Liu X, He L, Stensaas L, Dinger B, Fidone S. 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, 2009. First published October 31, 2008 doi:10.1152/ajplung.90383.2008.-Exposure to chronic hypoxia (CH; 3-28 days at 380 Torr) induces adaptation in mammalian carotid body such that following CH an acute hypoxic challenge elicits an abnormally large increase in carotid sinus nerve impulse activity. The current study examines the hypothesis that CH initiates an immune response in the carotid body and that chemoreceptor hyperexcitability is dependent on the expression and action of inflammatory cytokines. CH resulted in a robust invasion of ED1 ϩ macrophages, which peaked on day 3 of exposure. Gene expression of proinflammatory cytokines, IL-1, TNF␣, and the chemokine, monocyte chemoattractant protein-1, was increased Ͼ2-fold after 1 day of hypoxia followed by a Ͼ2-fold increase in IL-6 on day 3. After 28 days of CH, IL-6 remained elevated Ͼ5-fold, whereas expression of other cytokines recovered to normal levels. Cytokine expression was not restricted to immune cells. Studies of cultured type I cells harvested following 1 day of in vivo hypoxia showed elevated transcript levels of inflammatory cytokines. In situ hybridization studies confirmed expression of IL-6 in type I cells and also showed that CH induces IL-6 expression in supporting type II cells. Concurrent treatment of CH rats with anti-inflammatory drugs (ibuprofen or dexamethasone) blocked immune cell invasion and severely reduced CH-induced cytokine expression in carotid body. Drug treatment also blocked the development of chemoreceptor hypersensitivity in CH animals. Our findings indicate that chemoreceptor adaptation involves novel neuroimmune mechanisms, which may alter the functional phenotypes of type I cells and chemoafferent neurons. dexamethasone; interleukin-1; interleukin-6; tumor necrosis factor-␣ THE MAMMALIAN CAROTID BODY consists of integrated units of chemoreceptor, neural, glial, and vascular cells surrounded by connective tissue, which collectively constitute a highly adaptive chemosensory organ. Stimulus transduction occurs in paracrine type I (chemoreceptor) cells, which release multiple neuroactive agents in response to hypoxia, hypercapnia, and acidosis. Primary afferent neurons in the petrosal ganglia project axons through the carotid sinus nerve (CSN) to form synaptic terminals on type I cells, whereas glial-like type II cells envelop the type I cells and terminal axon enlargements, forming lobules that are embedded in connective tissue penetrated by a microvascular network of highly permeable sinusoidal capillaries. Fibroblasts, resident macrophages, and a small number of mast cells are also present in the tissue together with postganglionic parasympathetic and sympathetic axons (24).Prolonged and continuous exposure of mammals to a low PO 2 environment (i.e., chronic hypoxia; CH) elicits adaptation in...
Histopathological changes of the cerebral cortex in response to small, penetrating metal and non-metal implants were analyzed by means of light and electron microscopy. The needle-shaped implants were left in place during all stages of histological preparation and embedded in plastic together with the cortex. Changes of the brain-implant boundary were classified as non-reactive, reactive, or toxic, according to the reactive cellular constituents. Among the non-reactive materials were several plastics and metals such as aluminum, gold, platinum, and tungsten. The boundary of these implants displayed little or no gliosis and normal neuropile with synapses within 5 micron of the implant's surface. The boundary of reactive materials such as tantalum or silicon dioxide was marked by multinucleate giant cells and a thin layer (10 micron)) of connective tissue. Toxic materials such as iron and copper were separated from the cortical neuropile by a capsule of cellular connective tissue and a zone of astrocytosis. Cobalt, a highly toxic material, produced more extensive changes in the zones of connective tissue and astrocytes. These results indicate that a variety of materials are well tolerated by the brain and could be used in the fabrication of neuroprosthetic devices.
Chronic exposure in a low-PO(2) environment (i.e., chronic hypoxia, CH) elicits an elevated hypoxic ventilatory response and increased hypoxic chemosensitivity in arterial chemoreceptors in the carotid body. In the present study, we examine the hypothesis that changes in chemosensitivity are mediated by endothelin (ET), a 21-amino-acid peptide, and ET(A) receptors, both of which are normally expressed by O(2)-sensitive type I cells. Immunocytochemical staining showed incremental increases in ET and ET(A) expression in type I cells after 3, 7, and 14 days of CH (380 Torr). Peptide and receptor upregulation was confirmed in quantitative RT-PCR assays conducted after 14 days of CH. In vitro recordings of carotid sinus nerve activity after in vivo exposure to CH for 1-16 days demonstrated a time-dependent increase in chemoreceptor activity evoked by acute hypoxia. In normal carotid body, the specific ET(A) antagonist BQ-123 (5 microM) inhibited 11% of the nerve discharge elicited by hypoxia, and after 3 days of CH the drug diminished the hypoxia-evoked discharge by 20% (P < 0.01). This inhibitory effect progressed to 45% at day 9 of CH and to nearly 50% after 12, 14, and 16 days of CH. Furthermore, in the presence of BQ-123, the magnitude of the activity evoked by hypoxia did not differ in normal vs. CH preparations, indicating that the increased activity was the result of endogenous ET acting on an increasing number of ET(A). Collectively, our data suggest that ET and ET(A) autoreceptors on O(2)-sensitive type I cells play a critical role in CH-induced increased chemosensitivity in the rat carotid body.
The carotid body is an arterial chemoreceptor organ sensitive to blood levels of 02, COz and pH. The present immunocytochemical and neurochemical study has demonstrated the presence of an extensive plexus of nitric oxide (NO)-synthesizing nerve fibers in this organ. These nitric oxide synthase (NOS)-containing axons are closely associated with parenchymal type I cells and with blood vessels in the carotid body. Denervation and retrograde tracing experiments have revealed that these fibers arise from NOS-immunoreactive and nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase-positive neuronal cell bodies located in the petrosal ganglion and the carotid body, and dispersed along the glossopharyngeal and carotid sinus nerves (CSN). Within the petrosal ganglion, these neurons are topographically segregated from the catecholaminergic cells, and they contain the neuropeptide, substance P. NOS-positive autonomic microganglial cells in the carotid body and CSN also exhibit choline acetyltransferse (ChAT) immunoreactivity. Our results suggest that nitric oxide may be a novel neuronal messenger in the mammalian carotid body involved in the modulation of chemosensory transduction and transmission in this organ.
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