C. S. Mott Children's Hospital

University of Michigan Health System

Pulmonology: Research

Marc B. Hershenson, M.D.

Signal transduction mechanisms underlying airway smooth muscle cell proliferation and differentiation

In asthma, the airways, or bronchi, narrow excessively, making it difficult for individuals to breathe in and out (especially out). It has long been known that the airways of patients with chronic severe asthma show an increased amount of bronchial smooth muscle. Since airway narrowing in asthma is caused in large part by muscle contraction, this increase in smooth muscle mass likely plays a significant role in the pathogenesis of asthma. Increased airway smooth muscle mass may relate either to abnormal bronchial smooth muscle proliferation or accumulation of contractile proteins, that is, hypertrophy.

Dr. Hershenson's laboratory has focused on the biochemical signaling pathways regulating airway smooth muscle proliferation. Using cultures of bovine tracheal smooth muscle cells and, most recently, human bronchial smooth muscle cells, Dr. Hershenson's laboratory has focused on the role of the mitogen-activated protein (MAP) kinases in this process. The MAP kinases are a superfamily of serine/threonine kinases involved in the transduction (transfer) of proliferation and differentiation signals to the cell nucleus. Further studies have elucidated the role of reactive oxygen intermediates such as superoxide in airway smooth muscle proliferation. Dr. Hershenson is now investigating how another kinase, protein kinase C-delta, turns off cell proliferation.

Finally, Dr. Hershenson's laboratory is currently developing a cell culture model of airway smooth muscle hypertrophy. In this model, human bronchial smooth muscle cells are infected with a replication-deficient retrovirus encoding a temperature-sensitive SV40 large T antigen. Change to the non-permissive temperature significantly increases bronchial smooth muscle cell size and contractile protein expression. Dr. Hershenson plans to determine the molecular mechanisms involved in this change, with the long-term goal of determining whether smooth muscle hypertrophy is sufficient for the airways hyperresponsiveness classically observed in patients with asthma. All of the above work is funded by the National Institutes of Health.

Recent Publications:

  1. Page K, Li J, Hershenson MB. p38 mitogen-activated protein kinase negatively regulates cyclin D1 expression in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 280: L955-L964, 2001.
  2. Bauerfeld KP, Hershenson MB, Page K. Cdc42, but not RhoA regulates cyclin D1 expression in bovine tracheal myocytes. Am J Physiol Lung Cell Mol Physiol 280: 974 -982, 2001.
  3. Page K, Li J, Corbit KC, Rumilla KM, Soh J-W, Weinstein IB, Albanese C, Pestell RG, Rosner MR, Hershenson MB. Protein kinase C delta regulates cyclin D1 transcription in primary airway smooth muscle cells via multiple cis-acting elements. Am J Respir Cell Mol Biol 27:204-13, 2002.

Biochemical signaling pathways regulating pro-inflammatory molecule expression in airway epithelial cells.

Airway lining, or epithelial, cells not only serve to cover and protect the airways from microorganisms, allergens and other foreign substances, but they also produce large amounts of pro-inflammatory proteins such as cytokines, molecules that regulate the immune response. Airway epithelial cell cytokine production is increased in diseases such as asthma, cystic fibrosis and bronchopulmonary dysplasia, a chronic airways disease of prematurely-born infants.

In these studies, Dr. Hershenson has again focused on the role of MAP kinases and protein kinase C delta in regulating cell responses, as well as their “crosstalk” with the NF-kappa B signaling pathway. He is particularly interested in the signaling pathways activated by rhinovirus, which is responsible for a large percentage of asthma exacerbations in children and adults. Dr. Hershenson's laboratory is studying airway epithelial cell signaling not only in cells derived from normal individuals, but also in cells from patients with cystic fibrosis, a life-threatening airways disease of children and young adults. This work is funded by the National Institutes of Health and Cystic Fibrosis Foundation.

Recent Publications:

  1. Li J, Kartha S, Tan A, Iasvovskaia S, Bhat RK, Manaligod JM, Page K, Brasier AR, Hershenson MB. Regulation of human airway epithelial cell interleukin-8 expression by mitogen-activated protein kinases. Am J Physiol Lung Cell Mol Physiol 283:L690-9, 2002.
  2. Bhat RK, Page K, Tan A, Iasvovskaia S, Hershenson MB. Cockroach extract increases human bronchial epithelial cell interleukin-8 expression in a serine protease-dependent manner. Clin Exp Allergy 33:35-42, 2003.
  3. Li J, Johnson XD, Iasvovskaia S, Tan A, Lin A, Hershenson MB. Signaling intermediates required for NF-kB activation and IL-8 expression in CF bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 284: L307-15, 2003.
  4. Zhou L, Tan A, Iasvovskaia S, Li J, Lin A, Hershenson MB. Ras and MEKK1 co-regulate AP-1- and NF-kB-mediated gene expression in airway epithelial cells. Am J Respir Cell Mol Biol, 2003.
  5. Page K, Zhou L, Li J, Iazvovskaia S, Corbit KC, Soh J-W, Weinstein IB, Brasier AR, Lin A, Hershenson MB. Regulation of airway epithelial cell NF-kB-dependent gene expression by protein kinase-delta. J Immunol 170: 5681-5689, 2003.