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 O2-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.
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References
1.
BarclayJ, PatelS, DornG, WotherspoonG, MoffattS, EunsonL, Abdel'alS, NattF, HallJ, WinterJ, BevanS, WishartW, FoxA, GanjuP. 2002. Functional downregulation of P2X3 receptor subunit in rat sensory neurons reveals a significant role in chronic neuropathic and inflammatory pain. J Neurosci, 22:8139–8147.
2.
BarnesPJ. 1994. Endothelins and pulmonary diseases. J Appl Physiol, 77:1051–1059.
3.
ChenJ, HeL, DingerB, StensaasL, FidoneS. 2002. Role of endothelin and endothelin A-type receptor in physiological adaptation of the carotid body during chronic hypoxia. Am J Physiol Lung Cell Molec Physiol, 282:L1314–L1323.
4.
ChenJ, HeL, LiuX, DingerB, StensaasL, FidoneS. 2007. Effect of the endothelin receptor antagonist bosentan on chronic hypoxia-induced morphological and physiological changes in rat carotid body. Am J Physiol Lung Cell Mol Physiol, 292:L1257–L1262.
ChenY, TipoeGL, LiongE, LeungS, LamSY, IwaseR, TjongYW, FungML. 2002b. Chronic hypoxia enhances endothelin-1-induced intracellular calcium elevation in rat carotid body chemoreceptors and upregulates ETA receptor expression. Pflugers Arch, 443:565–573.
7.
DawesKE, PeacockAJ, GrayAJ, BishopJE, LaurentGJ. 1994. Characterization of fibroblast mitogens and chemoattractants produced by endothelial cells exposed to hypoxia. Am J Respir Cell Mol Biol, 10:552–559.
8.
DicarloVS, ChenS-J, MengQC, DurandJ, YanoM, ChenY-F, OparilS. 1995. ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat. Am J Physiol, 269:L690–L697.
9.
FidoneS, DingerBG, GonzalezC. 1995. Mechanisms of carotid body chemoreception. The Lung Biology in Health Disease, Vol. X, The Regulation of Breathing. DempseyJA, PackAI. Marcel Dekker, Inc.: New York, 391–471.
10.
FinleyJCW, KatzDM. 1992. The central organization of carotid body afferent projections to the brainstem of the rat. Brain Res, 572:108–116.
11.
FridMG, LiM, GnanasekharanM, BurkeDL, FragosoM, StrassheimD, SylmanJL, StenmarkKR. 2009. Sustained hypoxia leads to the emergence of cells with enhanced growth, migratory, and promitogenic potentials within the distal pulmonary artery wall. Am J Physiol Lung Cell Mol Physiol, 297:L1059–L1072.
12.
GonzalezC, AlmarazL, ObesoA, RigualR. 1994. Carotid body chemoreceptors: From natural stimuli to sensory discharges. Physiol Rev, 74:829–898.
13.
HuJ, SischerDJ, BishopricNH, WebsterKA. 1998. Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochem Biophys Res Comm, 245:894–899.
14.
JarvisMF. 2010. The neural-glial purinergic receptor ensemble in chronic pain states. Trends Neurosci, 33:48–57.
15.
KlineDD, PengYJ, ManaloDJ, SemenzaGL, PrabhakarNR. 2002. Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha. Proc Natl Acad Sci USA, 99:821–826.
16.
LahiriS, RoyA, BabySM, HoshiT, SemenzaGL, PrabhakarNR. 2006. Oxygen sensing in the body. Prog Biophys Mol Biol, 91:249–286.
17.
LightAR, HughenRW, ZhangJ, RainierJ, LiuZ, LeeJ. 2008. Dorsal root ganglion neurons innervating skeletal muscle respond to physiological combinations of protons, ATP, and lactate mediated by ASIC, P2X, and TRPV1. J Neurophysiol, 100:1184–1201.
18.
LiuX, HeL, DingerB, FidoneSJ. 2011. Chronic hypoxia-induced acid-sensitive ion channel expression in chemoafferent neurons contributes to chemoreceptor hypersensitivity. Am J Physiol Lung Cell Mol Physiol, 301:L985–L992.
19.
