Expression of functional leukotriene B₄ receptors on human airway smooth muscle cells

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• 作者：Satoko Watanabe ; Akira Yamasaki ; Kiyoshi Hashimoto ; Yasushi Shigeoka ; Hiroki Chikumi ; Yasuyuki Hasegawa ; Takashi Sumikawa ; Miyako Takata ; Ryota Okazaki ; Masanari Watanabe ; Tsuyoshi Yokogawa ; Miki Yamamura ; Tatsuya Hayabuchi ; William T. Gerthoffer ; Andrew J. Halayko ; Eiji Shimizu
• 关键词：Asthma ; airway remodeling ; airway smooth muscle cells ; LTB₄ ; BLT
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2009
• 出版时间：July 2009
• 年：2009
• 卷：124
• 期：1
• 页码：59-65.e3
• 全文大小：551 K

文摘

Background

Leukotriene B₄ (LTB₄) increases in induced sputum and exhaled breath condensate in people with asthma. Furthermore, the T_H2-type immune response and airway hyperresponsiveness induced by ovalbumin sensitization is markedly suppressed in LTB₄ receptor (BLT) 1 null mice. These studies suggest that LTB₄ may contribute to asthma pathophysiology. However, the direct effects of LTB₄ on human airway smooth muscle (ASM) have not been studied.

Objectives

We sought to determine the expression of LTB₄ receptors on human ASM and its functional role in mediating responses of human ASM cells, and the effect of LTB₄ on these cells.

Methods

Immunohistochemistry, RT-PCR, Western blotting, and flow cytometry were used to determine the expression of LTB₄ receptors. To determine the effect of LTB₄ on human ASM cells, cell proliferation was assessed by counting cells, and chemokinesis was assessed by gold particle phagokinesis assay.

Results

We confirmed expression of both BLT1 and BLT2 in human ASM cells in bronchial tissue and in cell culture. LTB₄ markedly induced cyclin D1 expression, proliferation, and chemokinesis of human ASM cells. LTB₄ also induced phosphorylation of both p42/p44 mitogen-activated protein kinase (MAPK) and downstream PI3 kinase effector, Akt1. However, we observed no induction of c-Jun N-terminal kinase or p38 MAPK. Notably, LTB₄-induced migration and proliferation of ASM cells were inhibited by the BLT1 specific antagonist, U75302, and by inhibitors of p42/p44 MAPK phosphorylation (U1026), and PI3 kinase (LY294002).

Conclusions

These observations are the first to suggest a role for a LTB₄-BLT1 signaling axis in ASM responses that may contribute to the pathogenesis of airway remodeling in asthma.