Inhalation of pollens induces allergic inflammation and mucus production in the lungs of allergic subjects. """"""""Allergenic"""""""" pollens have """"""""major antigenic proteins"""""""" such as Amb a 1 in ragweed. In addition, they have many other proteins, some with enzyme activities. An important unresolved question is whether these enzyme activities within pollens influences allergic inflammation induced by the major pollen antigen. We have discovered that all tested pollens have intrinsic NADPH oxidase activity. Challenge with pollen extract induces oxidative stress in the lungs within minutes, associated with generation of GSSG (oxidized glutathione) and 4-HNE (lipid peroxide). Our central hypothesis is that GSSG and 4-HNE are generated by intrinsic pollen NADPH oxidases in the airway lining fluid independent of adaptive immunity. These molecules are perceived as a """"""""Danger signal"""""""", leading to activation of signaling pathways such as p38 MAP kinases, and production of pro-inflammatory cytokines and chemokines that recruit inflammatory cells into the airways. These recruited pro-allergic inflammatory cells facilitate induction of Th2 phenotype in the airways by major pollen antigen. Here we propose to 1) Identify and quantify pro-inflammatory genes induced by GSSG and 4-HNE in the lungs independent of adaptive immunity, and determine the role of these genes in recruiting pro-allergic inflammatory cells; 2) Test the ability of GSSG and 4-HNE to provide a second signal that potentiates allergic airway inflammation induced by major pollen antigen in sensitized mice, and boosts allergic sensitization in naive mice; 3) Test the role of p38 MAPK isoforms in mediating induction of gene products by GSSG and 4-HNE that facilitates trafficking of pro-allergic inflammatory cells and augment mucin production in airway epithelial cells. At present, antigen presentation of major pollen antigen in allergic persons is thought to be to sole mechanism of induction of allergic inflammation. We propose that generation of GSSG and 4-HNE acts in concert with antigen presentation to augment allergic inflammation. These studies are likely to generate new therapeutic ideas for patients with allergic asthma that are based on suppression of GSSG and 4-HNE based signaling pathways in the lungs.
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