Expression of eicosanoid pathway enzymes in inflammatory cells

Abstract

We hypothesised that abnormal levels of expression and/or altered cellular localisation of 5-LO and COX pathway enzymes in the airway may predict the susceptibility of human subjects to common precipitants of asthma, and/or modify eicosanoid pathway enzyme expression in a way that promotes chronic inflammation.

The bronchial biopsy studies indicated that individual eicosanoid enzymes are expressed by subpopulations of leukocyte phenotypes. This was confirmed by immunocytochemical and FACS analysis of their expression within immunomagnetically purified mast cells from human lung and leukocytes from venous blood. In eosinophils, upregulation of 5-LO pathway enzymes was demonstrated in response to eosinophilopoietic cytokines (IL5, GM-CSF) that are generated by mast cells and T-cells within the asthmatic lung. The capacity of mast cells to generate cys-LT may be dependent on transcellular synthesis with accessory cells.

Preliminary efficacy data is presented on a compound (XR9173) that may be the precursor of a new class of leukotriene modifier drug which inhibit the proteins (MRP-1 and MRP-2) thought to export LTC₄ from cells. These drugs have potential applications in combating airway inflammation in asthma, and also enhancing the efficacy of cytotoxic drugs in cancer chemotherapy. The study highlighted the relative lack of selectivity for 5-LO pathway proteins not only of this compound but also of other anti-leukotriene drugs.

A combination of techniques including GMA immunohistochemistry, FACS analysis, immunocytochemistry, immunomagnetic purification, short-term cell culture, and immunoassays, was used to show that the influx of stimulus-specific leukocyte cell-types and induction of eicosanoid enzyme expression by NF-kB and other pathways, underlie abnormal metabolism of eicosanoids and may vary with diverse phenotypes of asthma. Better understanding of these mechanisms at the genetic, biochemical, cellular pharmacological and clinical levels may lead not only to novel therapies but also to better targeting of current and new therapies to those patients most likely to demonstrate clinical benefit.

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