Welcome to the University of South Alabama's Center for Lung Biology (CLB). Our Center is comprised of more than 40 faculty members and 25 postdoctoral fellows, clinical fellows, and graduate students representing both basic and clinical science departments, all interested in some aspect of lung biology. The CLB seeks to provide state of the art scientific development in lung biology that advances the understanding of human health and disease, to improve patient care and serve as the foundation for outstanding graduate, post-graduate, and fellowship training.
CLB faculty research interests include Acute Lung Injury, Airways Biology, Nano-scale Respiratory Cell Biology, Pulmonary Endothelial Cell Biology, and Pulmonary Hypertension. Summaries of these research groups can be found at our Scientific Programs site, located on the left-side panel. We provide resource information for scientists interested in cell culture and experimental gene manipulation at our Tissue and Cell Culture Core and Gene Delivery Core sites. Our PercipioTM program is highlighted in the Art in Science section, and our healthy lifestyles program is highlighted in the Running and Walking Club section. Faculty, Post-doc and Clinical Fellows, and Graduate Student research interests and biosketches are available with a click. Stream an interview in our Meet the Professor series, which shares the academic lives and careers of our CLB faculty. Information on how to Contact Us is easily accessible, and training opportunities are shown in the Training Opportunities section. Our Did You Know... series is highlighted on this homepage, and archives can be retrieved with a click. Explore the interests of our faculty, fellows and graduate students. Again, welcome to the CLB.
Did You Know
…there are taste buds in the respiratory tract?
There are taste receptors in the airways, and moreover that they may be future targets for treating obstructive airway diseases? Most are familiar with epithelial sensory receptors, first identified in 2000, on the tongue and palate as they allow us to differentiate bitter tastants . However, bitter taste receptors, or TAS2Rs, are also surprisingly located in several extraoral locations, including pulmonary and vascular tissues. For example, in 2003, TAS2Rs were discovered in the nasal cavity where they regulate respiratory rate and promote sneezing . In addition, in 2009, TAS2Rs on ciliated epithelial cells in the nasal cavity were shown to increase beat frequency . Perhaps most intriguing, airway smooth muscle (ASM) expression of TAS2Rs was observed to regulate bronchial tone .
TAS2Rs are G protein-coupled receptors (GPCRs). A variety of other GPCRs on ASM regulate bronchial tone and serve as therapeutic targets for obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) . These standard-of-care therapies (β-agonists) signal through the β2 adrenergic receptor, a GPCR, and increase the second messenger cAMP leading to relaxation of ASM and bronchodilation (Figure 1A). In contrast, contractile agonists such as leukotriene-D4, acetylcholine and histamine signal through other GPCRs and increase intracellular calcium leading to contraction of ASM and bronchoconstriction (Figure 1B).
Signaling cascades of TAS2Rs and GPCRs in ASM cells to regulate bronchodilation and bronchoconstriction. Adapted from [3, 9].Figure 1A. GPCR signaling leading to ASM relaxation and bronchodilation. In ASM, activation of TAS2Rs and Ggust in localized regions of the cell may lead to increased intracellular calcium, activation of membrane channels including large conductance calcium dependent potassium channels (BKCa) leading to membrane hyperpolarization, and potent ASM relaxation (black lines). Also, activated TAS2Rs may directly inhibit L-type voltage dependent calcium channels (VDCC) and blunt agonist induced calcium influx, leading to ASM relaxation (red lines). Activation of β2-Adrenergic receptors elicit airway smooth relaxation by Gs coupled activation of adenylate cyclase (AC), production of cyclic AMP (cAMP) and activation of protein kinase A (PKA), which phosphorylates multiple substrates to decrease intracellular cell calcium concentration. Decreasing calcium reduces activation of myosin light chain kinase (MLCK) thus favoring myosin light chain dephosphorylation by myosin phosphatase (complex of PP1c, MYPT and M20) and relaxation of ASM. Figure 1B. GPCR signaling leading to ASM contraction and bronchoconstriction. Bronchoconstrictor agonists activate multiple GPCRs and elicit ASM contraction through activation of multiple downstream signaling pathways that ultimately increase intracellular calcium. Intracellular calcium interacts with calmodulin to activate myosin light chain kinase (MLCK). Increasing calcium increases activation of MLCK thus favoring myosin light chain phosphorylation and contraction of ASM.
On oral sensory epithelia, bitter compounds activate TAS2Rs and lead to increased intracellular calcium, TRP channel activation, membrane depolarization, and neurotransmitter release. Since increased intracellular calcium and membrane depolarization on ASM promote bronchoconstriction, the discovery of TAS2Rs on ASM led to the hypothesis that TAS2Rs would mediate increased intracellular calcium on ASM and subsequent bronchoconstriction. However, a series of experiments by Stephen Liggett and colleagues revealed that agonist-induced activation of bitter taste receptors on ASM cells caused localized calcium-dependent signaling leading to membrane hyperpolarization, and marked airway smooth muscle relaxation (Figure 1A) . These results are now under debate as data from other groups shows activation of TAS2Rs does not produce a localized calcium increase. The suggested alternative is that TAS2R activation prevents agonist-induced contraction by limiting calcium influx through L-type voltage dependent calcium channels, thereby reducing calcium sensitivity leading to ASM relaxation (Figure 1A) [6, 7].
Regardless of the specific mechanism, delivery of bitter tastants proved more effective at reversing acute airway bronchoconstriction than β-agonists in experimental asthma [3, 8]. Thus, if issues regarding selectivity, toxicity, distribution, and palatability of bitter tastants can be solved, future drug therapy to control obstructive airway diseases may leave more than a bitter taste behind .
- Finger TE, Böttger B, Hansen A, Anderson KT, Alimohammadi H, Silver WL. Solitary chemoreceptor cells in the nasal cavity serve as sentinels of respiration. Proceedings of the National Academy of Sciences 2003;100(15):8981-8986.
- Shah AS, Ben-Shahar Y, Moninger TO, Kline JN, Welsh MJ. Motile cilia of human airway epithelia are chemosensory. Science (New York, NY) 2009;325(5944):1131-1134.
- Deshpande DA, Wang WC, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, Sham JS, Liggett SB. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nature medicine 2010;16(11):1299-1304.
- Deshpande DA, Penn RB. Targeting g protein-coupled receptor signaling in asthma. Cellular Signalling 2006;18(12):2105-2120.
- Liggett SB. Bitter taste receptors in the wrong place: Novel airway smooth muscle targets for treating asthma. Transactions of the American Clinical and Climatological Association 2014;125:64-75.
- Zhang CH, Lifshitz LM, Uy KF, Ikebe M, Fogarty KE, ZhuGe R. The cellular and molecular basis of bitter tastant-induced bronchodilation. PLoS biology 2013;11(3):e1001501.
- Tan X, Sanderson MJ. Bitter tasting compounds dilate airways by inhibiting airway smooth muscle calcium oscillations and calcium sensitivity. British journal of pharmacology 2014;171(3):646-662.
- Donovan C, Simoons M, Esposito J, Ni Cheong J, Fitzpatrick M, Bourke JE. Rosiglitazone is a superior bronchodilator compared to chloroquine and beta-adrenoceptor agonists in mouse lung slices. Respiratory research 2014;15:29.
- Gerthoffer WT, Solway J, Camoretti-Mercado B. Emerging targets for novel therapy of asthma. Current opinion in pharmacology 2013;13(3):324-330.
Author: Jared M. McLendon, October 2014
Chief Editor: Robert Barrington, Ph.D.
Co-Editor: Adam Morrow, Ph.D.