Department of Pathology and Laboratory Medicine

van der Vliet Lab Research

Goal:

To unravel the molecular mechanisms by which biological and environmental oxidants contribute to lung cell injury, inflammation, and remodeling, as major features of chronic lung diseases such as asthma, COPD and lung cancer. Another major goal is to provide a stimulating environment for education and training in academic research in the general areas of environmental pathology and lung biology.

Our Team 

Overview of current areas of research and approaches

Research focus

• interactions between common airborne pollutants and the major lung cell types involved in orchestrating innate and adaptive immune responses or mediate chronic inflammation, remodeling, or tumorigenesis.
• Our research is largely at the interface of chemistry and biology, and seeks to link chemical mechanisms of molecular modifications with alterations in lung cell biology.
• Multidisciplinary strategies, using complementary molecular, analytical, and proteomics approaches in in vitro studies with cultured (primary) respiratory epithelial and inflammatory/immune cells and in in vivo animal exposure and disease models.

Tobacco electrophiles and smoking-related disease

• Cigarette smoking continues to present a major health concern
  • largely responsible for chronic lung diseases such as COPD and lung cancer
  • molecular mechanisms are still largely unresolved
  • Our previous studies have indicated that common electrophiles in tobacco smoke, primarily acrolein, are largely responsible for the oxidative stress that is commonly associated with smoking
    • acrolein inhalation can mimic many of the known consequences of smoke exposure
      • epithelial injury and metaplasia
      • immunosuppressive properties leading to deregulated innate or adaptive immune responses
      • Proteomic approaches revealed that acrolein reacts primarily with susceptible redox-sensitive cellular targets through S-alkylation, and can thereby affect many cellular processes that are controlled by redox regulation (including redox regulating proteins such peroxiredoxins, thioredoxin/thioredoxin reductase, or glutathione S-transferase) and redox-sensitive proteins involved in inflammation or apoptosis (e.g. NF-kB, JNK1/2, caspases).
      • Our current goals are to explore the significance of these modifications for redox regulation and lung cell function, and to explore the potential importance of S-alkylation as a signaling mechanism, analogous to e.g. S-nitrosylation or S-glutathionylation. These studies have been funded by research grants from NIH NIH and the Flight Attendant Medical Research Institute (FAMRI).

Redox signaling in the airway epithelium

• Airway epithelium is endowed with several oxidant-generating enzyme systems
  • such as various isoforms of nitric oxide synthase (NOS)
  • several homologs of NADPH oxidase homolog.
• Primary function for these enzyme systems is innate airway mucosal host defense
  • our recent studies have shown that they can also impact on epithelial signaling pathways involved in
    • inflammatory mediator production
    • epithelial repair pathways
    • maintenance of epithelial barrier function
• Using a combination of molecular and proteomics strategies, we have observed
  • that the major epithelial NADPH oxidase, DUOX1, is involved in epithelial redox signaling mechanisms involved in epithelial homeostasis
  • their expression is allered during chronic airway inflammation
• Recent studies suggest increased expression or activation of DUOX1 in allergic asthma, suggesting a contributing role of DUOX1 in epithelial remodeling and mucus metaplasia. Conversely, more recent studies suggest that silencing of DUOX1 may contribute to epithelial-to-mesenchymal transition and as a potential active mediator of squamous metaplasia or lung cancer. Our current NIH-funded studies are aimed at exploring the molecular mechanisms involved in DUOX1-dependent signaling, and the potential implications for chronic lung disease.

Technologies and other available resources

• Our research is highly multidisciplinary
  • strong focus on biochemical and analytical approaches to determine chemical mechanisms involved in oxidant or electophile signaling
  • Strong efforts are made to translate findings in primary 3-dimensional epithelial cultures and in complex animal models of lung disease and in studies of patient materials
• Collaborations
  • several basic researchers in the Departments of Chemistry and Biochemistry
  • basic and clinical investigators in the Department of Pathology & Laboratory Medicine and the Department of Medicine
  • We provide intellectual and technical expertise from diversely skilled post-doctoral fellows, research associates, and visiting scholars
  • Close access to common facilities within the Department of Pathology & Laboratory Medicine's Environmental Pathology Program and Vermont Lung Center and core resources in the College of Medicine
  • Opportunities to interact with prominent invited speakers in weekly seminar series and to present research at national or international research conferences, ensure a rich and stimulating learning environment for students and fellows.