In newborns with acute respiratory distress syndrome, the peptide SS-31 reduced lung inflammation, oxidative damage, and cell death in both lab cells and mouse models. SS-31 works by suppressing a chain reaction involving a protein called TXNIP and an inflammatory complex called NLRP3, which together amplify lung injury. These results position SS-31 as a candidate treatment for a condition that currently lacks targeted therapies in newborns.
Abstract
BACKGROUND: Mitochondrial-targeting anti-oxidant Szeto-Schiller 31 (SS-31) can ease lung injury in several diseases, but whether SS-31 can ameliorate acute lung injury (ALI) in neonatal acute respiratory distress syndrome (ARDS) is unclear. The objective of this study is to explore the efficacy of SS-31 against ALI and the associated molecular mechanisms.
METHODS: Thioredoxin-interacting protein (TXNIP) was found to be a hub gene for ARDS by bioinformatics analysis. Using the Search Tool for Interactions of Chemicals (STITCH) database, SS-31 was found to work via mediating TXNIP expression. Serum levels of some parameters were analyzed by enzyme-linked immunosorbent assay (ELISA). The effect of SS-31 on oxidative stress (OxS) injury, inflammation, apoptosis, and vascular permeability in lipopolysaccharide (LPS)-induced human lung microvascular epithelial cells (HLMVECs) and ARDS mouse models were investigated to assess the efficiency of SS-31 on ALI by a series of experiments [5-ethynyl-2'-deoxyuridine (EDU), lactate dehydrogenase (LDH), western blot, flow cytometry, histopathological analysis, wet-to-dry weight ratio, and so on].
RESULTS: SS-31 treatment mitigated LPS-induced OxS, apoptosis, vascular permeability, and inflammatory response in HLMVECs. Consistently, SS-31 treatment ameliorated histopathological changes and oedema in the lungs of neonatal ARDS mice, accompanied by improved alveolar capillary barrier integrity as well as reduced OxS, inflammation, and apoptosis. Serum TXNIP, caspase-1, apoptosis-associated speck-like protein (ASC), and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) levels were overtly higher in newborns with ARDS, and a positive correlation was observed between TXNIP and NLRP3. Interestingly, SS-31 treatment repressed TXNIP and NLRP3 protein levels in ARDS cells and animal models.
CONCLUSIONS: SS-31 may repress OxS, inflammatory response, apoptosis, and vascular permeability by targeting the TXNIP/NLRP3 pathway in neonatal ARDS, thereby ameliorating ALI.