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Leukocyte Inflammatory Mediators and Lung Physiology

Thymulin evokes IL-6-C/EBP regenerative repair and TNF- silencing during endotoxin exposure in fetal lung explants

Tayside Institute of Child Health, Maternal and Child Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, United Kingdom

Submitted 20 November 2002 ; accepted in final form 13 March 2003

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 PO₂ explants. LPS (50 µg/ml) depressed ASC in both conditions to untreated ambient PO₂ control values without changes in necrosis or apoptosis. To manipulate LPS-evoked TNF- 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- and IL-6 release, yielding an IC_50(TNF-) of 0.5 ± 0.01 ng/ml and EC_50(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- and IL-6 transcripts at ambient PO₂. LPS+thymulin+Zn²⁺-treated explants showed proliferation of CCAAT-enhancer binding protein- (C/EBP) and fibroblast growth factor-9 immunoreactive mesenchyme, which was abolished by IL-6 antisense oligonucleotides. The posttranscriptional suppression of immunogenic TNF- synthesis coupled with raised IL-6 and C/EBP-dependent mesenchyme proliferation suggests a role for bioactive thymulin in regulating regenerative repair in the fetal lung.

bronchopulmonary dysplasia; lung morphogenesis; mitogen-activated protein kinase; fibroblast growth factor; cytoprotection

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