JNK suppresses pulmonary fibroblast elastogenesis during alveolar development

Abstract

BackgroundThe 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.MethodsAlveolar 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.ResultsBy 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.ConclusionsJNK suppresses fibroblast elastogenesis during the alveolar stage of lung development.

Involvement of c-Jun N-Terminal Kinase in TNF-α–Driven Remodeling

“…The data from SPC-TNF-a mice in this study are in line with a study showing that mice lacking JNK1 are protected against TGF-b-induced pulmonary fibrosis and fibrotic gene expression (31,32). This is also supported by another study showing that JNK knockout mice were found to have an increased pulmonary elastin content compared with wild-type mice, and showed increased elastogenesis, but had impaired alveolar septation during lung development (33). In addition, the JNK inhibitor, SP600125, partly prevented bleomycin-induced hydroxyproline and a smooth muscle actin levels in the lung tissue of rats, and thalidomide, an immunomodulatory drug able to suppress the generation of TNF-a, prevented the induction of JNK phosphorylation and hydroxyproline and a smooth muscle actin levels even more (34).…”

Three‐Dimensional Micro Computed Tomography Analysis of the Lung Vasculature and Differential Adipose Proteomics in the Sugen/Hypoxia Rat Model of Pulmonary Arterial Hypertension

“…10 The relatively small areas of lipidladen positive cells surrounding the vasculature within the lung tissue need further characterization. 54,55 We also detected extensive FABP4 labeling throughout both SU/hyp and control lung tissue not colocalized with the lipid-laden cells. FABP4 can also be produced by macrophages, which are readily abundant in both healthy lung tissue (alveolar spaces) and severe PAH-associated lung tissue (pulmonary lesions).…”

Remodeling of the pulmonary artery in idiopathic pleuroparenchymal fibroelastosis

“…Elastic fibers originally provide recoil tension to restore the structure of vascular tissues or organs and are essential for their function 17 . However, once elastic fibers are produced in a disorderly manner, they diminish the proper function of organs, leading to-for instance-restrictive ventilatory dysfunction in PPFE patients 6,18 .…”

“…However, once elastic fibers are produced in a disorderly manner, they diminish the proper function of organs, leading to-for instance-restrictive ventilatory dysfunction in PPFE patients 6,18 . Regulators of elastogenesis include transforming growth factor-β, fibroblast growth factor-2, epidermal growth factor, and insulin-like growth factor-1 17 . It is unknown whether these mediators contribute to the formation of subpleural fibroelastosis or medial elastosis in PPFE.…”