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

Author:

Shrestha Amrit Kumar1ORCID,Menon Renuka T.1,El-Saie Ahmed1,Barrios Roberto2,Reynolds Corey3,Shivanna Binoy1

Affiliation:

1. Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas

2. Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas

3. Mouse Phenotyping Core, Baylor College of Medicine, Houston, Texas

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.

Funder

National Institutes of Health

National Institutes of Heath

Publisher

American Physiological Society

Subject

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

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