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Marc Hershenson

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Primary Appointment: Pediatrics-Pulmonary Medicine
Primary PIBS Dept.: Molecular and Integrative Physiology
PubMed Name: Hershenson MB
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 DESCRIPTION OF RESEARCH
  My laboratory studies cellular and molecular mechanisms underlying chronic airways diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and bronchopulmonary dysplasia. At this time, we are focusing on three main projects.

First, we are studying the mechanisms by which rhinovirus (RV), a common cold virus, induces exacerbations of asthma and COPD. We have found that binding and endocytosis of the virus is sufficient for airway epithelial cell cytokine expression, explaining how RV can induce exacerbations of asthma without substantial viral replication in the lower airways. On the other hand, viral replication is required for airway epithelial cell expression of interferons and interferon-dependent genes. We are currently examining the contributions of various pattern recognition receptors and cytoplasmic RNA helicases to this process. We are employing mouse models of RV infection, asthma and COPD in order to study these processes in vivo. Our latest results indicate that allergen sensitization and challenge alters the polarization and RV response of airway macrophages, leading to increased airway inflammation. Also, we have found using knockout mice that recognition of dsRNA by TLR3, while not required for viral clearance, initiates a pro-inflammatory signaling pathway leading to airways inflammation and hyperresponsiveness.

Second, we are studying the biochemical signaling mechanisms by which airway smooth muscle cells increase their size and contractile protein expression, processes which would be expected to increase airway narrowing in asthma. We have found that phosphorylation and inactivation of glycogen synthase kinase 3-beta increases cell size, contractile protein expression and cell shortening via both transcriptional and translational pathways. On the other hand, our recent results indicate that activation of p70 ribosomal S6 kinase increases cell size but not contractile protein expression or cell shortening. These data suggest that airway smooth muscle hypertrophy, without a selective increase in contractile protein expression, is insufficient for airway narrowing.

Third, we are studying fetal lung mesenchymal stromal cells found in the airways of premature infants with respiratory distress syndrome, and their potential role in lung injury and repair. Our studies indicate that these cells are capable of differentiating into either lipo- or myofibroblasts and likely originate in the lung, not bone marrow. Further, isolation of these cells from the tracheal aspirates of premature infants is associated with a greatly increased risk of bronchopulmonary dysplasia, a chronic lung disease. Future studies will attempt to examine the physiologic role of these cells in development and lung injury.