LiuX, HeL, StensaasL, DingerB, FidoneS. 2009. Adaptation to chronic hypoxia involves immune cell invasion and increased expression of inflammatory cytokines in rat carotid body. Am J Physiol Lung Cell Mol Physiol, 296:L158–L166.
20.
LukiwWJ, OttleczA, LambrouG, GrueningerM, FinleyJ, ThompsonHW, BazanNG. 2003. Coordinate activation of HIF-1 and NF-kappaB DNA binding and COX-2 and VEGF expression in retinal cells by hypoxia. Invest Ophthalmol Vis Sci, 44:4163–4170.
21.
MametJ, BaronA, LazdunskiM, VoilleyN. 2002. Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. J Neurosci, 22:10662–10670.
22.
NassarMA, StirlingLC, ForlaniG, BakerMD, MatthewsEA, DickensonAH, WoodJN. 2004. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc Natl Acad Sci USA, 101:12706–12711.
23.
NurseCA. 2010. Neurotransmitter and neuromodulatory mechanisms at peripheral arterial chemoreceptors. Exp Physiol, 95:657–667.
24.
OparilS, ChenS-J, MengQC, EltonTS, YanoM, ChenY-F. 1995. Endothelin-A receptor antagonist prevents acute hypoxia-induced pulmonary hypertension in the rat. Am J Physiol, 268:L95–L100.
25.
PeacockAJ, DawesKE, ShockA, GrayAJ, ReevesJT, LaurentGJ. 1992. Endothelin-1 and endothelin-3 induce chemotaxis and replication of pulmonary artery fibroblasts. Am J Respir Cell Mol Biol, 7:492–499.
26.
PeersC, WyattCN, EvansAM. 2010. Mechanisms for acute oxygen sensing in the carotid body. Respir Physiol Neurobiol, 174:292–298.
27.
PengYJ, NanduriJ, RaghuramanG, SouvannakittiD, GadallaMM, KumarGK, SnyderSH, PrabhakarNR. 2010. H2S mediates O2 sensing in the carotid body. Proc Natl Acad Sci USA, 107:10719–10724.
28.
PowellFL, FuZ. 2008. HIF-1 and ventilatory acclimatization to chronic hypoxia. Respir Physiol Neurobiol, 164:282–287.
29.
PowellFL, MilsomWK, MitchellGS. 1998. Time domains of the hypoxic ventilatory response. Respir Physiol, 112:123–134.
30.
PrabhakarNR, JaconoFJ. 2005. Cellular and molecular mechanisms associated with carotid body adaptations to chronic hypoxia. High Alt Med Biol, 6:112–120.
31.
PrabhakarNR, PengYJ, KumarGK, NanduriJ, DiGC, LahiriS. 2009. Long-term regulation of carotid body function: Acclimatization and adaptation—Invited article. Adv Exp Med Biol, 648:307–317.
32.
Reyes-GarciaMG, Garcia-TamayoF. 2009. A neurotransmitter system that regulates macrophage pro-inflammatory functions. J Neuroimmunol, 216:20–31.
33.
SallmannS, JuttlerE, PrinzS, PetersenN, KnopfU, WeiserT, SchwaningerM. 2000. Induction of interleukin-6 by depolarization of neurons. J Neurosci, 20:8637–8642.
34.
StenmarkKR, DavieNJ, ReevesJT, FridMG. 2005. Hypoxia, leukocytes, and the pulmonary circulation. J Appl Physiol, 98:715–721.
35.
StuckyCL, DubinAE, JeskeNA, MalinSA, McKemyDD, StoryGM. 2009. Roles of transient receptor potential channels in pain. Brain Res Rev, 60:2–23.
36.
TederP, NoblePW. 2000. A cytokine reborn? Endothelin-1 in pulmonary inflammation and fibrosis. Am J Respir Cell Mol Biol, 23:7–10.
37.
VoilleyN, deWJ, MametJ, LazdunskiM. 2001. Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors. J Neurosci, 21:8026–8033.
38.
YamashitaK, DischerDJ, HuJ, BishopricNH, WebsterKA. 2001. Molecular regulation of the endothelin-1 gene by hypoxia. J Biol Chem, 276:12645–12653.
