Regulation of Proteinase-Activated Receptor-2 (PAR-2) in Airway Epithelium

• Author / Creator

  Gandhi, Vivek D

• Proteinase-activated receptor-2 (PAR-2), a pro-inflammatory G-coupled receptor, is activated by exogenous or endogenous serine proteinases. PAR-2 is involved in the pathogenesis of inflammatory diseases including asthma. PAR-2 activation on airway epithelial cells (AECs) results in the release of inflammatory mediators that play an important role in the development of asthma. PAR-2 expression is upregulated on AECs in asthma and upregulated PAR-2 expression augments airway inflammation. Hence it is important to inhibit PAR-2 upregulation, but mechanisms involved in PAR-2 regulation are poorly studied.
  Using in vivo and in vitro models, we showed that insulin regulates PAR-2 expression and upregulated PAR-2 increased the pro-inflammatory potential of AECs. We further showed that insulin regulates PAR-2 expression through PI3K-Akt-FOXO-1 pathway. This observation led to the hypothesis for future studies that inflammation-induced localized insulin resistance in the airway epithelium in asthma may result in PAR-2 upregulation on AECs.
  PAR-2 expression is increased in inflammatory diseases, thus we studied the effect of stress stimuli, which are associated with inflammation, on PAR-2 expression in AECs. Our preliminary results suggest that oxidative stress and hypoxia do not modulate PAR-2 expression. We found that withdrawal of media supplements containing growth factors and hormones resulted in PAR-2 upregulation, and again PAR-2 upregulation increased the pro-inflammatory potential of AECs. We also showed that, in addition to insulin, hydrocortisone, bovine pituitary extract and retinoic acid regulate PAR-2 expression in AECs.
  We cultured AECs obtained from asthmatic patients. We found that PAR-2 expression is increased in AECs from asthmatic compared to healthy individuals and this upregulated PAR-2 expression is maintained when cells were cultured ex vivo for multiple passages. Asthmatic AECs also showed similar media supplement deprivation-mediated PAR-2 regulation.
  Our study indicates the possibility that inflammatory microenvironments such as insulin resistance and decreased cell growth nutrients may play a role in regulation of expression of pro-inflammatory PAR-2 receptors. Since our study highlights the role of inflammatory microenvironment in PAR-2 expression, our observations can be applied to inflammatory diseases of other organs such as colon and skin, where localized inflammation is present and PAR-2 expression is increased. Similar studies can be performed which may identify common dysregulatory mechanisms involved in increased PAR-2 expression in different inflammatory conditions and may lead to the development of novel therapeutic strategies to inhibit PAR-2 upregulation and control PAR-2-mediated inflammation.

• Subjects / Keywords

  • PAR-2
  • asthma
  • airway epithelium
  • proteinase-activated receptor-2
  • insulin

• Graduation date

  Fall 2018

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3251G208

• License

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