A population of asthmatics exists who are insensitive to treatment with glucocorticoids (glucocorticoid insensitive asthmatics (GIA)). The asthmatic process in these individuals is often severe and difficult to treat. Administration of glucocorticoids to these individuals may worsen the disease and the inflammation associated with it. Studies to date have shown that the inflammation associated with severe asthma appears to be neutrophilic in nature and associated with elevations in leukotriene (LT) B4 and interleukin (IL)-8 after glucocorticoid (GC) treatment. The mechanisms behind this neutrophilic inflammation are unclear, but understanding this inflammation has clear implications for the treatment of severe GIA The hypothesis for this proposal is that inflammatory cells from GIA are exposed to a different array of cytokines than seen in asthmatics sensitive to GCs, including granulocyte- macrophage colony stimulating factor (GM-CSF) and IL-13. These cytokines, alone or in combination, alter the response of airway monocyte/macrophages and/or neutrophils such that LTB4 levels increase after GC administration. This proposal will investigate the mechanisms by which LTB4 is upregulated, including effects on levels and activity of 5 lipoxygenase (5 LO) and 5 LO activating protein (FLAP).
Specific Aim #1 will determine whether the increase in LTB4 in response to GCs exists in GIA alone and what cell type(s) are involved. This will be done by evaluating bronchoalveolar lavage fluid and cells for LTB4 before and after in vivo administration of GCs in GIA and numerous control groups. The in vitro response to GCs will also be assessed at a cellular level and the relationship of LTB4 to IL-8 in the presence of GCs addressed.
Specific Aim # 2 will identify the cytokines which are responsible for driving the adherent LTB4 response. Attention will be paid to the ability of GM-CSF and IL-13 to induce normal monocytes and/or neutrophils to behave similar to those from GIA, with increased LTB4 to treatment with GCs. These cytokines have previously been shown to 1) prime cells for increased LO activity, 2) alter the binding affinity of the GC receptor and 3) be present in severe asthmatic patients. Lastly, Specific Aim # 3 will investigate the effect of GCs on elements of the LT metabolic pathway in GIA and in the presence of GM-CSF and/or IL-13, most specifically the effect of GCs on FLAP mRNA and 5 LO levels and activity. The studies outlined here should greatly improve the understanding of severe and glucocorticoid insensitive asthma, with the implication that modulation of the 5 LO pathway in these patients will limit the neurophilic inflammation and improve the clinical response to GCs in these patients.
| Wenzel, Sally E; Tyurina, Yulia Y; Zhao, Jinming et al. (2017) PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell 171:628-641.e26 |
| Zhao, Jinming; Minami, Yoshinori; Etling, Emily et al. (2017) Preferential Generation of 15-HETE-PE Induced by IL-13 Regulates Goblet Cell Differentiation in Human Airway Epithelial Cells. Am J Respir Cell Mol Biol 57:692-701 |
| Wenzel, Sally E (2016) Emergence of Biomolecular Pathways to Define Novel Asthma Phenotypes. Type-2 Immunity and Beyond. Am J Respir Cell Mol Biol 55:1-4 |
| Ray, Anuradha; Raundhal, Mahesh; Oriss, Timothy B et al. (2016) Current concepts of severe asthma. J Clin Invest 126:2394-403 |
| Albano, Giusy D; Zhao, Jinming; Etling, Emily B et al. (2015) IL-13 desensitizes ?2-adrenergic receptors in human airway epithelial cells through a 15-lipoxygenase/G protein receptor kinase 2 mechanism. J Allergy Clin Immunol 135:1144-53.e1-9 |
| Xie, Min; Mustovich, Anthony T; Jiang, Yi et al. (2015) IL-27 and type 2 immunity in asthmatic patients: association with severity, CXCL9, and signal transducer and activator of transcription signaling. J Allergy Clin Immunol 135:386-94 |
| Traister, Russell S; Uvalle, Crystal E; Hawkins, Gregory A et al. (2015) Phenotypic and genotypic association of epithelial IL1RL1 to human TH2-like asthma. J Allergy Clin Immunol 135:92-9 |
| Watanabe, Tetsuya; Fajt, Merritt L; Trudeau, John B et al. (2015) Brain-Derived Neurotrophic Factor Expression in Asthma. Association with Severity and Type 2 Inflammatory Processes. Am J Respir Cell Mol Biol 53:844-52 |
| Ray, Anuradha; Oriss, Timothy B; Wenzel, Sally E (2015) Emerging molecular phenotypes of asthma. Am J Physiol Lung Cell Mol Physiol 308:L130-40 |
| Trejo Bittar, Humberto E; Yousem, Samuel A; Wenzel, Sally E (2015) Pathobiology of severe asthma. Annu Rev Pathol 10:511-45 |
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