L-citrulline attenuates lipopolysaccharide-induced inflammatory lung injury in neonatal rats

Pediatr Res. 2023 Nov;94(5):1684-1695. doi: 10.1038/s41390-023-02684-1. Epub 2023 Jun 22.

Abstract

Background: Prenatal or postnatal lung inflammation and oxidative stress disrupt alveolo-vascular development leading to bronchopulmonary dysplasia (BPD) with and without pulmonary hypertension. L-citrulline (L-CIT), a nonessential amino acid, alleviates inflammatory and hyperoxic lung injury in preclinical models of BPD. L-CIT modulates signaling pathways mediating inflammation, oxidative stress, and mitochondrial biogenesis-processes operative in the development of BPD. We hypothesize that L-CIT will attenuate lipopolysaccharide (LPS)-induced inflammation and oxidative stress in our rat model of neonatal lung injury.

Methods: Newborn rats during the saccular stage of lung development were used to investigate the effect of L-CIT on LPS-induced lung histopathology and pathways involved in inflammatory, antioxidative processes, and mitochondrial biogenesis in lungs in vivo, and in primary culture of pulmonary artery smooth muscle cells, in vitro.

Results: L-CIT protected the newborn rat lung from LPS-induced: lung histopathology, ROS production, NFκB nuclear translocation, and upregulation of gene and protein expression of inflammatory cytokines (IL-1β, IL-8, MCP-1α, and TNF-α). L-CIT maintained mitochondrial morphology, increased protein levels of PGC-1α, NRF1, and TFAM (transcription factors involved in mitochondrial biogenesis), and induced SIRT1, SIRT3, and superoxide dismutases protein expression.

Conclusion: L-CIT may be efficacious in decreasing early lung inflammation and oxidative stress mitigating progression to BPD.

Impact: The nonessential amino acid L-citrulline (L-CIT) mitigated lipopolysaccharide (LPS)-induced lung injury in the early stage of lung development in the newborn rat. This is the first study describing the effect of L-CIT on the signaling pathways operative in bronchopulmonary dysplasia (BPD) in a preclinical inflammatory model of newborn lung injury. If our findings translate to premature infants, L-CIT could decrease inflammation, oxidative stress and preserve mitochondrial health in the lung of premature infants at risk for BPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Bronchopulmonary Dysplasia* / metabolism
  • Citrulline / metabolism
  • Citrulline / pharmacology
  • Disease Models, Animal
  • Female
  • Humans
  • Hyperoxia*
  • Infant, Newborn
  • Inflammation / metabolism
  • Lipopolysaccharides / pharmacology
  • Lung
  • Lung Injury*
  • Pneumonia* / metabolism
  • Pregnancy
  • Rats

Substances

  • Lipopolysaccharides
  • Citrulline