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Proteomic Profiling of Hypoplastic Lungs Suggests an Underlying Inflammatory Response in the Pathogenesis of Abnormal Lung Development in Congenital Diaphragmatic Hernia.
Wagner, Richard; Lieckfeldt, Paula; Piyadasa, Hadeesha; Markel, Moritz; Riedel, Jan; Stefanovici, Camelia; Peukert, Nicole; Patel, Daywin; Derraugh, Gabrielle; Min, Suyin A Lum; Gosemann, Jan-Hendrik; Deprest, Jan; Pascoe, Christopher D; Tse, Wai Hei; Lacher, Martin; Mookherjee, Neeloffer; Keijzer, Richard.
Afiliação
  • Wagner R; Departments of Surgery, Division of Pediatric Surgery, Pediatrics & Child Health, University of Manitoba, Winnipeg, MB, Canada.
  • Lieckfeldt P; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.
  • Piyadasa H; Biology of Breathing Theme, Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.
  • Markel M; Department of Pediatric Surgery, University Hospital Leipzig, Leipzig, Germany.
  • Riedel J; Departments of Surgery, Division of Pediatric Surgery, Pediatrics & Child Health, University of Manitoba, Winnipeg, MB, Canada.
  • Stefanovici C; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.
  • Peukert N; Biology of Breathing Theme, Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.
  • Patel D; Department of Pediatric Surgery, University Hospital Leipzig, Leipzig, Germany.
  • Derraugh G; Biology of Breathing Theme, Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.
  • Min SAL; Manitoba Center for Proteomics and Systems Biology, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.
  • Gosemann JH; Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.
  • Deprest J; Departments of Surgery, Division of Pediatric Surgery, Pediatrics & Child Health, University of Manitoba, Winnipeg, MB, Canada.
  • Pascoe CD; Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.
  • Tse WH; Biology of Breathing Theme, Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.
  • Lacher M; Department of Pediatric Surgery, University Hospital Leipzig, Leipzig, Germany.
  • Mookherjee N; Department of Pediatric Surgery, University Hospital Leipzig, Leipzig, Germany.
  • Keijzer R; Department of Pathology, University of Manitoba, and Shared Services Manitoba, Winnipeg, MB, Canada.
Ann Surg ; 278(2): e411-e421, 2023 08 01.
Article em En | MEDLINE | ID: mdl-35920560
The pathogenesis of lung hypoplasia in congenital diaphragmatic hernia (CDH), a common birth defect, is poorly understood. The diaphragmatic defect can be repaired surgically, but the abnormal lung development contributes to a high mortality in these patients. To understand the underlying pathobiology, we compared the proteomic profiles of fetal rat lungs at the alveolar stage (E21) that were either exposed to nitrofen in utero (CDH lungs, n=5) or exposed to vehicle only (non-CDH control lungs, n=5). Pathway analysis of proteomic datasets showed significant enrichment in inflammatory response proteins associated with cytokine signaling and Epstein Barr Virus in nitrofen CDH lungs. Among the 218 significantly altered proteins between CDH and non-CDH control lungs were Tenascin C, CREBBP, LYN, and STAT3. We showed that Tenascin C was decreased around the distal airway branches in nitrofen rat lungs and human CDH lungs, obtained from stillborn fetuses that did not receive pre- or postnatal treatment. In contrast, STAT3 was significantly increased in the airway epithelium of nitrofen lungs at E21. STAT3 inhibition after direct nitrofen exposure to fetal rat lung explants (E14.5) partially rescued the hypoplastic lung phenotype ex vivo by increasing peripheral lung budding. Moreover, we demonstrated that several STAT3-associated cytokines (IL-15, IL-9, andIL-2) are increased in fetal tracheal aspirates of CDH survivors compared with nonsurvivors after fetoscopic endoluminal tracheal occlusion. With our unbiased proteomics approach, we showed for the first time that downstream inflammatory processes are likely involved in the pathogenesis of abnormal lung development in CDH.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Infecções por Vírus Epstein-Barr / Hérnias Diafragmáticas Congênitas / Pneumopatias Tipo de estudo: Etiology_studies Limite: Animals / Humans Idioma: En Revista: Ann Surg Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Infecções por Vírus Epstein-Barr / Hérnias Diafragmáticas Congênitas / Pneumopatias Tipo de estudo: Etiology_studies Limite: Animals / Humans Idioma: En Revista: Ann Surg Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Canadá