Endothelial monocyte-activating polypeptide II mediates macrophage migration in the development of hyperoxia-induced lung disease of prematurity

Daniel D. Lee, Charitharth V. Lal, Elizabeth A. Persad, Chinn Woan Lowe, Anna M. Schwarz, Niranjan Awasthi, Roderich E. Schwarz, Margaret Schwarz

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Myeloid cells are key factors in the progression of bronchopulmonary dysplasia (BPD) pathogenesis. Endothelial monocyte-activating polypeptide II (EMAP II) mediates myeloid cell trafficking. The origin and physiological mechanism by which EMAP II affects pathogenesis in BPD is unknown. The objective was to determine the functional consequences of elevated EMAP II levels in the pathogenesis of murine BPD and to investigate EMAP II neutralization as a therapeutic strategy. Three neonatal mouse models were used: (1)BPD(hyperoxia), (2)EMAPII delivery, and (3) BPD with neutralizing EMAP II antibody treatments. Chemokinic function of EMAP II and its neutralization were assessed by migration in vitro and in vivo. We determined the location of EMAP II by immunohistochemistry, pulmonary proinflammatory and chemotactic gene expression by quantitative polymerase chain reaction and immunoblotting, lung outcome by pulmonary function testing and histological analysis, and right ventricular hypertrophy by Fulton's Index. In BPD, EMAP II initially is a bronchial clubcell-specific protein-derived factor that later is expressed in galectin-31 macrophages as BPD progresses. Continuous elevated expression corroborates with baboon and human BPD. Prolonged elevation ofEMAP II levels recruits galectin-31 macrophages,which is followed by an inflammatory state that resembles a severe BPD phenotype characterized by decreased pulmonary compliance, arrested alveolar development, and signs of pulmonary hypertension. In vivo pharmacological EMAP II inhibition suppressed proinflammatory genes Tnfa, Il6, and Il1b and chemotactic genes Ccl2 and Ccl9 and reversed the severe BPD phenotype. EMAP II is sufficient to induce macrophage recruitment, worsens BPD progression, and represents a targetable mechanism of BPD development.

Original languageEnglish (US)
Pages (from-to)602-612
Number of pages11
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume55
Issue number4
DOIs
StatePublished - Oct 1 2016

Fingerprint

Bronchopulmonary Dysplasia
Pulmonary diseases
Hyperoxia
Macrophages
Lung Diseases
Galectins
Myeloid Cells
Lung
Genes
small inducible cytokine subfamily E, member 1
Polymerase chain reaction
Right Ventricular Hypertrophy
Phenotype
Lung Compliance
Gene expression
Papio
Immunoblotting
Pulmonary Hypertension

Keywords

  • Bronchopulmonary dysplasia
  • Endothelial monocyte-activating polypeptide II
  • Inflammation
  • Lung

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Endothelial monocyte-activating polypeptide II mediates macrophage migration in the development of hyperoxia-induced lung disease of prematurity. / Lee, Daniel D.; Lal, Charitharth V.; Persad, Elizabeth A.; Lowe, Chinn Woan; Schwarz, Anna M.; Awasthi, Niranjan; Schwarz, Roderich E.; Schwarz, Margaret.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 55, No. 4, 01.10.2016, p. 602-612.

Research output: Contribution to journalArticle

Lee, Daniel D. ; Lal, Charitharth V. ; Persad, Elizabeth A. ; Lowe, Chinn Woan ; Schwarz, Anna M. ; Awasthi, Niranjan ; Schwarz, Roderich E. ; Schwarz, Margaret. / Endothelial monocyte-activating polypeptide II mediates macrophage migration in the development of hyperoxia-induced lung disease of prematurity. In: American Journal of Respiratory Cell and Molecular Biology. 2016 ; Vol. 55, No. 4. pp. 602-612.
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