Adrenomedullin Deficiency Potentiates Lipopolysaccharide-Induced Experimental Bronchopulmonary Dysplasia in Neonatal Mice

Amrit K. Shrestha, Renuka T. Menon, Chandrasekhar Yallampalli, Roberto Barrios, Binoy Shivanna

Research output: Contribution to journalArticlepeer-review

Abstract

Lung inflammation interrupts alveolarization and causes bronchopulmonary dysplasia (BPD). Besides mechanical ventilation and hyperoxia, sepsis contributes to BPD pathogenesis. Adrenomedullin (Adm) is a multifunctional peptide that exerts anti-inflammatory effects in the lungs of adult rodents. Whether Adm mitigates sepsis-induced neonatal lung injury is unknown. The lung phenotype of mice exposed to early postnatal lipopolysaccharide (LPS) was recently shown to be similar to that in human BPD. This model was used to test the hypothesis that Adm-deficient neonatal mice will display increased LPS-induced lung injury than their wild-type (WT) littermates. Adm-deficient mice or their WT littermates were intraperitoneally administered 6 mg/kg of LPS or vehicle daily on postnatal days (PNDs) 3 to 5. The lungs were harvested at several time points to quantify inflammation, alveolarization, and vascularization. The extent of LPS-induced lung inflammation in Adm-deficient mice was 1.6-fold to 10-fold higher than their WT littermates. Strikingly, Adm deficiency induced STAT1 activation and potentiated STAT3 activation in LPS-exposed lungs. The severity of LPS-induced interruption of lung development was also greater in Adm-deficient mice at PND7. At PND14, LPS-exposed WT littermates displayed substantial improvement in lung development, whereas LPS-exposed Adm-deficient mice continued to have decreased lung development. These data indicate that Adm is necessary to decrease lung inflammation and injury and promote repair of the injured lungs in LPS-exposed neonatal mice.

Original languageEnglish (US)
Pages (from-to)2080-2090
Number of pages11
JournalAmerican Journal of Pathology
Volume191
Issue number12
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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