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A Murine Model of Fetal Exposure to Maternal Inflammation to Study the Effects of Acute Chorioamnionitis on Newborn Intestinal Development
Published on: June 24, 2020
Intra-amniotic LPS modulates expression of antimicrobial peptides in the fetal sheep lung
Augusto F Schmidt1, Paranthaman S Kannan1, Matthew W Kemp2
1Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
Background:
Damage-associated molecular patterns (DAMPs) and antimicrobial peptides (AMPs) are components of pulmonary innate immunity and tissue repair. We hypothesized that DAMPs and AMPs would increase in response to fetal pulmonary inflammation caused by chorioamnionitis in a time-dependent manner.
Methods:
Fetal sheep were exposed to intra-amniotic saline or lipopolysaccharide (LPS) (10 mg) between 5 h and 15 d prior to preterm delivery at 125 ± 2 d. Lung tissue mRNAs for proinflammatory cytokines; AMPs: myeloid AMP-29 (MAP29), dodecapeptide, sheep β-defensin-1 (SBD1), and sheep β-defensin-2 (SBD2); and DAMPs: interleukin (IL)-1α, lactoferrin, heat-shock protein-70 (HSP70), high-mobility group box protein-B1 (HMGB1), and receptor for advanced glycation endproducts (RAGE) were measured by reverse-transcriptase quantitative polymerase chain reaction. Immunohistochemistry of DAMPs and in situ hybridization of AMPs was performed.
Results:
IL-1α, IL-1β, IL-6, IL-8, IL-10, MCP-1, and tumor necrosis factor (TNF)-α mRNA increased after LPS exposure. MAP29, dodecapeptide, SBD1, and SBD2 mRNA were suppressed at 24 h. MAP29 and dodecapeptide mRNA then increased at 8 d. Lactoferrin increased at 24 h. There were no changes for HMGB1, HSP70, or RAGE. MAP29 and dodecapeptide localized to alveolar cells, increased 8 d after exposure to LPS.
Conclusion:
AMPs are initially suppressed in the fetal lung by LPS-induced chorioamnionitis. The late induction of MAP29 and dodecapeptide may be related to lung repair.
Insights
Antimicrobial peptides (AMPs) and damage-associated molecular patterns (DAMPs) initially decrease in fetal lungs during chorioamnionitis. Late increases in specific AMPs suggest a role in fetal lung repair following inflammation.
Area of Science:
- Pulmonary immunology
- Fetal development
- Innate immunity
Background:
- Damage-associated molecular patterns (DAMPs) and antimicrobial peptides (AMPs) are key components of pulmonary innate immunity and tissue repair.
- Fetal pulmonary inflammation, often caused by chorioamnionitis, can significantly impact lung development.
- The time-dependent changes in DAMPs and AMPs during fetal inflammation are not fully understood.
Purpose of the Study:
- To investigate the temporal changes in DAMPs and AMPs in the fetal sheep lung in response to lipopolysaccharide (LPS)-induced chorioamnionitis.
- To determine if these changes correlate with inflammatory responses and potential lung repair mechanisms.
Main Methods:
- Fetal sheep were exposed to LPS or saline intra-amniotically at varying times before preterm delivery.
- Lung tissue mRNA levels of specific DAMPs (IL-1α, lactoferrin, HSP70, HMGB1, RAGE) and AMPs (MAP29, dodecapeptide, SBD1, SBD2) were quantified using RT-qPCR.
- Immunohistochemistry and in situ hybridization were employed to localize DAMPs and AMPs in lung tissue.
Main Results:
- LPS exposure led to increased pro-inflammatory cytokine mRNA.
- Antimicrobial peptide (AMP) mRNAs (MAP29, dodecapeptide, SBD1, SBD2) were initially suppressed at 24 hours but increased by 8 days post-exposure.
- Specific DAMPs (lactoferrin) increased, while others (HMGB1, HSP70, RAGE) showed no significant changes. MAP29 and dodecapeptide localized to alveolar cells and increased late.
Conclusions:
- Lipopolysaccharide-induced chorioamnionitis initially suppresses antimicrobial peptides (AMPs) in the developing fetal lung.
- The delayed induction of certain AMPs, such as MAP29 and dodecapeptide, suggests a potential role in fetal lung tissue repair following inflammatory insults.
