Adaptation to chronic hypoxia involves immune cell invasion and increased expression of inflammatory cytokines in rat carotid body

Abstract

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...

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