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

BackgroundPrenatal 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.MethodsNewborn 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.ResultsL-CIT protected the newborn rat lung from LPS-induced: lung histopathology, ROS production, NF & kappa;B nuclear translocation, and upregulation of gene and protein expression of inflammatory cytokines (IL-1 & beta;, IL-8, MCP-1 & alpha;, and TNF-& alpha;). L-CIT maintained mitochondrial morphology, increased protein levels of PGC-1 & alpha;, NRF1, and TFAM (transcription factors involved in mitochondrial biogenesis), and induced SIRT1, SIRT3, and superoxide dismutases protein expression.ConclusionL-CIT may be efficacious in decreasing early lung inflammation and oxidative stress mitigating progression to BPD.ImpactThe 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.