Remodeling of Murine Branch Pulmonary Arteries Under Chronic Hypoxia and Short-Term Normoxic Recovery.

Chronic hypoxia plays a central role in diverse pulmonary pathologies, but its effects on longitudinal changes in the biomechanical behavior of proximal pulmonary arteries remain poorly understood. Similarly, effects of normoxic recovery have not been well studied. Here, we report hypoxia-induced changes in composition, vasoactivity, and passive biaxial mechanics in the main branch pulmonary artery of male C57BL/6J mice exposed to 10% FiO2 for 1, 2, or 3 weeks. We observed significant changes in extracellular matrix, and consequently wall mechanics, as early as 1 week of hypoxia. While circumferential stress and stiffness returned toward normal values by 2-3 weeks of hypoxia, area fractions of cytoplasm and thin collagen fibers did not return toward normal until after 1 week of normoxic recovery. By contrast, elastic energy storage and overall distensibility remained reduced after 3 weeks of hypoxia as well as following 1 week of normoxic recovery. While smooth muscle and endothelial cell responses were attenuated under hypoxia, smooth muscle but not endothelial cell responses recovered following 1 week of subsequent normoxia. Collectively, these data suggest that homeostatic processes were unable to preserve or restore overall function, at least over a brief period of normoxic recovery. Longitudinal changes are critical in understanding large pulmonary artery remodeling under hypoxia, and its reversal, and will inform predictive models of vascular adaptation.

Fragment-based screening and hit-based substructure search: Rapid discovery of 8-hydroxyquinoline-7-carboxylic acid as a low-cytotoxic, nanomolar metallo ß-lactamase inhibitor.

Metallo-ß-lactamases (MBLs) are zinc-containing carbapenemases that inactivate a broad range of ß-lactam antibiotics. There is a lack of ß-lactamase inhibitors for restoring existing ß-lactam antibiotics arsenals against common bacterial infections. Fragment-based screening of a non-specific metal chelator library demonstrates 8-hydroxyquinoline as a broad-spectrum nanomolar inhibitor against VIM-2 and NDM-1. A hit-based substructure search provided an early structure-activity relationship of 8-hydroxyquinolines and identified 8-hydroxyquinoline-7-carboxylic acid as a low-cytotoxic ß-lactamase inhibitor that can restore ß-lactam activity against VIM-2-expressing E. coli. Molecular modeling further shed structural insight into its potential mode of binding within the dinuclear zinc active site. 8-Hydroxyquinoline-7-carboxylic acid is highly stable in human plasma and human liver microsomal study, making it an ideal lead candidate for further development.