Chronic lung diseases such as asthma and COPD are one of the leading causes of death in the US and the mechanisms for the progressive remodeling of lung tissue that occurs in these diseases are incompletely understood. Adenosine levels are elevated in the lungs of these subjects where it engages four subtypes of receptors which results in the release of the pro-fibrotic cytokine IL-6, leading to augmented bronchoconstriction to stimuli, airway inflammation and remodeling. In animal models, decreasing the accumulation of adenosine is known to alter the course of lung inflammation and increase survival. The bronchospastic response in subjects with asthma and COPD to adenosine is not seen in normal subjects, indicating that the underlying mechanisms of increased bronchospasm, airway inflammation and remodeling are augmented in these diseases. Adenosine is generated by dephosphorylation of ATP at sites of inflammation and remodeling as well as generated intracellularly and transported through the nucleoside transporters. In this proposal, we will generate evidence that CD38, a cell surface protein expressed in airway smooth muscle, is a significant source of adenosine from NAD+ by the enzymatic cascade CD38/CD203a/CD73. The enzymatic activity that converts NAD+ to AMP involves CD38 whose expression in airway smooth muscle is augmented by inflammatory and Th2 cytokines and to a greater extent in cells derived from asthmatics. This pathway of adenosine and IL-6 production are sufficient to cause airway hyperresponsiveness, airway inflammation and airway remodeling independent of the roles of CD38 in intracellular calcium signaling and innate immunity. Thus we postulate that inhibiting CD38 expression in airway smooth muscle will limit the progression of chronic lung diseases by decreasing adenosine and IL-6. In the studies with airway smooth muscle cells from asthmatics and non-asthmatics maintained in an inflammatory environment, in a mouse model of chronic allergen challenge and in the Cd38-/- mice, we will provide evidence for airway smooth muscle as a significant source of adenosine and IL-6 and that targeting the enzymes involved in the conversion of NAD+ to adenosine can reverse the lung damage. We have identified the roles of two specific miRNAs in the regulation of CD38 expression and will demonstrate their ability to decrease adenosine and IL-6 release in airway smooth muscle cells and reversal of the airway phenotype by delivering in vivo in mice.

Public Health Relevance

Adenosine which is derived by dephosphorylation of ATP at sites of inflammation plays a key role in chronic lung diseases such as asthma and COPD. By signaling through one or more of the four subtypes of receptors, adenosine causes tissue destruction and remodeling in these diseases through the production of the pro-fibrotic cytokine IL-6. The major cellular source of adenosine in the lungs is thought to be from dephosphorylation of ATP at inflammatory sites. In this proposal, we will show evidence that airway smooth muscle cells are a major source of adenosine from NAD+ through the enzymatic cascade CD38/CD203a/CD73. By regulating the expression of CD38 by miRNAs or genetic deletion or siRNA knockdown, we will demonstrate significant attenuation of NAD+- derived adenosine and IL-6 release in cells. We will evaluate the contribution of CD38/NAD+ axis to lung damage and remodeling in mouse models of chronic allergen challenge to provide a translational relevance to the study.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI119395-02
Application #
9242566
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Dong, Gang
Project Start
2016-03-15
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2017
Total Cost
$190,833
Indirect Cost
$65,833
Name
University of Minnesota Twin Cities
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455