The development and severity of allergic asthma is influenced by both genetic and environmental factors. Epidemiological data often show no clear relationship between the levels of putative allergens and clinical symptoms. Recent data suggest that environmental exposure to bacterial LPS may be a risk factor related to asthma severity. Airborne LPS is typically present at levels that are insufficient to activate alveolar macrophages in the absence of the accessory molecule LBP. LBP levels are markedly elevated in BAL fluids obtained from asthmatic subjects compared with normal controls. We hypothesized that LBP present in the lung could augment the pulmonary inflammation and AHR associated with allergic asthma by sensitizing alveolar macrophages to LPS or other bacterial products and triggering them to release pro-inflammatory mediators. We compared WT and LBP-deficient mice using a defined antigen immunization and aerosol challenge model of allergic inflammation and AHR. Immunized LBP-deficient mice did not develop substantial antigen-induced AHR, whereas WT mice developed marked bronchoconstriction following aerosol antigen sensitization and challenge with methacholine. Similarly, production of NO synthase 2 (iNOS) protein and the NO catabolite peroxynitrite were dramatically higher in the lungs of WT mice following challenge, compared with LBP-deficient mice. Thus nitric oxide production and metabolism appears to correlate with AHR. In contrast, both mice developed similar pulmonary inflammatory cell infiltrates and elevated mucin production. Thus, LBP appears to participate in the development of antigen-induced AHR and peroxynitrite production, but does not appear to be required for the development of pulmonary inflammation. This project has three specific aims. First, we will determine whether knockout mice that lack the ability to respond normally to bacterial products fail to develop AHR in the allergic asthma model. Second, we will determine whether myeloid cells mediate LBP-dependent development of AHR. Third, we will determine how LBP contributes to the nature and extent of cellular immune responses to aeroallergen.
| Lu, Chen; O'Connor, George T; Dupuis, Josée et al. (2016) Meta-Analysis for Penalized Regression Methods with Multi-Cohort Genome-Wide Association Studies. Hum Hered 81:142-149 |
| Li, Yun; O'Connor, George T; Dupuis, Josée et al. (2015) Modeling gene-covariate interactions in sparse regression with group structure for genome-wide association studies. Stat Appl Genet Mol Biol 14:265-77 |
| Lu, Chen; Latourelle, Jeanne; O'Connor, George T et al. (2013) Network-guided sparse regression modeling for detection of gene-by-gene interactions. Bioinformatics 29:1241-9 |
| Granada, Mark; Wilk, Jemma B; Tuzova, Marina et al. (2012) A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study. J Allergy Clin Immunol 129:840-845.e21 |
| McFadden, Caroline; Morgan, Ross; Rahangdale, Shilpa et al. (2007) Preferential migration of T regulatory cells induced by IL-16. J Immunol 179:6439-45 |
| Burkart, Kristin M; Barton, Sheila J; Holloway, John W et al. (2006) Association of asthma with a functional promoter polymorphism in the IL16 gene. J Allergy Clin Immunol 117:86-91 |
| Rahangdale, Shilpa; Morgan, Roger; Heijens, Claudia et al. (2006) Chemokine receptor CXCR3 desensitization by IL-16/CD4 signaling is dependent on CCR5 and intact membrane cholesterol. J Immunol 176:2337-45 |
| O'Connor, George T (2005) Allergen avoidance in asthma: what do we do now? J Allergy Clin Immunol 116:26-30 |
| Ren, Fucheng; Zhan, Xin; Martens, Gregory et al. (2005) Pro-IL-16 regulation in activated murine CD4+ lymphocytes. J Immunol 174:2738-45 |
| Lynch, Elizabeth A; Heijens, Claudia A W; Horst, Noah F et al. (2003) Cutting edge: IL-16/CD4 preferentially induces Th1 cell migration: requirement of CCR5. J Immunol 171:4965-8 |
