Effect of endothelin receptor antagonist bosentan on chronic hypoxia-induced inflammation and chemoafferent neuron adaptation in rat carotid body.
HIGH ALTITUDE MEDICINE & BIOLOGY(2012)
Abstract
Liu, Xuemei, Liang He, Bruce Dinger, Larry Stensaas, and Salvatore Fidone. Effect of endothelin receptor antagonist bosentan on chronic hypoxia-induced inflammation and chemoafferent neuron adaptation in rat carotid body. High Alt Med Biol. 13:209-216, 2012.-Chronic hypoxia (CH) induces an inflammatory response in rat carotid body that is characterized by immune cell invasion and the expression of pro-inflammatory cytokines. In the present study, we have investigated the role of type-A endothelin (ET-A) receptors in the development of CH-induced inflammation. After 7 days of CH (380 Torr), double-label immunofluorescence studies demonstrated elevated levels of ET-A receptor and tyrosine hydroxylase (TH) in O-2-sensitive type I cells. Following CH, ET-A receptors were also expressed on resident and invasive CD45+ immune cells distributed in tissue surrounding chemosensory cell lobules. Immnofluorescence and quantitative PCR studies showed that concurrent treatment with the ET-A/B receptor antagonist, bosentan (200 mg/kg/day), blocked CH-induced ED-1 + macrophage invasion and the upregulation of cytokines, including interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF alpha), and monocyte chemoattractant protein-1 (MCP-1). Moreover, bosentan treatment blocked the CH-induced increases in expression of acid-sensitive ion channels (ASICs) in chemoafferent neurons in the petrosal ganglion (PG). Our findings are consistent with the hypothesis that CH-induced inflammation involves the upregulation and release of ET-1 from type I cells. ET-1 may act in an autocrine/paracrine mechanism via ET-A receptors on chemosensory type I cells and immune cells to promote an inflammatory response.
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Key words
gene expression,cytokines,macrophages,immunocytochemistry,sensory adaptation
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