Effects and Mechanisms of NAD + on Lung Injury After Cardiac Arrest and Cardiopulmonary Resuscitation in Swine.

INTRODUCTION: This study aimed to investigate the effects of nicotinamide adenine dinucleotide (NAD + ) on lung injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in swine and to explore the potential underlying mechanisms.

METHODS: Twenty-two domestic male swine were randomly assigned to Sham (n = 6), CPR (n = 8), and CPR + NAD + (n = 8) groups. The CA/CPR model was established by 10 minutes ventricular fibrillation followed by 6 minutes CPR. The Sham group underwent surgical preparation only. At 5 minutes after successful resuscitation, the CPR + NAD + group received intravenous NAD + (20 mg/kg over 1 hour), while the other groups received a vehicle solution. Before model induction and during the 4 hours post-resuscitation observation period, extravascular lung water index (ELWI) and pulmonary vascular permeability index (PVPI) were measured using pulse index continuous cardiac output monitoring, oxygenation index (OI) was obtained from arterial blood gas analysis, and serum surfactant protein D (SP-D) concentrations were determined. At 24-hour post-resuscitation, lung tissue samples were harvested for histopathological analysis, apoptosis assessment, and evaluation of ferroptosis-related markers, including ferrous iron (Fe 2+ ), malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), glutathione (GSH), and reactive oxygen species. Expression of Yes-associated protein (YAP) and acyl-CoA synthetase long-chain family member 4 (ACSL4) was also evaluated.

RESULTS: Six animals in each intervention group achieved return of spontaneous circulation. Compared with the CPR group, NAD + treatment significantly improved lung injury indices, including SP-D, ELWI, PVPI, and OI. Significant differences between the CPR and CPR + NAD + groups were observed in serum SP-D at multiple time points, lung tissue SP-D at 24 hours, and ELWI and PVPI at 4 hours. Histopathological analysis revealed marked lung tissue injury and increased apoptosis in both intervention groups compared with the Sham group; however, these changes were significantly attenuated in the CPR + NAD + group. Compared with the Sham group, lung tissue levels of Fe 2+ , MDA, 4-HNE, reactive oxygen species, and ACSL4 expression were significantly increased, whereas GSH levels and YAP expression were significantly decreased in both intervention groups. Notably, NAD + administration significantly reversed these ferroptosis-related alterations compared with the CPR group.

CONCLUSIONS: NAD + effectively attenuates lung injury after CA/CPR in swine. The underlying mechanism may be associated with suppression of ferroptosis through modulation of the YAP/ACSL4 signaling pathway.