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Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity.

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) EMAP II 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 club-cell-specific protein-derived factor that later is expressed in galectin-3+ macrophages as BPD progresses. Continuous elevated expression corroborates with baboon and human BPD. Prolonged elevation of EMAP II levels recruits galectin-3+ 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.

SUBMITTER: Lee DD

PROVIDER: S-EPMC5070113 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity.

Lee Daniel D DD Lal Charitharth V CV Persad Elizabeth A EA Lowe Chinn-Woan CW Schwarz Anna M AM Awasthi Niranjan N Schwarz Roderich E RE Schwarz Margaret A MA

American journal of respiratory cell and molecular biology 20161001 4

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 mod ...[more]

PMID: 27254784

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Project description:Endothelial monocyte‑activating polypeptide II (EMAP II) is a sensitive marker of neurotoxic injury, the expression of which increases significantly under conditions of stress, such as hypoxia or apoptosis. Studies have confirmed the extensive apoptosis of nerve cells in the brain following status epilepticus (SE), and the occurrence of SE can confer a hypoxic state on cells. The purpose of the present study was to observe the changes in the expression of EMAP II, and in the numbers and tight junction protein levels of microvascular endothelial cells in the hippocampus of rats with pilocarpine‑induced SE. The protein expression levels of EMAP II, CD31, zonula occludens 1 (ZO‑1) and occludin in the hippocampus were determined by immunofluorescence and western blot analyses. It was found that almost 75.6% of the rats in the SE group developed Racine stage IV‑V seizures at approximately 44.7±18.8 min after the pilocarpine administration, and the 24‑h mortality rate was almost 10.4%. The weight of the rats in the SE group was significantly decreased within 24 h following SE. Immunofluorescence staining revealed a low EMAP II expression in the hippocampus of the rats in the control group; however, the numbers of EMAP II‑positive cells were significantly increased in the SE group from 2 h to 21 days. The trend of EMAP II protein expression was consistent with that obtained with immunofluorescence staining. The numbers of CD31‑positive microvascular endothelial cells were significantly increased from 24 h to 21 days compared with the levels in the control group. The protein expression of ZO‑1 and occludin was most significantly decreased in the SE group. On the whole, the present study demonstrated that the expression of EMAP II in the rat hippocampus was upregulated in the SE model, which may promote angiogenesis and alter the TJ integrity of brain microvascular endothelial cells, with an increased number of CD31‑positive microvascular endothelial cells and a decreased expression of ZO‑1 and occludin.

Dataset Information

Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity.

Publications

Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity.

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