KD025 Shifts Pulmonary Endothelial Cell Bioenergetics and Decreases Baseline Lung Permeability.

KD025 Shifts Pulmonary Endothelial Cell Bioenergetics and Decreases Baseline Lung Permeability. Am J Respir Cell Mol Biol. 2020 Jul 06;: Authors: Lee JY, Stevens RP, Kash M, Zhou C, Koloteva A, Renema P, Paudel SS, Stevens T Abstract KD025 is a ROCK2 inhibitor currently being tested in clinical trials for treatment of fibrotic lung diseases. The therapeutic effects of KD025 are partly due to its inhibition of profibrotic pathways and fat metabolism. However, whether KD025 affects pulmonary microvascular endothelial cell (PMVEC) function is unknown, despite evidence that alveolar capillary membrane disruption constitutes major causes of death in fibrotic lung diseases. We hypothesized that KD025 regulates PMVEC metabolism, pH, migration and survival, a series of inter-related functional characteristics that determine pulmonary barrier integrity. We used PMVECs isolated from Sprague Dawley rats. KD025 dose-dependently decreased lactate production and glucose consumption. The inhibitory effect of KD025 was more potent compared to other metabolic modifiers, including 2-deoxy-glucose (2DG), extracellular acidosis, dichloroacetate and remogliflozin. Interestingly, KD025 increased oxidative phosphorylation, while 2DG did not. KD025 also decreased intracellular pH and induced a compensatory increase in anion exchanger 2. KD025 inhibited PMVEC migration, but fasudil (non-specific ROCK inhibitor) did not. We tested endothelial permeability in ...
Source: Am J Respir Cell Mol... - Category: Respiratory Medicine Authors: Tags: Am J Respir Cell Mol Biol Source Type: research