The Destructive Cycle in Bronchopulmonary Dysplasia: The Rationale for Systems Pharmacology Therapeutics. Antioxidants (Basel) 2025 Jul 10;14(7)
Date
07/29/2025Pubmed ID
40722948Pubmed Central ID
PMC12291855DOI
10.3390/antiox14070844Scopus ID
2-s2.0-105011539490 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
Bronchopulmonary dysplasia (BPD) remains a significant complication of premature birth and neonatal intensive care. While much is known about the drivers of lung injury, few studies have addressed the interrelationships between oxidative stress, inflammation, and downstream events, such as endoplasmic reticulum (ER) stress. In this review, we explore the concept of a "destructive cycle" in which these drivers self-amplify to push the lung into a state of maladaptive repair. Animal models, primarily the hyperoxic rat pup model, support a sequential progression from the generation of reactive oxygen species (ROS) and inflammation to endoplasmic reticulum (ER) stress and mitochondrial injury. We highlight how these intersecting pathways offer not just therapeutic targets but also opportunities for interventions that reprogram system-wide responses. Accordingly, we explore the potential of systems pharmacology therapeutics (SPTs) to address the multifactorial nature of BPD. As a prototype SPT, we describe the development of N-acetyl-L-lysyl-L-tyrosyl-L-cysteine amide (KYC), a systems chemico-pharmacology drug (SCPD), which is selectively activated in inflamed tissues and modulates key nodal targets such as high-mobility group box-1 (HMGB1) and Kelch-like ECH-associated protein-1 (Keap1). Collectively, the data suggest that future therapies may require a coordinated, network-level approach to break the destructive cycle and enable proper regeneration rather than partial repair.
Author List
Teng M, Wu TJ, Pritchard KA Jr, Day BW, Naylor S, Teng RJAuthors
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of WisconsinRu-Jeng Teng MD Professor in the Pediatrics department at Medical College of Wisconsin
