106 - Hyperoxia-Induced Liver Injury: Elucidating Underlying Molecular Pathways in Newborn Rat Model

Publication Number: 2101.106

Mane Sargsyan, Cohen Children's Medical Center, GLEN OAKS, NY, United States; Sohini Alim, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Dix Hills, NY, United States; Namita Sen, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, flushing, NY, United States; Elizabeth A. Eckman, MidAtlantic Neonatology Associates, Morristown, NJ, United States; Mansoor Nasim, New York University Long Island School of Medicine, Mineola, NY, United States; Shahana Perveen, Cohen Children's Medical Center New York, Manhasset, NY, United States

Background: Hyperoxia is widely used in neonatal intensive care for respiratory failure, but its hepatic effects remain poorly defined. Our prior work showed histologic liver injury in neonatal rats despite normal aminotransferases, with perivenular inflammation, vascular congestion, multinucleated hepatocytes, microvesicular steatosis, and apoptosis. These findings, together with increased ABCC2 and unchanged SLC10A1 expression, suggest altered hepatocellular transport and redox balance. This study explores whether injury arises from bile acid accumulation, oxidative stress, or activation of apoptotic and inflammasome pathways related to glutathione depletion.

Objective: To identify key molecular pathways driving hyperoxia-induced hepatic injury in neonatal rats.

Design/Methods: Newborn Sprague-Dawley rat pups were divided into two groups: a control group in room air and a hyperoxia group exposed to 60% oxygen from birth until day 14 of life under a normal light–dark cycle. On day 14, pups were euthanized, and liver and serum were collected for histopathology and markers of inflammation and oxidative stress. Bile acids were quantified using a colorimetric enzymatic assay (Immundiagnostik), with protein normalization by BCA. Western blots assessed cleaved caspase-1, cleaved caspase-3, and 4-hydroxynonenal (4-HNE).

Results: Serum sorbitol dehydrogenase (SDH) increased in the hyperoxia group, consistent with oxidative injury. Hyperoxia-exposed livers showed higher cleaved caspase-1 (P < 0.014) and caspase-3 (P < 0.003), indicating inflammasome and apoptotic activation. Elevated 4-HNE (P < 0.05) confirmed lipid peroxidation. ABCC2 mRNA was significantly upregulated, whereas total hepatic bile acids did not differ between groups. Histopathology revealed hepatocellular degeneration, microvesicular steatosis, apoptosis, and inflammation in hyperoxia.

Conclusion(s): Hyperoxia-associated ABCC2 upregulation may deplete intracellular glutathione, heightening oxidative stress, lipid peroxidation, and production of toxic 4-HNE. These events activate apoptotic (caspase-3) and inflammasome (caspase-1) pathways, leading to hepatocyte injury and sterile inflammation. These mechanisms define distinct molecular pathways of oxygen-induced liver toxicity in early life. Future studies will assess glutathione levels and targeted antioxidant or anti-inflammatory strategies to reduce hyperoxia-related damage.