title: Effect of endothelin receptor antagonist bosentan on chronic hypoxia-induced inflammation and chemoafferent neuron adaptation in rat carotid body.
abstract: 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-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), 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.
authors.affiliation: Department of Physiology, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Liu
authors.forename: Liang
authors.initials: L
authors.lastname: He
authors.forename: Bruce
authors.initials: B
authors.lastname: Dinger
authors.forename: Larry
authors.initials: L
authors.lastname: Stensaas
authors.forename: Salvatore
authors.initials: S
authors.lastname: Fidone
mesh_terms: D062565:Acid Sensing Ion Channels / Q000187:drug effects; D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000077300:Bosentan; D002344:Carotid Body / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002628:Chemoreceptor Cells / Q000187:drug effects / Q000502:physiology*; D002908:Chronic Disease; D019332:Endothelin-1 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D000860:Hypoxia / Q000150:complications / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D051381:Rats; D044022:Receptor, Endothelin A / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D062565:Acid Sensing Ion Channels; D000959:Antihypertensive Agents; D018932:Chemokine CCL2; D019332:Endothelin-1; D007375:Interleukin-1; D053583:Interleukin-1beta; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D014446:Tyrosine 3-Monooxygenase; D017493:Leukocyte Common Antigens; D000077300:Bosentan