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Dendritic-epithelial cells crosstalk in lung inflammation

Institution: University of California, Irvine
Investigator(s): Anshu Agrawal, Ph.D.
Award Cycle: 2016 (Cycle 25) Grant #: 25IP-0012 Award: $300,000
Subject Area: Pulmonary Disease
Award Type: High Impact Pilot Award

Initial Award Abstract

Increased inflammation in the lung in the absence of infection or diseases is a major risk factor for respiratory disease and infections.  Smokers are at high risk for infections of the lung and diseases such as asthma, lung cancer, COPD (chronic obstructive pulmonary disease). We inhale a lot of harmless antigens during respiration. It would be harmful to generate immune response against these non-pathogenic antigens. The cells of the airway suppress the immune response to harmless antigens. Dendritic cells (DCs) are cells of the innate immune system that start and regulate the nature of immune response. DCs possess the capacity to prevent response to harmless antigens (tolerance) while mounting inflammatory responses against harmful pathogens. DCs are present below the epithelial cell layer in the lung. Since DCs and airway epithelial cells (AECs) are in close contact, both cells can affect the functions of each other. For example, AECs secrete factors which prevent DCs from becoming activated in response to harmless antigens. Besides preventing DC activation, AECs can also enhance the response of DCs to respiratory infections. We also found that DCs can affect the barrier function of AECs by virtue of the factors secreted by them.  The epithelial cells-DC crosstalk is thus extremely important in preventing inflammation, maintaining tolerance and generating immunity in the lung. Changes in the function of any of the cells in smokers can result in loss of tolerance and airway inflammation. Strikingly, there is a scarcity of information regarding the interaction between AECs and DCs, particularly after nicotine exposure. The objective of the present proposal is to fill this key gap in knowledge. The hypothesis is that nicotine modifies the crosstalk between AECs and DCs in the lung resulting in reduced mucosal tolerance increased lung inflammation and reduced lung immunity. Specific aims are 1) Compare the functions of the AECs and DCs after acute and chronic nicotine exposure; 2) To investigate the modifications in AECs functions after culture with DCs from smokers and non-smokers.