It is well established that activation of beta2-adrenergic receptors ((beta2AR) on airway smooth muscle (ASM) cells decreases bronchomotor tone. Less well appreciated is that bronchial epithelial cells have a higher density of (beta2ARs than do ASM and that in vitro studies of primary and immortalized airway epithelial cells have identified cAMP sensitive mechanisms capable of causing ASM relaxation. Conversely, ex vivo studies using epithelium intact and denuded tracheal tubes suggest that the epithelium impedes beta-agonist mediated ASM relaxation by serving as diffusion barrier that limits access of beta-agonists to ASM (2ARs. Thus, the results of cell-based in vitro experiments regarding epithelial (2ARs have not translated into physiologically relevant mechanisms in animal models nor are there data to suggest that epithelial beta2ARs participate in the regulation of bronchomotor tone in humans with asthma. This lack of consensus about epithelial beta2ARs has resulted in a paradigm of asthma that assumes, by default, that beta-agonists affect bronchodilation solely via activation of beta2ARs on ASM. We find it striking that the location and mechanism of action of a key therapeutic modality for asthma, inhaled beta-agonists, are uncertain. The absence of a defined role for epithelial beta2ARs, stems from the inability of prior in vivo studies to separate the physiologic effects of epithelial (beta2ARs from the direct bronchodilating effects of ASM beta2ARs. We believe that resolution of the role of epithelial beta2ARs could improve our understanding of reactive airway disease and better define how beta-agonists interacts with the airway to reduce airway reactivity. We have conducted preliminary experiments in which we observed that overexpression of a human beta2ARs cDNA in the airway epithelium of normal mice confers substantial protection from methacholine-induced bronchospasm. We also noted that the absence or inhibition of epithelial beta2ARs significantly increases airway reactivity in mice. These observations have caused us to hypothesize that: Bronchial epithelial beta2ARs participate in the regulation of airway reactivity. The lack of consensus regarding bronchial epithelial (2ARs and our ongoing studies of alveolar beta2ARs have led us to several questions regarding airway epithelial beta2ARs: 1) Do airway epithelial (2ARs regulate airway reactivity in normal mice? 2) Does agonist-induced receptor desensitization of epithelial beta2ARs affect airway reactivity? and 3) Does bronchopulmonary inflammation affect epithelial beta2ARs function? To address our hypothesis and questions we have structured 3 inter-related scientific aims that merge molecular tools with in vivo models to help repair the long-standing gap in knowledge regarding the role of epithelial beta2ARs. These studies will tell us how beta2ARs interact with catecholamines, if they affect airway reactivity, and whether they are affected by bronchopulmonary inflammation. We believe that confirmation of an important role for epithelial beta2ARs could justify the development of epithelial cell specific, gene-based, therapies that positively modulate epithelial beta-receptor function to produce sustained protection from bronchospastic challenges. Such therapies could significantly improve the health of patients with asthma.
| Jelic, Sanja; Lederer, David J; Adams, Tessa et al. (2010) Vascular inflammation in obesity and sleep apnea. Circulation 121:1014-21 |
| Mutlu, Gokhan M; Factor, Phillip (2008) Alveolar epithelial beta2-adrenergic receptors. Am J Respir Cell Mol Biol 38:127-34 |
| 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 |
| 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 |
| 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; 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 |
