Pre- and Postnatal Lung Development, Maturation, and Plasticity: MEK-1/2 inhibition reduces branching morphogenesis and causes mesenchymal cell apoptosis in fetal rat lungs
1 Pediatric Surgical Research Laboratories, Pediatric Surgical Services, and the Department of Surgery; and 2 Laboratory of Developmental Immunology and the Department of Pediatrics; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 The roles of the mitogen-activa...
Gespeichert in:
Veröffentlicht in: | American journal of physiology. Lung cellular and molecular physiology 2002-03, Vol.282 (3), p.370 |
---|---|
Hauptverfasser: | , , , , , |
Format: | Artikel |
Sprache: | eng |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | 1 Pediatric Surgical Research Laboratories, Pediatric
Surgical Services, and the Department of Surgery; and
2 Laboratory of Developmental Immunology and the Department of
Pediatrics; Massachusetts General Hospital, Harvard Medical School,
Boston, Massachusetts 02114
The roles of the
mitogen-activated protein (MAP) kinases extracellular signal-regulated
kinases-1 and -2 (ERK-1/2) in fetal lung development have not been
extensively characterized. To determine if ERK-1/2 signaling plays a
role in fetal lung branching morphogenesis, U-0126, an inhibitor of the
upstream kinase MAP ERK kinase (MEK), was added to fetal lung
explants in vitro. Morphometry as measured by branching, area,
perimeter, and complexity were significantly reduced in
U-0126-treated lungs. At the same time, U-0126 treatment reduced ERK-1/2, slightly increased p38 kinase, but did not change c-Jun NH 2 -terminal kinase activities, indicating that
U-0126 specifically inhibited the ERK-1/2 enzymes. These changes were
associated with increased apoptosis as measured by terminal
deoxynucleotidyl transferase-mediated dUTP nick end labeling and
immunofluorescent labeling of anti-active caspase-3 in the mesenchyme
of explants after U-0126 treatment compared with the control. Mitosis
characterized by immunolocalization of proliferating cell nuclear
antigen was found predominantly in the epithelium and was reduced in
U-0126-treated explants. Thus U-0126 causes specific inhibition of
ERK-1/2 signaling, diminished branching morphogenesis, characterized by
increased mesenchymal apoptosis, and decreased epithelial
proliferation in fetal lung explants.
lung development; mitogen-activated protein kinase; extracellular
signal-regulated kinase; U-0126 |
---|---|
ISSN: | 1040-0605 1522-1504 |
DOI: | 10.1152/ajplung.00200.2001 |