Thymulin evokes IL-6-C/EBPβ regenerative repair and TNF-α silencing during endotoxin exposure in fetal lung explants
| Autor: | Froogh Darakhshan, Stephen C. Land |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Fibroblast Growth Factor 9
Lipopolysaccharides Pulmonary and Respiratory Medicine Thymic Factor Circulating Transcription Genetic Physiology Cellular differentiation Adenocarcinoma Protein Serine-Threonine Kinases Chorioamnionitis Mesoderm Thymulin chemistry.chemical_compound Fetus Adjuvants Immunologic Cell Line Tumor Physiology (medical) medicine Humans Gene silencing Interleukin 6 Lung Hyperplasia biology Interleukin-6 Tumor Necrosis Factor-alpha CCAAT-Enhancer-Binding Protein-beta Intracellular Signaling Peptides and Proteins Cell Differentiation Cell Biology medicine.disease Fibroblast Growth Factors Oxygen Zinc medicine.anatomical_structure chemistry Immunology biology.protein Lung morphogenesis Fibroblast Growth Factor 10 Cell Division Signal Transduction |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 286:L473-L487 |
| ISSN: | 1522-1504 1040-0605 |
| DOI: | 10.1152/ajplung.00401.2002 |
| Popis: | Chorioamnionitis is associated with increased risks of perinatal respiratory failure; however, components of the inflammatory acute-phase response are known to actively promote lung maturation. To manipulate this relationship, we examined the effect of the thymic immunomodulator thymulin on fetal lung mesenchyme-epithelial differentiation during exposure to Escherichia coli lipopolysaccharide (LPS). Gestation day 14 fetal rat lung explants were cultured for 96 h at fetal (23 mmHg) or ambient (142 mmHg) Po2. Airway surface complexity (ASC, perimeter/√area2) was greater at fetal vs. ambient Po2; however, exposure to 0.1–50 μg/ml LPS significantly raised ASC at 2 μg/ml in ambient Po2explants. LPS (50 μg/ml) depressed ASC in both conditions to untreated ambient Po2control values without changes in necrosis or apoptosis. To manipulate LPS-evoked TNF-α and IL-6 release, we exposed explants and A549 cells to combinations of 50 μg/ml LPS, 10 μM ZnCl2, and 0.1–1,000 ng/ml thymulin at either Po2. Thymulin+Zn2+suppressed and potentiated LPS-evoked TNF-α and IL-6 release, yielding an IC50(TNF-α)of 0.5 ± 0.01 ng/ml and EC50(IL-6)of 1.4 ± 0.3 ng/ml in A549 cells. This was accompanied by activation of the p38 MAPKMAPKAP-K2 pathway with sustained expression of TNF-α and IL-6 transcripts at ambient Po2. LPS+thymulin+Zn2+-treated explants showed proliferation of CCAAT-enhancer binding protein-β (C/EBPβ) and fibroblast growth factor-9 immunoreactive mesenchyme, which was abolished by IL-6 antisense oligonucleotides. The posttranscriptional suppression of immunogenic TNF-α synthesis coupled with raised IL-6 and C/EBPβ-dependent mesenchyme proliferation suggests a role for bioactive thymulin in regulating regenerative repair in the fetal lung. |
| Databáze: | OpenAIRE |
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