Published online before print September 28, 2006, doi: 10.1161/01.RES.0000247065.11756.19
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Submitted on May 17, 2006
Revised on August 16, 2006
Accepted on September 14, 2006
Transient Receptor Potential Vanilloid 4-Mediated Disruption of the Alveolar Septal Barrier. A Novel Mechanism of Acute Lung Injury
Diego F. Alvarez ;
From the Departments of Physiology (D.F.A., D.W., E.A., M.I.T.), Pharmacology (J.A.K.), and Pathology (J.A.K.) and Center for Lung Biology (D.F.A., J.A.K., M.I.T.), University of South Alabama, Mobile; and Departments of Medicine, Neurology, and Neurobiology (W.L.), Duke University, Durham, NC.
* To whom correspondence should be addressed. E-mail: mtownsley{at}usouthal.edu.
Disruption of the alveolar septal barrier leads to acute lung injury, patchy alveolar flooding, and hypoxemia. Although calcium entry into endothelial cells is critical for loss of barrier integrity, the cation channels involved in this process have not been identified. We hypothesized that activation of the vanilloid transient receptor potential channel TRPV4 disrupts the alveolar septal barrier. Expression of TRPV4 was confirmed via immunohistochemistry in the alveolar septal wall in human, rat, and mouse lung. In isolated rat lung, the TRPV4 activators 4
-phorbol-12,13-didecanoate and 5,6- or 14,15-epoxyeicosatrienoic acid, as well as thapsigargin, a known activator of calcium entry via store-operated channels, all increased lung endothelial permeability as assessed by measurement of the filtration coefficient, in a dose- and calcium-entry dependent manner. The TRPV antagonist ruthenium red blocked the permeability response to the TRPV4 agonists, but not to thapsigargin. Light and electron microscopy of rat and mouse lung revealed that TRPV4 agonists preferentially produced blebs or breaks in the endothelial and epithelial layers of the alveolar septal wall, whereas thapsigargin disrupted interendothelial junctions in extraalveolar vessels. The permeability response to 4-phorbol-12,13-didecanoate was absent in TRPV4-/- mice, whereas the response to thapsigargin remained unchanged. Collectively, these findings implicate TRPV4 in disruption of the alveolar septal barrier and suggest its participation in the pathogenesis of acute lung injury.
Key words: permeability • TRP channels • TRPV4 • acute lung injury
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