The clearance of pulmonary edema fluid occurs by means of active Na+ transport by alveolar epithelial cells. It is widely accepted that the coordinated function of Na+ and CI- channels in the apical membrane and Na,K-ATPase in the basolateral aspect of alveolar epithelial cells creates a transepithelial osmotic gradient that causes fluid to exit the alveolus. It has been observed in animal models and humans that in some types of lung injury active Na+ transport is impaired. Substantial experimental data suggests that beta2-adrenergic agonists accelerate active Na+ transport and speed edema resolution. These data offer the possibility that beta2-adrenergic agonists may be useful for the treatment of pulmonary edema. The overall goal of our experimental program is to improve our understanding of how beta2-adrenergic receptors (beta2AR) regulate alveolar active Na+ transport. We have reported that mice with no beta1 or beta2 adrenergic receptors have normal total lung cAMP levels but are unable to upregulate active Na+ transport in response to excess alveolar fluid. This finding led us to consider that beta2AR regulation of active Na+ transport requires more than cAMP production. It has recently been noted that the a2AR interacts with scaffold and adaptor proteins that are in close proximity to beta2AR effector molecules such as PKA and CFTR and, anchor it to the sub-membrane cytoskeleton. These protein-protein interactions allow for compartmentalized signaling and tight regulation of beta2AR function. In preparation for this competitive renewal we conducted preliminary immunoprecipitation studies that suggest that alveolar epithelial (2ARS form macromolecular complexes with other transport proteins. This new data led us to hypothesize that: beta2AR regulation of alveolar epithelial active transport occurs via highly regulated interactions with scaffold and/or adaptor proteins. If confirmed, this hypothesis would support a new paradigm where beta2AR regulation of alveolar active Na+ transport is dependent not only on cAMP generation but also formation of a macromolecular regulatory complex at the cell membrane. To address this hypothesis we have formulated the following three specific aims:
Aim 1 : Determine if beta2AR-scaffold/adaptor protein interactions are necessary for regulation of beta2AR sensitive active Na+ transport in alveolar epithelial cells in vitro.
Aim 2 : Ascertain if beta2AR -scaffold interactions are necessary for beta2AR regulation of active Na+ transport in normal lungs.
Aim 3 : Determine if acute lung injury alters beta2AR -scaffold/adaptor protein interactions in mouse lung. The focused studies in this competitive renewal application are structured to define which scaffold and adaptor proteins alveolar beta2AR interacts with, which are required for regulation of active Na+ transport, and if these proteins are affected by acute lung injury. These studies offer an opportunity to expand our understanding of the mechanisms by which the alveolar epithelium regulates active Na+ transport. It is hoped that our studies will identify injury-induced alterations in beta2AR protein-protein interactions that would be amenable to therapeutic manipulation for purposes of speeding resolution of pulmonary edema in the millions of patients with acute pulmonary edema each year.
| Jelic, Sanja; Lederer, David J; Adams, Tessa et al. (2010) Vascular inflammation in obesity and sleep apnea. Circulation 121:1014-21 |
| Jelic, Sanja; Padeletti, Margherita; Kawut, Steven M et al. (2008) Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation 117:2270-8 |
| Mutlu, Gokhan M; Factor, Phillip (2008) Alveolar epithelial beta2-adrenergic receptors. Am J Respir Cell Mol Biol 38:127-34 |
| Factor, Phillip; Mutlu, Goskhan M; Chen, Lan et al. (2007) Adenosine regulation of alveolar fluid clearance. Proc Natl Acad Sci U S A 104:4083-8 |
| Azzam, Zaher S; Adir, Yochai; Welch, Lynn et al. (2006) Alveolar fluid reabsorption is increased in rats with compensated heart failure. Am J Physiol Lung Cell Mol Physiol 291:L1094-100 |
| Dharmarajan, Sekhar; Hayama, Makio; Kozlowski, James et al. (2005) In vivo molecular imaging characterizes pulmonary gene expression during experimental lung transplantation. Am J Transplant 5:1216-25 |
| Mutlu, Gokhan M; Kuzniar, Tomasz; Factor, Phillip (2005) A 41-year-old man with altered mental status and acute flaccid paralysis. Chest 127:391-4 |
| Mutlu, Gokhan M; Adir, Yochai; Jameel, Mohammed et al. (2005) Interdependency of beta-adrenergic receptors and CFTR in regulation of alveolar active Na+ transport. Circ Res 96:999-1005 |
| Mutlu, Gokhan M; Dumasius, Vidas; Burhop, James et al. (2004) Upregulation of alveolar epithelial active Na+ transport is dependent on beta2-adrenergic receptor signaling. Circ Res 94:1091-100 |
| Mutlu, Gokhan M; Koch, Walter J; Factor, Phillip (2004) Alveolar epithelial beta 2-adrenergic receptors: their role in regulation of alveolar active sodium transport. Am J Respir Crit Care Med 170:1270-5 |
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