N-acetyl-lysyltyrosylcysteine amide, a novel systems pharmacology agent, reduces bronchopulmonary dysplasia in hyperoxic neonatal rat pups
| Autor: | Xigang Jing, Dustin P. Martin, Ru-Jeng Teng, Stephen Naylor, Girija G. Konduri, Neil Hogg, Billy W. Day, Kirkwood A. Pritchard, Aaron Haefke |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Programmed cell death NF-E2-Related Factor 2 chemical and pharmacologic phenomena Inflammation Hyperoxia Pharmacology medicine.disease_cause HMGB1 Biochemistry Article 03 medical and health sciences 0302 clinical medicine In vivo Physiology (medical) medicine Animals Humans Lung Bronchopulmonary Dysplasia Kelch-Like ECH-Associated Protein 1 biology Chemistry Infant Newborn Hydrogen Peroxide Amides Rats Endothelial stem cell 030104 developmental biology Animals Newborn Myeloperoxidase TLR4 biology.protein medicine.symptom 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | Free Radic Biol Med |
| ISSN: | 0891-5849 |
| DOI: | 10.1016/j.freeradbiomed.2021.02.006 |
| Popis: | Bronchopulmonary dysplasia (BPD) is caused primarily by oxidative stress and inflammation. To induce BPD, neonatal rat pups were raised in hyperoxic (>90% O2) environments from day one (P1) until day ten (P10) and treated with N-acetyl-lysyltyrosylcysteine amide (KYC). In vivo studies showed that KYC improved lung complexity, reduced myeloperoxidase (MPO) positive (+) myeloid cell counts, MPO protein, chlorotyrosine formation, increased endothelial cell CD31 expression, decreased 8-OH-dG and Cox-1/Cox-2, HMGB1, RAGE, TLR4, increased weight gain and improved survival in hyperoxic pups. EPR studies confirmed that MPO reaction mixtures oxidized KYC to a KYC thiyl radical. Adding recombinant HMGB1 to the MPO reaction mixture containing KYC resulted in KYC thiylation of HMGB1. In rat lung microvascular endothelial cell (RLMVEC) cultures, KYC thiylation of RLMVEC proteins was increased the most in RLMVEC cultures treated with MPO + H2O2, followed by H2O2, and then KYC alone. KYC treatment of hyperoxic pups decreased total HMGB1 in lung lysates, increased KYC thiylation of HMGB1, terminal HMGB1 thiol oxidation, decreased HMGB1 association with TLR4 and RAGE, and shifted HMGB1 in lung lysates from a non-acetylated to a lysyl-acetylated isoform, suggesting that KYC reduced lung cell death and that recruited immune cells had become the primary source of HMGB1 released into the hyperoxic lungs. MPO-dependent and independent KYC-thiylation of Keap1 were both increased in RLMVEC cultures. Treating hyperoxic pups with KYC increased KYC thiylation and S-glutathionylation of Keap1, and Nrf2 activation. These data suggest that KYC is a novel system pharmacological agent that exploits MPO to inhibit toxic oxidant production and is oxidized into a thiyl radical that inactivates HMGB1, activates Nrf2, and increases antioxidant enzyme expression to improve lung complexity and reduce BPD in hyperoxic rat pups. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect