TGF-BETA AND 15 HETE IN POORLY STEROID RESPONSIVE ASTHMA

National Jewish Health, Denver CO

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Abstract

The pathobiology of severe asthma, poorly response to glucocorticoids, remains poorly understood. Recent evidence suggests that a nonspecific and chronic wound repair process exists in severe asthmatic airways highlighted by increases in the "anti-inflammatory" and profibrotic cytokine, transforming growth factor-beta (TGF-beta). An associated up-regulation of a specific allergic response also is present, hallmarked by increases in the TH2 cytokine, interleukin (IL)-13, and the eicosanoid, 15 hydroxyeicosatetraenoic (HETE). Little is known regarding the interactions between these nonspecific and specific "inflammatory modulating" pathways. This proposal will examine the regulation and interrelationships of these two pathways, and how dysregulation in these pathways could promote fibrotic responses in severe asthma. To accomplish this, specific aim number 1 will evaluate the quantitative and qualitative differences in the enzyme 15 lipoxygenase (LO) (protein and mRNA), its product, 15S HETE. and TGF-beta1 (protein and mRNA) in the airways of severe asthmatics, compared to control groups. This will include an evaluation of the differences in the cell types and patterns of expression of these mediators utilizing colocalization studies for protein/mRNA in tissue and specific isolated cell culture systems. Specific aim number 2 will focus on the direct and indirect regulatory effects of IL-13 and angiotensin II (potential stimulatory factors) on 15S HETE/15L0 and TGF-beta1. IL-13 and angiotensin II will be quantified in the tissue. Then, the effects of these mediators on TGF-beta1 and 15S HETE in fell systems will be evaluated. Specific aim number 3 will determine whether 15S HETE, the product of 15 LO, influences signaling in angiotensin II/TGF-beta1 pathways through incorporation into membrane phospholipids. Additional studies will determine whether membrane incorporation of 15S HETE decreases activation of protein kinase C pathways through increased oxidation of diacylglycerol. In all the specific aims, comparison will be made between the normal responses and the abnormal responses occurring in asthma, particularly severe asthma. It is hoped than a better understanding of the interactions of these two "anti-inflammatory" pathways (one nonspecific, the other specific (allergic)) will improve not only the understanding of responses to injury in asthma, but also in many other diseases associated with an injury/repair/fibrosis cycle.