Michael M. Grunstein, M.D., Ph.D.

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Emeritus Professor of Pediatrics
Department: Pediatrics

Contact information
Abramson Research Bldg. Room 410
Philadelphia, PA 19104
Office: 215-590-3497
Fax: 215-590-1397
Sir George Williams University, 1970.
M.Sc. (Pulmonary Physiology)
McGill University, Montreal , 1972.
Ph.D. (Pulmonary Physiology)
McGill University, Montreal, 1974.
McGill University, Montreal, 1977.
M.A. (Hon)
University of Pennsylvania, 1987.
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Description of Research Expertise

Research in my laboratory focuses on identifying genes and molecular signaling pathways that underlie the altered airway function that characterizes asthma. We have shown that airway smooth muscle (ASM) exhibits a synthetic phenotype of inflammatory cytokine production when sensitized by exposure to specific pro-asthmatic risk factors. These risk factors include IgE immune complexes that stimulate the low affinity receptor for IgE, viral and bacterial respiratory pathogens that stimulate specific toll-like receptors, and Der p1, a dust mite allergen that activates a specific protease-activating receptor.

We also found that sensitized ASM and T lymphocytes exhibit cooperative intercellular signaling that elicits cytokine release from both cell types. The production of cytokines that occurs under these different conditions of airway sensitization evokes pro-asthmatic changes in airway responsiveness. These changes are regulated by stimulation of mitogen-activating protein kinase (MAPK) signaling pathways, coupled to activation of specific gene transcription factors. Specifically, we identified that induction of the pro-asthmatic phenotype in sensitized ASM is mediated by activation of the ERK1/2 signaling pathway that, in turn, leads to activation of the NF-kB and AP-1 transcriptional mechanisms. Co-activation of p38 MAPK exerts a homeostatic (protective) action by negatively regulating ERK1/2 signaling. Moreover, we were the first to identify that ASM can present superantigen to CD4+ cells and, thereby, provoke T cell activation and release of the pro-inflammatory cytokine, IL-13, that reciprocally mediates pro-asthmatic changes in ASM reactivity. Finally, we recently identified that a mechanism involving cross-talk between the protein kinase A and ERK1/2 signaling pathways is responsible for upregulating expression of the phosphodiesterase isozyme, PDE4D5, in airway smooth muscle, which is responsible for mediating pro-asthmatic changes in airway function accompanying prolonged beta-adrenoceptor desensensitization of the airways. Collectively, these findings have provided the rationale for developing new asthma pharmacological treatment approaches that are based on modulation of specific receptor-coupled molecular signaling pathways in airway smooth muscle.

In studies on gene expression profiling in ASM, we have identified a number of glucocorticoid-sensitive genes that may potentially contribute to the induction and alleviation of the pro-asthmatic phenotype in ASM. We are currently examining the roles of these candidate genes and their biological pathways in determining steroid sensitivity. We have also initiated genome-wide association studies using a high-density SNP-based genotyping analysis of pediatric asthma cohorts. The aim of these studies is to identify SNP alleles and haplotypes associated with varying phenotypes of asthma in children. Our goal is to uncover genes and genetic variants that underlie asthma and set the stage for future translational research and the development of new targeted therapies.

Selected Publications

Prolonged heterologous b2-adrenoceptor desensitization promotes proasthmatic airway smooth muscle function via PKA/ERK1/2-mediated phosphodiesterase-4 induction. Am J. Physiol. Lung Cell Mol Physiol. 294: L1055, 2008.

Superantigen presentation by airway smooth muscle to CD4+ T lymphocytes elicits reciprocal pro-asthmatic changes in airway function. J. Immunol. 178: 3627, 2007.

Regulation of toll-like receptor 4-induced pro-asthmatic changes in airway smooth muscle function by opposing actions of ERK1/2 and p38 MAPK signaling. Am. J. Physiol. Lung Cell. Mol. Physiol. 291: L324, 2006.

Pro-Asthmatic effects and mechanisms of action of the dust mite allergen, Der p 1, in airway smooth muscle. J. Allergy Clin. Immunol. 116: 94, 2006.

Whelan, R., C. Kim, M. Chen, J. Leiter, M.M. Grunstein and H. Hakonarson: Role and regulation of IL-1 molecules in pro-asthmatic sensitized airway smooth muscle. Eur. Respir. J. 24: 559, 2004.

Hakonarson, H., and M.M. Grunstein: Autocrine regulation of airway smooth muscle responsiveness. Respir. Physiol. Neurobiol. 137: 263-276, 2003.

Hakonarson, H., R.S. Whelan, J.A. Leiter, and M.M. Grunstein: Altered airway smooth muscle regulation of inflammatory transcription factors in response to treatment with IL-1รข and activated T-lymphocytes. Am. Thoracic Soc. 167(7): 688A, 2003.

Hakonarson, H., R.S. Whelan, J.A. Leiter, C. Kim, and M.M. Grunstein: Activated airway smooth muscle modulates pro-asthmatic inflammatory cytokine production by T-lymphocytes. Am. Thoracic Soc. 167(7): 688A, 2003.

Shan, X., S. Chuang, H. Hakonarson, and M.M. Grunstein: Induction of the pro-asthmatic phenotype in airway smooth muscle transfected to over-express CD23. Am. Thoracic Soc. 167(7): 328A, 2003.

Grunstein, M.M., H. Hakonarson, J. Leiter, M. Chen, R. Whelan, J.S. Grunstein, and S. Chuang: IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle. Am. J. Physiol. (Lung Cell. Mol. Physiol.) 282: L520-L528, 2002.

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Last updated: 08/31/2012
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