Interactive and independent effects of early lipopolysaccharide and hyperoxia exposure on developing murine lungs

Amrit Kumar Shrestha, Renuka T. Menon, Ahmed El-Saie, Roberto Barrios, Corey Reynolds, Binoy Shivanna

Research output: Contribution to journalArticlepeer-review

Abstract

Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is a chronic infantile lung disease that lacks curative therapies. Infants with BPD-associated PH are often exposed to hyperoxia and additional insults such as sepsis that contribute to disease pathogenesis. Animal models that simulate these scenarios are necessary to develop effective therapies; therefore, we investigated whether lipopolysaccharide (LPS) and hyperoxia exposure during saccular lung development cooperatively induce experimental BPD-PH in mice. C57BL/6J mice were exposed to normoxia or 70% O2 (hyperoxia) during postnatal days (PNDs) 1-5 and intraperitoneally injected with varying LPS doses or a vehicle on PNDs 3-5. On PND 14, we performed morphometry, echocardiography, and gene and protein expression studies to determine the effects of hyperoxia and LPS on lung development, vascular remodeling and function, inflammation, oxidative stress, cell proliferation, and apoptosis. LPS and hyperoxia independently and cooperatively affected lung development, inflammation, and apoptosis. Growth rate and antioxidant enzyme expression were predominantly affected by LPS and hyperoxia, respectively, while cell proliferation and vascular remodeling and function were mainly affected by combined exposure to LPS and hyperoxia. Mice treated with lower LPS doses developed adaptive responses and hyperoxia exposure did not worsen their BPD phenotype, whereas those mice treated with higher LPS doses displayed the most severe BPD phenotype when exposed to hyperoxia and were the only group that developed PH. Collectively, our data suggest that an additional insult such as LPS may be necessary for models utilizing short-term exposure to moderate hyperoxia to recapitulate human BPD-PH.

Original languageEnglish (US)
Pages (from-to)L981-L996
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume319
Issue number6
DOIs
StatePublished - Dec 18 2020

Keywords

  • Bronchopulmonary dysplasia
  • Hyperoxia
  • Inflammation
  • Lipopolysaccharide
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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