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

TY - JOUR

T1 - Thymulin evokes IL-6-C/EBP beta regenerative repair and TNF-alpha silencing during endotoxin exposure in fetal lung explants

AU - Land, Stephen C.

AU - Darakhshan, Froogh

N1 - dc.publisher: American Physiological Society The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. dc.description.sponsorship: Medical Research Council (UK) Wellcome Trust Tenovus (Scotland) Anonymous Trust

PY - 2004

Y1 - 2004

N2 - 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/varea2) 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-a 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-a and IL-6 release, yielding an IC50(TNF-a) 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-a 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-a 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.

AB - 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/varea2) 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-a 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-a and IL-6 release, yielding an IC50(TNF-a) 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-a 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-a 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.

KW - Bronchopulmonary dysplasia

KW - Lung morphogenesis

KW - Mitogen-activated protein kinase

KW - Fibroblast growth factor

KW - Cytoprotection

KW - Tumour necrosis factor-alpha immunology

KW - CCAAT-Enhancer-Binding Protein-beta immunology

KW - Interleukin-6 immunology

KW - Lung immunology

KW - Thymic factor

U2 - 10.1152/ajplung.00401.2002

DO - 10.1152/ajplung.00401.2002

M3 - Article

C2 - 12639846

SN - 1040-0605

VL - 286

SP - L473-L487

JO - American Journal of Physiology: Lung Cellular and Molecular Physiology

JF - American Journal of Physiology: Lung Cellular and Molecular Physiology

IS - 3

ER -