title: Decreased CXCL12 is associated with impaired alveolar epithelial cell migration and poor lung healing after lung resection.
abstract: BACKGROUND
  Prolonged air leak (PAL) is an important cause of morbidity and mortality after lung resection, but its pathogenesis has not been elucidated. Migration of alveolar type II epithelial cells is essential for lung wound repair. Here we determined the role of C-X-C motif chemokine 12 (CXCL12) on alveolar epithelial cell migration and lung wound healing.
  
  
  METHODS
  CXCL12 in the pleural fluid of patients was analyzed using enzyme-linked immunosorbent assay. Human A549 and murine MLE12 alveolar epithelial cell lines were used for wound closure, cell migration, and proliferation assays. Western blot was used to analyze Rac1 and cofilin.
  
  
  RESULTS
  Pleural CXCL12 was decreased in patients with PAL (1,389 ± 192 vs 3,270 ± 247 pg/mL; P < .0001). CXCL12 enhanced scratch wound closure in both A549 (77.9 ± 0.7% vs 71.5 ± 0.4%; P = .0016) and MLE12 (92.9 ± 4.9% vs 66.0 ± 4.8%; P = .017). CXCL12 enhanced migration by 57% in A549 (P = .0008) and by 86% in MLE12 (P < .0001). AMD3100, a selective CXCR4 antagonist, prevented the effects of CXCL12. CXCL12 increased Rac1 and cofilin activation but did not change bromodeoxyuridine incorporation or cell counts.
  
  
  CONCLUSIONS
  Reduced pleural CXCL12 is associated with PAL. CXCL12 promotes alveolar epithelial cell migration by binding to its receptor CXCR4 and may have a role in lung healing. CXCL12-mediated alveolar epithelial cell migration is associated with Rac1 and cofilin activation.
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Kanter
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors.forename: Haiying
authors.initials: H
authors.lastname: Sun
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chiu
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors.forename: Malcolm M
authors.initials: MM
authors.lastname: DeCamp
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL; Jesse Brown Veterans Affairs Medical Center, Chicago, IL.
authors.forename: Peter H S
authors.initials: PH
authors.lastname: Sporn
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL. Electronic address: abharat@nm.org.
authors.forename: Ankit
authors.initials: A
authors.lastname: Bharat
mesh_terms: D000328:Adult; D000368:Aged; D056809:Alveolar Epithelial Cells / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008171:Lung Diseases / Q000209:etiology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D011013:Pneumonectomy; D011183:Postoperative Complications / Q000209:etiology* / Q000503:physiopathology; D011184:Postoperative Period; D014945:Wound Healing / Q000502:physiology*
chemical_list: D015415:Biomarkers; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12