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Specific Role of Eotaxin-1 and Eotaxin-2 in Allergic Pulmonary Eosinophilia

Pope, Samuel M.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1098472372

Abstract Details

2004, PhD, University of Cincinnati, Medicine : Molecular Genetics, Biochemistry, and Microbiology.
Eosinophilia has long been recognized as a key pathologic feature of asthma causing direct damage to the lung. Numerous studies have implicated the eotaxin chemokines in regulating allergen-induced eosinophil responses in the lung. However, the individual and combined contribution of each of the individual eotaxins was not understood. To examine the individual and combined roles of the eotaxin chemokines in experimental asthma mice were utilized that were genetically altered to be deficient in eotaxin-1 or eotaxin-2 alone, eotaxin-1 and eotaxin-2 together, and the eotaxin receptor CCR3. Accordingly, novel eotaxin-2-deficient and eotaxin-1/eotaxin-2 double-deficient (eotaxin-1/2 DKO) mice were generated. The various genetically altered mice were subjected to either IL-13-induced or ovalbumin (OVA)-induced experimental asthma. Analysis of airway eosinophilia as measured in the bronchial alveolar lavage fluid (BALF) revealed a dominant role for eotaxin-2 compared with eotaxin-1. Conversely, analysis of peribronchial tissue eosinophilia implicated a role for eotaxin-1 and not eotaxin-2 in the IL-13 model, but not the OVA model. Interestingly, analysis of eotaxin-1/2 DKO and CCR3-deficient mice showed substantial, synergistic reductions in both airway and peribronchial tissue eosinophilia compared to mice deficient in eotaxin-1 or eotaxin-2 alone and wild type mice. Notably, eosinophils in the lung tissue of eotaxin-1/2 DKO and CCR3-deficient mice were dispersed throughout the parenchyma compared with wild type mice were concentrations around the blood vessels and airways were observed. Northern blot analysis of eotaxin-1 and 2 expression revealed that IL-13 is critical for OVA-induced eotaxin-1 and eotaxin-2 mRNA. Temporal analysis revealed only modest differences in eotaxin-1 and 2 induction patterns. However, only eotaxin-2 was markedly induced in the airway inflammatory macrophages/mononuclear cells. In contrast, eotaxin-1 was expressed primarily in the lung tissue. Collectively, these data suggest that the dominant role of eotaxin-2 in regulating airway eosinophilia is mechanistically related to its unique spatial expression pattern. Taken together, these results provide definitive evidence for a fundamental role of the eotaxin/CCR3 pathway in the development of pulmonary eosinophilia in experimental asthma. As such, these results imply that potential therapeutic blockade of antigen-induced pulmonary eosinophilia will likely require antagonism of multiple CCR3 ligands.
Dr. Marc Rothenberg (Advisor)
183 p.
eotaxin-1; eotaxin-2; macrophages/mononuclear cells; CCR3 ligands

Recommended Citations

Citations

  • Pope, S. M. (2004). Specific Role of Eotaxin-1 and Eotaxin-2 in Allergic Pulmonary Eosinophilia [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1098472372

    APA Style (7th edition)

  • Pope, Samuel. Specific Role of Eotaxin-1 and Eotaxin-2 in Allergic Pulmonary Eosinophilia. 2004. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1098472372.

    MLA Style (8th edition)

  • Pope, Samuel. "Specific Role of Eotaxin-1 and Eotaxin-2 in Allergic Pulmonary Eosinophilia." Doctoral dissertation, University of Cincinnati, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1098472372

    Chicago Manual of Style (17th edition)

ucin1098472372
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© 2004, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.