracheal aspirates.

Conclusions:

  • Downstream inflammatory processes, driven by STAT3 signaling, are critically involved in the pathogenesis of abnormal lung development in CDH.
  • Targeting STAT3 signaling presents a potential therapeutic strategy to improve lung development in CDH patients.
  • This study provides novel insights into the molecular mechanisms underlying CDH lung hypoplasia using an unbiased proteomics approach.

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