Sustained Exposure to Cytokines and Hypoxia Enhances Excitability of Oxygen-Sensitive Type I Cells in Rat Carotid Body: Correlation with the Expression of HIF-1α Protein and Adrenomedullin

Abstract

Liu, X., L. He, B. Dinger, L. Stensaas, and S. Fidone. Sustained exposure to cytokines and hypoxia enhances excitability of oxygen-sensitive type I cells in rat carotid body: Correlation with the expression of HIF-1a protein and adrenomedullin. High Alt Med Biol 14:53-60, 2013.-Recent studies in our laboratory demonstrated that chronic hypoxia (CH) induces a localized inflammatory response in rat carotid body that is characterized by macrophage invasion and increased expression of inflammatory cytokines. Moreover, CH-induced increased hypoxic sensitivity is blocked by concurrent treatment with the common anti-inflammatory drugs, ibuprofen and dexamethasone. The present study examines the hypothesis that selected cytokines enhance the excitability of oxygen-sensitive type I cells in the carotid body, and that downstream effects of cytokines involve upregulation of the transcription factor, hypoxia inducible factor-1a (HIF-1a). Cultured type I cells were exposed for 24 h to hypoxia and/or a cocktail of cytokines consisting of interleukin-1b, interleukin-6, and tumor necrosis factor-a. Subsequent evaluation of hypoxia-evoked intracellular Ca 2 + -responses showed that previous exposure to cytokines plus hypoxia resulted in a 110% ( p < 0.001) increase in cell excitability, whereas exposure to cytokines or hypoxia alone elicited smaller increases of 22% (not significant) and 35% ( p < 0.01), respectively. These changes were correlated with increased immunostaining for HIF-1a in similarly treated type I cells, where exposure to cytokines plus hypoxia promoted the nuclear translocation of the transcription factor. Moreover, treatment with cytokines and/or hypoxia elevated the expression of the HIF-1-regulated gene, adrenomedullin. These in vitro results are supported by studies which show that elevated type I cell sensitivity following in vivo CH is blocked by concurrent treatment with ibuprofen. The data suggest that CH-induced adaptation in arterial chemoreceptors may in part be mediated by cytokine/hypoxia-induced upregulation of HIF-1a, and consequent enhanced expression of specific hypoxia-sensitive genes in type I cells.

Enhanced Firing in NTS Induced by Short-Term Sustained Hypoxia Is Modulated by Glia-Neuron Interaction

“…SH also induces several adaptive changes in peripheral chemoreflex pathways, such as, enhancement of gene transcription and excitability of glomus cells in carotid body (Wang et al, 2000;Ortiz et al, 2009;Liu et al, 2013). Long-term SH for 10 d also affected NTS neurons, which presented an increased NTS neuronal discharge due to an evoked excitatory inputs to NTS neurons, as well as a decrease in K ATP channel subunits expression (Kir 6.1 and Kir 6.2 subunits; Zhang et al, 2008Zhang et al, , 2009.…”

The human carotid body releases acetylcholine, ATP and cytokines during hypoxia

“…Extended hypoxia increases inflammatory cytokine expression in the rat carotid body and augments the sensory response to hypoxia (Liu et al . ). Our previous study showed that human carotid bodies express genes encoding pro‐inflammatory cytokines (Mkrtchian et al .…”

“…; Liu et al . ). In line with this, we observed a suppressed or blocked release of cytokines by hypoxia from one patient in the present study who received parecoxib prior to the removal of the carotid body.…”

“…Thus, animal studies suggest that the carotid body possesses an immunological function by instigating the plastic changes observed within the carotid body during exposure to chronic or intermittent hypoxia and communicating peripheral systemic immune status to the CNS (Kumar & Prabhakar, 2012). Anti-inflammatory drugs have been demonstrated to abolish the acclimatization to chronic hypoxia mediated by modulation of inflammatory gene expression in the carotid body (Popa et al 2011;Liu et al 2013). In line with this, we observed a suppressed or blocked release of cytokines by hypoxia from one patient in the present study who received parecoxib prior to the removal of the carotid body.…”

“…A recent study reported that inflammatory cytokines contribute to augmented type 1 cell and sensory response of the carotid body to extended hypoxia in rats (Liu et al . ). We previously reported that the human carotid body expresses mRNA encoding several cytokines and their corresponding receptors (Mkrtchian et al .…”