Asthma is a chronic relapsing airways disease that represents a major public health problem worldwide. Intermittent exacerbations are provoked by airway mucosal exposure to pro-inflammatory stimuli, with RNA viral infections or inhaled allergens representing the two most common precipitants. In this setting, inducible signaling pathways operating in the airway mucosa play a central role in the initiation of airway inflammation through the production of antimicrobial peptides (defensins), cytokines, chemokines and arachidonic acid metabolites that coordinate the complex processes of vascular permeability, cellular recruitment, mucous hyper-secretion, bronchial constriction and tissue remodeling. These signals also are responsible for leukocytic infiltration into the submucosa, T helper-lymphocyte skewing, and allergic sensitization. How the mucosa functions as a transducing tissue is incompletely understood.
The long-term goal of our program project (P01) is to understand the role the mucosa plays in facilitating viral and allergen-induced airway inflammation. Our objective is to further extend these studies to understand the biochemical mechanism(s) by which ROS stress modulates mucosal cell signaling to produce inflammation.
The overall hypothesis is that ROS production by the respiratory mucosa activates the innate immune response (IIR), producing airway inflammation. This mucosally initiated airway inflammation is modulated by antioxidant proteins and products of endogenous DNA damage-repair. Our studies will result in the identification of novel signaling pathways that influence epithelial and dendritic cell responses to two common asthma exacerbants, respiratory paramyxoviruses and pollen allergens.
The four projects in this P01 are:
- Project (P)1, Transcriptional elongation in NF-kB-mediated inflammation led by Allan R. Brasier, MD;
- P2, entitled Role of antioxidant responses in viral bronchiolitis co-led by Antonella Casola MD, and Roberto Garofalo, MD;
- P3, entitled Role of the DNA glycosylase OGG1 in oxidative stress-induced innate inflammation led by Istvan Boldogh, PhD;
- P4, Innate regulation of pollen-oxidase induced inflammation led by Sanjiv Sur, MD
Read more about our projects and people by navigating the links on the left.