Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways

Maladaptive changes in the carotid body (CB) induced by chronic intermittent hypoxia (IH) account for the pathogenesis of cardiovascular morbidity in patients with sleep-disordered breathing. We postulated that the proinflammatory cytokines, namely interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and cytokine receptors (IL-1r1, gp130 and TNFr1) locally expressed in the rat CB play a pathophysiological role in IH-induced CB inflammation. Results showed increased levels of oxidative stress (serum 8-isoprostane and nitrotyrosine in the CB) in rats with 7-day IH treatment resembling recurrent apneic conditions when compared with the normoxic control. Local inflammation shown by the amount of ED1-containing cells (macrophage infiltration) and the gene transcripts of NADPH oxidase subunits (gp91phox and p22phox) and chemokines (MCP-1, CCR2, MIP-1α, MIP-1β and ICAM-1) in the CB were significantly more in the hypoxic group than in the control. In addition, the cytokines and receptors were expressed in the lobules of chemosensitive glomus cells containing tyrosine hydroxylase and the levels of expressions were significantly increased in the hypoxic group. Exogenous cytokines elevated the intracellular calcium ([Ca2+]i) response to acute hypoxia in the dissociated glomus cells. The effect of cytokines on the [Ca2+]i response was significantly greater in the hypoxic than in the normoxic group. Moreover, daily treatment of IH rats with anti-inflammatory drugs (dexamethasone or ibuprofen) attenuated the levels of oxidative stress, gp91phox expression and macrophage infiltration in the CB. Collectively, these results suggest that the upregulated expression of proinflammatory cytokine pathways could mediate the local inflammation and functional alteration of the CB under chronic IH conditions

Reflex influence of carotid baroreceptor inactivation on respiratory resistance in humans

<p>Abstract</p> <p>Our previous study demonstrated that selective carotid baroreceptors activation decreases airway resistance. The aim of the present study was to evaluate the effect of carotid baroreceptor inactivation on the reflex change of respiratory resistance. Twenty healthy men aged between 20 and 25 were included in the study. Selective inactivation of carotid baroreceptors was induced by generating a positive pressure of 40 mmHg for 5 s in two capsules placed bilaterally on the neck over the bifurcation of the carotid arteries. The oscillatory method (Siregnost FD5, Siemens) was used to measure continuously respiratory resistance. Inactivation of carotid baroreceptors produced a short increase in respiratory resistance by 0.39 ± 0.01(SE) mbar/l/s, i.e., 21.7% above the resting level. We conclude that in humans, carotid baroreceptors might have a background contribution to bronchodilator tone. This observation seems to be important for clinical situations of impairment of baroreflex function.</p

Chronic hypoxia modulates the function and expression of melatonin receptors in the rat carotid body

Melatonin modulates the carotid chemoreceptor response to chemical stimuli, and chronic hypoxia changes circadian activities and carotid body function. The purpose of this study was to test the hypothesis that chronic hypoxia alters the function and expression of melatonin receptors in the rat carotid body. Effects of melatonin on the carotid responses to hypercapnic acidosis and to hypoxia were determined by spectrofluorometric measurement of cytosolic calcium ([Ca2+]i) in fura-2-loaded type-I (glomus) cells dissociated from carotid bodies obtained from normoxic (Nx) or chronically hypoxic (CH) rats breathing 10% oxygen for 4 wk. In the Nx control, melatonin concentration dependently attenuated the peak [Ca2+]i response to hypercapnic acidosis, whereas it augmented the [Ca 2+]i response to cyanide or deoxygenated buffer. Yet, melatonin enhanced the peak [Ca2+]i responses to hypercapnic acidosis or hypoxia in the CH glomus cells. An agonist of melatonin receptors, iodomelatonin also elevated the hypercapnic or hypoxic responses in the CH groups. The melatonin-induced changes in the [Ca2+] i responses were abolished by pretreatment with nonselective mt 1/MT2 antagonist, luzindole, and by MT2 antagonists, 4-phenyl-2-propionamidotetraline or DH97. These findings suggest a functional modulation of melatonin receptors in the glomus cells in chronic hypoxia. To evaluate the level of expression of the melatonin receptors, in situ hybridization study with antisense mt1 and MT2 receptor mRNA oligonucleotide probes was performed on the Nx and CH carotid bodies. There were significant increases in the expression of mt1 and MT 2 receptors in the CH comparing with the Nx group. Taken together, our results suggest an upregulation of the carotid expression of melatonin receptors by chronic hypoxia, which modulates the carotid response to melatonin for the circadian influence on breathing. © 2005 Blackwell Munksgaard.link_to_subscribed_fulltex

Understanding Pathophysiological Concepts Leading to Obstructive Apnea.

Obstructive sleep apnea (OSA) results from a combination of several factors leading to the obstruction of the upper respiratory tract (URT). OSA represents a systemic pathophysiological entity and leads to many comorbidities such as hypertension, coronary ischemia, and stroke. Patients with this pathophysiological entity experience also an increased risk of postoperative complications. Obesity is certainly the main cause of developing OSA. However, many other predisposing factors influence the genesis of obstructive apnea. It is important to understand the complexity of the interactions between predisposing factors to understand the relationship between weight loss following obesity surgery and the improvement in the severity of OSA. In this narrative review, we expose the seven major categories of predisposing factors that interact to generate obstructive apneas in patients, namely the anatomic abnormalities of the URT, the mechanical and the metabolic responses of the upper airway musculature, the loop gain, the arousal threshold, and the hormonal abnormalities. The genesis of apnea is the result of a complex dynamic interaction between the anatomical risk factors and the compensatory neuromuscular reflexes. All of these points are integrally part of the perioperative care of the obese patients. Finally, we will discuss different options for weight reduction