Mechanical ventilation (MV) is an important procedure for the treatment of patients with acute lung injury or acute respiratory distress syndrome in a clinical setting; however, MV can lead to severe complications, including ventilator-induced lung injury (VILI). Telocytes (TCs) can promote tissue repair following injury in the heart, kidneys, and other organs. The aim of this study was to investigate the role of TCs in VILI in mice and the associated mechanisms. By using in vivo studies in mice and in vitro studies in cells, we demonstrated that an airway injection of TCs can reduce the pulmonary inflammatory response and improve the lung function in mice with VILI and promote the proliferation of pulmonary vascular endothelial cells. We also demonstrated that the impact of TCs on VILI repair might partially due to vascular endothelial growth factor (VEGF) secreted by TCs upon VILI stimulation, and that VEGF could induce the proliferation of hemangioendothelioma endothelial cells (EOMA). Collectively, our results revealed novel functions of TCs in VILA repair and shed light on the complications that are caused by MV.
The human cannabinoid G-protein-coupled receptor 1 (CB1) is highly expressed in central nervous system. CB1-selective antagonists show therapeutic promise in a wide range of disorders, such as obesity-related metabolic disorders, dyslipidemia, drug abuse, and type 2 diabetes. Rimonabant (SR141716A), MJ08, and MJ15 are selective CB1 antagonists with selectivity >1,000-folds over CB2 despite 42% sequence identity between CB1 and CB2. The integration of homology modeling, automated molecular docking, and molecular dynamics simulation were used to investigate the binding modes of these selective inverse agonists/antagonists with CB1 and CB2 and their selectivity. Our analyses showed that the hydrophobic interactions between ligands and hydrophobic pockets of CB1 account for the main binding affinity. In addition, instead of interacting with ligands directly as previously reported, the Lys192 in CB1 was engaged in indirect interactions with ligands to keep inactive-state CB1 stable by forming the salt bridge with Asp176 . Lastly, our analyses indicated that the selectivity of these antagonists came from the difference in geometry shapes of binding pockets of CB1 and CB2. The present study could guide future experimental works on these receptors and has the guiding significance for the design of functionally selective drugs targeting CB1 or CB2 receptors.
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