Date Published: January 1, 2018
Publisher: American Physiological Society
Author(s): Elizabeth O. Harrington, Alexander Vang, Julie Braza, Aparna Shil, Havovi Chichger.
A hallmark of acute respiratory distress syndrome (ARDS) is pulmonary vascular permeability. In these settings, loss of barrier integrity is mediated by cell-contact disassembly and actin remodeling. Studies into molecular mechanisms responsible for improving microvascular barrier function are therefore vital in the development of therapeutic targets for reducing vascular permeability in ARDS. The sweet taste receptor T1R3 is a G protein-coupled receptor, activated following exposure to sweet molecules, to trigger a gustducin-dependent signal cascade. In recent years, extraoral locations for T1R3 have been identified; however, no studies have focused on T1R3 within the vasculature. We hypothesize that activation of T1R3, in the pulmonary vasculature, plays a role in regulating endothelial barrier function in settings of ARDS. Our study demonstrated expression of T1R3 within the pulmonary vasculature, with a drop in expression levels following exposure to barrier-disruptive agents. Exposure of lung microvascular endothelial cells to the intensely sweet molecule sucralose attenuated LPS- and thrombin-induced endothelial barrier dysfunction. Likewise, sucralose exposure attenuated bacteria-induced lung edema formation in vivo. Inhibition of sweet taste signaling, through zinc sulfate, T1R3, or G-protein siRNA, blunted the protective effects of sucralose on the endothelium. Sucralose significantly reduced LPS-induced increased expression or phosphorylation of the key signaling molecules Src, p21-activated kinase (PAK), myosin light chain-2 (MLC2), heat shock protein 27 (HSP27), and p110α phosphatidylinositol 3-kinase (p110αPI3K). Activation of T1R3 by sucralose protects the pulmonary endothelium from edemagenic agent-induced barrier disruption, potentially through abrogation of Src/PAK/p110αPI3K-mediated cell-contact disassembly and Src/MLC2/HSP27-mediated actin remodeling. Identification of sweet taste sensing in the pulmonary vasculature may represent a novel therapeutic target to protect the endothelium in settings of ARDS.
Acute respiratory distress syndrome (ARDS) is a major cause of morbidity and mortality in patients suffering from several predisposing factors such as trauma, sepsis, and pneumonia. The syndrome occurs when vascular fluid and protein leak across the pulmonary microvascular endothelium into the alveolar air space, causing pulmonary edema formation, which is characteristic of the disease. Respiratory failure then occurs as a result of decreased gas exchange and lung compliance and initiation of inflammatory cascades (79). Thus a key hallmark of ARDS is permeability of the pulmonary microvascular endothelium to vascular fluid and protein.
In the present study we demonstrate, for the first time, the localization and function of the sweet taste receptor at the pulmonary endothelium. Our research identified the expression of T1R3 in the lung and microvascular endothelial cells, with reduced protein levels in response to the barrier-disruptive agents LPS, thrombin, and VEGF. We observed that activation of T1R3 by exposure to the artificial sweetener sucralose protects the microvasculature in vitro and in vivo against barrier disruptive agents through a sweet taste receptor-dependent pathway. Lastly, we implicated a role for sucralose in attenuating LPS-mediated Src, PAK, MLC2, HSP27, and p110αPI3K signaling. Therefore, the stimulation of T1R3 by artificial sweetener sucralose represents a novel mechanism through which the pulmonary microvasculature is regulated.
This material is based on work supported by Diabetes UK Grant 15/0005284, Wellcome Trust Grant 202624/Z/16/Z, and American Heart Association Grant 13POST16860031 (to H. Chichger). E. O. Harrington was supported by National Heart, Lung, and Blood Institute Grants R01-HL-67795 and R01-HL-123965 and an Institutional Development Award (IDeA) under National Institute of General Medical Sciences Grant P20-GM-103652. A. Vang was supported by National Heart, Lung, and Blood Institute Grant 1R01HL128661.
The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs.
No conflicts of interest, financial or otherwise, are declared by the authors.
E.O.H., A.V., A.S., and H.C. interpreted results of experiments; E.O.H. and H.C. edited and revised manuscript; E.O.H. and H.C. approved final version of manuscript; A.V., J.B., A.S., and H.C. performed experiments; A.V., A.S., and H.C. analyzed data; A.S. and H.C. prepared figures; H.C. conceived and designed research; H.C. drafted manuscript.