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JNK suppresses pulmonary fibroblast elastogenesis during alveolar development Liu S; Parameswaran H; Young SM; Varisco BMRespir Res 2014[Mar]; 15 (1): 34BACKGROUND: The formation of discrete elastin bands at the tips of secondary alveolar septa is important for normal alveolar development, but the mechanisms regulating the lung elastogenic program are incompletely understood. JNK suppress elastin synthesis in the aorta and is important in a host of developmental processes. We sought to determine whether JNK suppresses pulmonary fibroblast elastogenesis during lung development. METHODS: Alveolar size, elastin content, and mRNA of elastin-associated genes were quantitated in wild type and JNK-deficient mouse lungs, and expression profiles were validated in primary lung fibroblasts. Tropoelastin protein was quantitated by Western blot. Changes in lung JNK activity throughout development were quantitated, and pJNK was localized by confocal imaging and lineage tracing. RESULTS: By morphometry, alveolar diameters were increased by 7% and lung elastin content increased 2-fold in JNK-deficient mouse lungs compared to wild type. By Western blot, tropoelastin protein was increased 5-fold in JNK-deficient lungs. Postnatal day 14 (PND14) lung JNK activity was 11-fold higher and pJNK:JNK ratio 6-fold higher compared to PN 8 week lung. Lung tropoelastin, emilin-1, fibrillin-1, fibulin-5, and lysyl oxidase mRNAs inversely correlated with lung JNK activity during alveolar development. Phosphorylated JNK localized to pulmonary lipofibroblasts. PND14 JNK-deficient mouse lungs contained 7-fold more tropoelastin, 2,000-fold more emilin-1, 800-fold more fibrillin-1, and 60-fold more fibulin-5 than PND14 wild type lungs. Primarily lung fibroblasts from wild type and JNK-deficient mice showed similar differences in elastogenic mRNAs. CONCLUSIONS: JNK suppresses fibroblast elastogenesis during the alveolar stage of lung development.|Animals[MESH]|Animals, Newborn[MESH]|Cells, Cultured[MESH]|Elasticity/*physiology[MESH]|Enzyme Activation/physiology[MESH]|Fibroblasts/*enzymology[MESH]|Lung/cytology/enzymology/growth & development[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Mice, Knockout[MESH]|Mice, Transgenic[MESH]|Mitogen-Activated Protein Kinase 8/*physiology[MESH]|Pulmonary Alveoli/cytology/*enzymology[MESH] |
