Published ahead of print on March 29, 2007, doi:10.1165/rcmb.2006-0327OC Am. J. Respir. Cell Mol. Biol., Volume 37, Number 2, August 2007, 222-231 A more recent version of this article appeared on August 1, 2007
Submitted on August 31, 2006 Attenuation of Vascular Permeability by Methylnaltrexone: Role of mOP-R and S1P3 TransactivationPatrick A Singleton1,1 Department of Medicine, University of Chicago, Chicago, IL, USA, 2 Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, USA * To whom correspondence should be addressed. E-mail: jgarcia{at}medicine.bsd.uchicago.edu.
Endothelial cell (EC) barrier dysfunction, i.e. increased vascular permeability, is observed in inflammatory states, tumor angiogenesis, atherosclerosis and both sepsis and acute lung injury. Therefore, agents that preserve vascular integrity have important clinical therapeutic implications. We examined the effects of methylnaltrexone (MNTX), a mu opioid receptor (mOP-R) antagonist, on human pulmonary EC barrier disruption produced by edemagenic agents including morphine, DAMGO, thrombin and lipopolysaccharide (LPS). Pretreatment of EC with MNTX (0.1 µM, 1 hour) or the uncharged mOP-R antagonist naloxone attenuated morphine and DAMGO -induced barrier disruption in vitro. However, MNTX, but not naloxone, pretreatment of EC inhibited thrombin- and lipopolysaccharide (LPS)-induced barrier disruption indicating potential mOP-R-independent effects of MNTX. Further, intravenously-delivered MNTX attenuated LPS-induced vascular hyperpermeability in the murine lung. We next examined the mechanistic basis for this MNTX barrier protection and observed that silencing of mOP-R attenuated the morphine- and DAMGO-induced EC barrier disruption, but not the permeability response to either thrombin or LPS. Because activation of the sphingosine 1-phosphate receptor, S1P3, is key to a number of barrier-disruptive responses, we examined the role of this receptor in our permeability responses. Morphine, DAMGO, thrombin and LPS induced RhoA/ROCK-mediated threonine phosphorylation of S1P3 which was blocked by MNTX suggesting S1P3 transactivation. In addition, silencing of S1P3 receptor expression (siRNA) abolished the permeability response to each edemagenic agonist. These results indicate that MNTX provides barrier protection against edemagenic agonists via inhibition of S1P3 receptor activation and represents a potentially useful therapeutic agent for syndromes of increased vascular permeability.
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