The Leukotriene Pathway in Structural Cells of the Human Airway

Abstract

LTs are thought to be derived predominantly from cells of myeloid origin. Airway structural cell types such as human bronchial epithelial (HBE) cells, human airway smooth muscle (HASM) cells and lung fibroblasts generate pro-inflammatory cytokines and lipid mediators such as prostanoids and 15-lipoxygenase products, but their capacity to generate leukotrienes is unclear. In leukocytes LT synthesis is initiated from membrane-derived arachidonic acid by 5-lipoxygenase (5-LO) and its activating protein FLAP, followed by conversion of LTA₄ to LTB₄ by LTA₄ hydrolase or to LTC₄ to LTC₄ synthase. We hypothesised that HBE cells, HASM cells and fibroblasts may express 5-LO pathway enzymes and synthesise LTC₄ to LTB₄, either spontaneously or in response to stimulation with inflammatory mediators, and that they may also express CysLT₁ and/or BLT.

Using RT-PCR, basal expression of mRNA for 5-LO, FLAP, LTA₄ hydrolase and LTC₄ synthase was detected in primary HBE cells, HASM cells and bronchial fibroblasts, as well as in the 16-HBE cell line.

These results show that HBE cells, HASM cells and fibroblasts constitutively express a complete and active 5-LO pathway for the synthesis of LTB₄ and LTC₄ and that this may be regulated by exposure to inhaled asthma triggers or endogenously released inflammatory cytokines and autacoids. Constutive expression of CysLT₁R on all three cell-types may be up-regulated in an inflammatory environment leading to increased CysLT₁ mediated effects such as collagen or mucus secretion, bronchoconstriction and proliferation. The role of BLT or HASM cells and fibroblasts is not yet clear, although LTB₄ is chemotactic for fibroblasts. LTs released by HBEC, HASM and fibroblasts may lead both to autocrine effects and to leukocyte infiltration, and in combination with other mediators produced by structural cells, contribute to the vicious circle of inflammation and remodelling within the asthmatic airway.

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