This Article Full Text Full Text (PDF) All Versions of this Article: 200902-0215OCv1 180/12/1239    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kumarasamy, A. Articles by Morty, R. E. PubMed PubMed Citation Articles by Kumarasamy, A. Articles by Morty, R. E.

Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

¹ Department of Internal Medicine, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany; ² Department of Pediatric Surgery, and ⁴ Department of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands; ³ Departments of Anesthesia and Critical Care, Pediatrics and Medicine, and the Cardiovascular Research Center, Massachusetts General Hospital, Boston, and Harvard Medical School, Cambridge, Massachusetts; ⁵ Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; ⁶ Institute of Lung Biology and Disease, Helmholz Zentrum, Munich, Germany

Correspondence and requests for reprints should be addressed to Rory E. Morty, Ph.D., Department of Internal Medicine, University of Giessen Lung Center, Justus Liebig University, Aulweg 123 (Room 6-11), D-35392 Giessen, Germany. E-mail: rory.morty{at}innere.med.uni-giessen.de

Rationale: Disordered extracellular matrix production is a feature of bronchopulmonary dysplasia (BPD). The basis of this phenomenon is not understood.

Objectives: To assess lysyl oxidase expression and activity in the injured developing lungs of newborn mice and of prematurely born infants with BPD or at risk for BPD.

Methods: Pulmonary lysyl oxidase and elastin gene and protein expression were assessed in newborn mice breathing 21 or 85% oxygen, in patients who died with BPD or were at risk for BPD, and in control patients. Signaling by transforming growth factor (TGF-β) was preemptively blocked in mice exposed to hyperoxia using TGF-β–neutralizing antibodies. Lysyl oxidase promoter activity was assessed using plasmids containing the lox or loxl1 promoters fused upstream of the firefly luciferase gene.

Measurements and Main Results: mRNA and protein levels and activity of lysyl oxidases (Lox, LoxL1, LoxL2) were elevated in the oxygen-injured lungs of newborn mice and infants with BPD or at risk for BPD. In oxygen-injured mouse lungs, increased TGF-β signaling drove aberrant lox, but not loxl1 or loxl2, expression. Lox expression was also increased in oxygen-injured fibroblasts and pulmonary artery smooth muscle cells.

Conclusions: Lysyl oxidase expression and activity are dysregulated in BPD in injured developing mouse lungs and in prematurely born infants. In developing mouse lungs, aberrant TGF-β signaling dysregulated lysyl oxidase expression. These data support the postulate that excessive stabilization of the extracellular matrix by excessive lysyl oxidase activity might impede the normal matrix remodeling that is required for pulmonary alveolarization and thereby contribute to the pathological pulmonary features of BPD.

Key Words: lung development • septation • TGF-β • transforming growth factor

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The formation of extracellular matrix structures is perturbed in bronchopulmonary dysplasia (BPD), which is believed to contribute to the arrested alveolarization seen in "new BPD." What This Study Adds to the Field The expression and activity of lysyl oxidases, which regulate collagen and elastin cross-linking, are dysregulated in BPD in mice and humans. These data could suggest that overstabilization of the extracellular matrix may impede normal matrix remodeling, thereby creating a less plastic lung structure.