Liu X, He L, Dinger B, Fidone SJ. 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, 2011. First published September 2, 2011 doi:10.1152/ajplung.00132.2011.-Previously we demonstrated that chronic hypoxia (CH) induces an inflammatory condition characterized by immune cell invasion and increased expression of inflammatory cytokines in rat carotid body. It is well established that chronic inflammatory pain induces the expression of acid-sensitive ion channels (ASIC) in primary sensory neurons, where they contribute to hyperalgesia and allodynia. The present study examines the effect of CH on ASIC expression in petrosal ganglion (PG), which contains chemoafferent neurons that innervate oxygen-sensitive type I cells in the carotid body. Five isoforms of ASIC transcript were increased ϳ1.5-2.5-fold in PG following exposure of rats to 1, 3, or 7 days of hypobaric hypoxia (380 Torr). ASIC transcript was not increased in the sympathetic superior cervical ganglion (SCG). In the PG, CH also increased the expression of channel-interacting PDZ domain protein, a scaffolding protein known to enhance the surface expression and the low pH-induced current density mediated by ASIC3. Western immunoblot analysis showed that CH elevated ASIC3 protein in PG, but not in SCG or the (sensory) nodose ganglion. ASIC3 transcript was likewise elevated in PG neurons cultured in the presence of inflammatory cytokines. Increased ASIC expression was blocked in CH rats concurrently treated with the nonsteroidal anti-inflammatory drug ibuprofen (4 mg·kg Ϫ1 ·day Ϫ1 ). Electrophysiological recording of carotid sinus nerve (CSN) activity in vitro showed that the specific ASIC antagonist A-317567 (100 M) did not significantly alter hypoxiaevoked activity in normal preparations but blocked ϳ50% of the hypoxic response following CH. Likewise, a high concentration of ibuprofen, which is known to block ASIC1a, reduced hypoxia-evoked CSN activity by ϳ50% in CH preparations. Our findings indicate that CH induces inflammation-dependent phenotypic adjustments in chemoafferent neurons. Following CH, ASIC are important participants in chemotransmission between type I cells and chemoafferent nerve terminals, and these proton-gated channels appear to enhance chemoreceptor sensitivity.

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sGC in oxygen‐sensitive carotid body type I cells is activated by the diffusible gas, nitric oxide (NO). In rats exposed to CH, sGC is down‐regulated, with a corresponding drop in NO‐stimulated production in cGMP. Moreover, CH induces an invasion of activated macrophages and the production of inflammatory cytokines in chemosensory tissue. The present study investigates the relationship between inflammation and the down‐regulation of sGC in type I cells. Quantitative PCR (qPCR) assays of carotid bodies from 7‐day CH (380 Torr) rats demonstrated a 50–500% increase in expression of cytokines interleukin‐1β (IL‐1β), IL‐6, and tumor necrosis factor‐α (TNFα). CH (7 days) elicited a >90% reduction in the expression of sGC. In contrast, animals concurrently treated with anti‐inflammatory drugs, ibuprofen (4mg/kg/day) or bosentan (200mg/kg/day), expressed normal levels of the sGC gene. sGC expression was reduced by 50% in normal type I cells cultured for 48 hrs in the presence of TNFα (50 ng/ml). However, exposure to TNFα did not alter the expression of the gene for tyrosine hydroxylase (TH). Our data indicate that a CHinduced increase in cytokine production directly influences the expression of sGC, a signaling molecule which mediates type I cell inhibition. Inflammation appears to be an important factor in the readjustment of chemoreceptor sensitivity following CH. USPHS Grants NS 12636 and NS 07938.

CH in rat carotid body induces an inflammatory response which is characterized by immune cell invasion and the expression of pro‐inflammatory cytokines. In the present study, we have investigated the role of ET‐1 and ET‐A receptors in the development of CH‐induced inflammation. Following 7 days of CH (380 Torr), immunocytochemical (ICC) studies demonstrated elevated levels of ET‐1 and ET‐A receptors in O2‐sensitive type I cells. In addition, double‐label ICC showed that following CH, ET‐A receptors were also expressed on invasive CD45+ immune cells distributed in tissue surrounding chemosensory cell lobules. Concurrent treatment with the ET‐A/B receptor antagonist, bosentan (200mg/kg/day), blocked ED‐1+ immune cell invasion and the up‐regulation of cytokines, including interleukin‐1β (IL‐1β), IL‐6 and tumor necrosis factorα (TNFα). Moreover, bosentan treatment blocked CH‐induced increased expression of acid sensitive ion channels (ASICs) in chemoafferent neurons in the petrosal ganglion (PG), and drug treatment significantly reduced chemoreceptor hypersensitivity. Our findings are consistent with the hypothesis that CH‐induced inflammation involves the up‐regulation and release of ET‐1 from type I cells; ET‐1 acts in an autocrine/paracrine mechanism via ET‐A receptors on chemosensory type I cells, and immune cells to promote an inflammatory response. USPHS Grants NS 12636 and NS 07938.

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