Toward the achievement of the overall goal of this AADRC, Project 3 """"""""Eosinophilic Inflammation in Intrinsic Asthma"""""""" will address why eosinophilia inflammation persists in the airways of patients with asthma and what significance eosinophil degranulation has in the disease process of human asthma. Bronchial mucosal abnormalities that characterize asthma, such as persistent airway eosinophilia and increased T cells producing IL-5, strongly suggest an ongoing T helper (Th)2-like immune response of the airways. Atopy and an IgE-mediated response to extrinsic antigens are the known and identifiable predisposing factors for asthma. However, many adult patients with asthma do not seem to be particularly atopic. The objective of this project is to elucidate the causes and pathophysiologic mechanisms of asthma in patients that are not demonstrably atopic, a condition commonly referred to a non-atopic or intrinsic asthma. We will test the hypothesis that bronchial asthma in patients with non-atopic asthma is caused by a chronic immunologic reaction to intrinsic antigen, namely fungi present in the airways, resulting in persistent IL-5 production and eosinophil activation in the airways.
In Specific Aim 1, we will define the enhanced immunological responses, especially IL-5 and IFN-gamma production, of patients' immune cells to non-pathologic fungal organisms present in the airways.
In Specific Aim 2, we will directly test whether fungal organisms present in the airways are involved in the disease process by removing the fungi from the airways by instillation of an antifungal agent. Conversely, the effects of an increased fungal antigen burden will be investigated by segmental broncho-provocation.
In Specific Aim 3, we will use novel antibodies that recognize eosinophil degranulation activities to define the clinical relevance of eosinophil activation in human asthma by testing the hypothesis that enhanced eosinophil activation and degranulation in the airway lead to exacerbation of asthma symptoms in patients with non-atopic asthma. Elucidation of the causes and mechanisms of inflammation in non-atopic asthma will likely foster a better understanding of eosinophilia inflammation in human asthma and will enhance development of specific and effective therapies for this difficult disorder.
| Wylam, Mark E; Xue, Ailing; Sieck, Gary C (2012) Mechanisms of intrinsic force in small human airways. Respir Physiol Neurobiol 181:99-108 |
| Shan, Jiajie; Liao, Jie; Huang, Junwei et al. (2012) Bicarbonate-dependent chloride transport drives fluid secretion by the human airway epithelial cell line Calu-3. J Physiol 590:5273-97 |
| Kim, Chang Keun; Choi, Jungi; Callaway, Zak et al. (2010) Increases in airway eosinophilia and a th1 cytokine during the chronic asymptomatic phase of asthma. Respir Med 104:1436-43 |
| Xue, Ailing; Wang, John; Sieck, Gary C et al. (2010) Distribution of major basic protein on human airway following in vitro eosinophil incubation. Mediators Inflamm 2010:824362 |
| Kim, Chang K; Kita, Hirohito; Callaway, Zak et al. (2010) The roles of a Th2 cytokine and CC chemokine in children with stable asthma: potential implication in eosinophil degranulation. Pediatr Allergy Immunol 21:e697-704 |
| Plager, Douglas A; Davis, Mark D P; Andrews, Amy G et al. (2009) Eosinophil ribonucleases and their cutaneous lesion-forming activity. J Immunol 183:4013-20 |
| Kim, Hyo-Bin; Kim, Chang-Keun; Iijima, Koji et al. (2009) Protein microarray analysis in patients with asthma: elevation of the chemokine PARC/CCL18 in sputum. Chest 135:295-302 |
| Yamazaki, Kiyoshi; Murray, Joseph A; Kita, Hirohito (2008) Innate immunomodulatory effects of cereal grains through induction of IL-10. J Allergy Clin Immunol 121:172-178.e3 |
| Lee, So Yeong; Palmer, Melissa L; Maniak, Peter J et al. (2007) P2Y receptor regulation of sodium transport in human mammary epithelial cells. Am J Physiol Cell Physiol 293:C1472-80 |
| Chanson, Marc; Kotsias, Basilio A; Peracchia, Camillo et al. (2007) Interactions of connexins with other membrane channels and transporters. Prog Biophys Mol Biol 94:233-44 |
Showing the most recent 10 out of 23 publications
