Durham Research Center, 3042
985800 Nebraska Medical Center
Omaha, NE 68198-5800
E-mail: Myron Toews
Keywords: Receptors and cell signaling; Agricultural lung disease; EGF receptor signaling and regulation in airway diseases; Lipid mediators of lung disease; Adrenergic receptor drugs and actions
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Dr. Toews discusses a career in pharmacology and his research in hog barn dust and lung disease.
Current studies in my laboratory are focused on extracellular mediators and their receptors and signaling pathways in relation to lung diseases other than lung cancer, mainly diseases of the "airways" such as asthma, pulmonary fibrosis and chronic bronchitis.
One major current focus is on the cellular and molecular mechanisms involved in development of obstructive lung disease in agricultural workers exposed to animal barn dusts, especially hog barn dust. Our recent studies have shown that an extract of this dust both activates and then down-regulates receptors for epidermal growth factor (EGF receptors) on airway epithelial cells. We are also working to identify the specific factors in the dust that mediate the disease-relevant effects on airway epithelial cells. Proteomics analysis of all of the proteins in the dust extract identified heat-stable proteases, and subsequent studies have shown that these proteases seem to mediate the hog barn dust responses that are not mediated by EGF receptors. Drugs targeting both EGF receptors and proteases are already available, which may allow us to develop new therapies for preventing or treating the occupational and environmental diseases caused by the dust.
A newer set of studies focus on the regulation of lung cell responses by prostaglandin E1 (PGE1), a lipid mediator that signals via a family of G protein-coupled receptors that stimulate cAMP formation to mediate their cellular effects. Recent studies have shown that PGE1 causes desensitization (loss of response) of its own actions by increasing the PDE4 enzyme that degrades cAMP, rather than by decreasing its own stimulation of cAMP production, the mechanism utilized by most other related receptors. Because PGE1 is thought to play protective roles in lung disease, understanding how to prevent or overcome this loss of PGE1 responses has multiple important clinical implications.
A long-term and continuing focus is on the roles of the simple lipid mediator lysophosphatidic acid (LPA) in airway disease. LPA is known to be released at sites of tissue injury and to mediate wound repair. Many diseases of the lung, including asthma, chronic bronchitis, and pulmonary fibrosis, are thought to result from repeated lung injury followed by inappropriate repair responses that lead to an altered structure of the lung tissue. We published many studies showing disease-relevant effects of LPA on lung cells. Recent studies from other groups have now confirmed the importance of LPA in airway disease using knockout mice and human patient samples, and LPA receptor-targeted drugs are in early phase clinical trials. We continue to work on this project, with a major focus the sources of this LPA and on identifying the specific LPA receptors and signaling pathways involved in these airway diseases. The long-term goal is to identify drugs that alter the production, destruction, or actions of LPA to treat these lung diseases.
Adrenergic receptor signaling and regulation have also been long-term interests in my laboratory, in particular in relation to the use of beta-2 adrenergic receptor agonists (activators) to help dilate (open up) asthmatic airways. We are studying a variety of lung responses that are altered by these beta agonist drugs. We are also comparing the more traditional mechanisms of desensitization for beta-2 adrenergic receptors with the novel PDE4 mechanism for PGE1 receptors in the studies mentioned above.
Finally, because my laboratory remains one of the most experienced in classic methods of studying receptors and cell signaling, I have authored many articles on proper methods and analyses for these experiments, including two recent articles for a focused journal issue on problems with reproducibility in studies of drug action that are thought be slowing progress on new drug development.
- To dissect the detailed molecular mechanisms involved in receptor activation and inactivation, especially for LPA receptors, EGF receptors, and adrenergic receptors
- To use this information to develop more selective, more effective, and safer drugs, especially for airway disease
- Dodmane PR, Schulte NA, Heires AJ, Band H, Romberger DJ, and Toews ML. Airway epithelial EGF receptor mediates hogbarn dust-induced cytokine release but not Ca2+ response. Am. J. Respir. Cell Mol. Biol. 45:882-888, 2011. PMID: 21441380
- Jiang H, Abel, PW, Toews ML, Deng ., Casale TB, Xie Y, and Tu Y. Phosphoinositide 3-kinase γ regulates airway smooth muscle contraction by modulating calcium oscillations. J. Pharmacol. Exptl. Ther. 334:703-709, 2010. PMID: 20501633
- Tian C, Shao CH, Fenster DS, Mixan M, Romberger DJ, Toews ML, Bidasee KR. Chloroform extract of hog barn dust modulates skeletal muscle ryanodine receptor calcium-release channel (RyR1). J Appl Physiol. Sep;109(3):830-9, 2010. PMID: 20576841
- Kassel, K.M., N.A. Schulte, and M.L. Toews. Modulation of epidermal growth factor receptor binding to human airway smooth muscle cells by glucocorticoids and beta-2 adrenergic receptor agonists. Am. J. Physiol.-Lung Cell Mol. Physiol., 296(4):L693-9, 2009. PMID: 19201814
- Hashimoto M., X. Wang, L. Mao, T. Kobayashi, S. Kawasaki, N. Mori, M.L. Toews, H.J. Kim, D.R. Cerutis, X. Liu and S.I. Rennard SI. Sphingosine 1-phosphate potentiates human lung fibroblast chemotaxis through the S1P2 receptor. Am. J. Respir. Cell Mol. Biol. 39:356-363, 2008. PMID: 18367729
- Bruchas, M.R., M.L. Toews, C.S. Bockman and P.W. Abel. Characterization of the α1-adrenergic receptor subtype activating extracellular signal-regulated kinase in submandibular gland acinar cells. Eur. J Pharmacol. 578:349-358, 2008. PMID: 17936747
- Kassel, K.M., T.A. Wyatt, R.A. Panettieri, Jr. and M.L. Toews. Inhibition of human airway smooth muscle cell proliferation by β2 adrenergic receptor activation and cAMP-elevating agents: Evidence for EPAC involvement. Am. J. Physiol: Lung Cell Mol. Physiol. 294:L131-138, 2008. PMID: 17993585
- Kassel, K.M., P.R. Dodmane, N.A. Schulte and M.L. Toews. Lysophosphatidic acid induces rapid and sustained decreases in epidermal growth factor binding via different signaling pathways in BEAS-2B airway epithelial cells. J. Pharmacol. Exptl. Ther. 325:809-817, 2008. PMID: 18309089
- Kassel, K.M., N.A. Schulte, S.M. Parker, A.D. Lanik and M.L. Toews. Lysophosphatidic acid decreases epidermal growth factor receptor binding in airway epithelial cells. J. Pharmacol. Exptl. Ther. 323:109-118, 2007. PMID: 18309089