HIF-1α is expressed in healthy and diseased periodontium and may be related to TNF-α and VEGF function during periodontitis.

The structure and function of the carotid body are greatly altered during chronic hypoxia. Recent studies showed the expression of interleukin (IL)-1 receptor and IL-6 receptor in the carotid body, suggesting a role of proinflammatory cytokines in the chemoreceptor function. The present study aimed to examine the hypothesis that the expression of pro-inflammatory cytokines, namely IL-1beta, IL-6 and tumor necrosis factor (TNF)alpha, plays a role in the rat carotid body in chronic hypoxia. Levels of the mRNA expression of the cytokines and their receptors IL-1r1, gp130 and TNFr1, were significantly increased in the carotid body of hypoxic rats when compared with the normoxic control. Immunohistochemistry showed that the expressions of cytokines and receptors were localized in the lobules of chemosensitive glomus cells containing tyrosine hydroxylase. There were significantly more positive-staining cells in the hypoxic groups with treatment for 3, 7 and 28 days than those of the normoxic controls. Application of exogenous cytokines (0.1 nM) elevated intracellular calcium ([Ca(2+)](i)) responses to acute hypoxia in the dissociated fura-2-loaded glomus cells. The increased [Ca(2+)](i) response in the hypoxic group was significantly greater than that of the normoxic group. Moreover, the gene transcripts of inflammatory mediator inducible nitric oxide synthase and chemokines (MCP-1, CCR2, MIP-1alpha, and ICAM-1) were increased in the carotid body of hypoxic rats. Collectively, results suggest that the increased expressions of proinflammatory cytokines play a functional role in the carotid body with local inflammation during chronic hypoxia.

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.

Obstructive sleep apnea (OSA) associated with chronic intermittent hypoxia (CIH) increases the morbidity and mortality of ischemic heart disease in patients. Yet, there is a paucity of preventive measures targeting the pathogenesis of CIH-induced myocardial injury. We examined the cardioprotective effect of melatonin against the inflammation, fibrosis and the deteriorated sarcoplasmic reticulum (SR) Ca(2+) homeostasis, and ischemia/reperfusion (I/R)-induced injury exacerbated by CIH. Adult male Sprague Dawley rats that had received a daily injection of melatonin (10 mg/kg) or vehicle were exposed to CIH treatment mimicking a severe OSA condition for 4 wk. Systolic pressure, heart weights, and malondialdehyde were significantly increased in hypoxic rats but not in the melatonin-treated group, when compared with the normoxic control. Levels of the expression of inflammatory cytokines (TNF-α, IL-6, and COX-2) and fibrotic markers (PC1 and TGF-β) were significantly elevated in the hypoxic group but were normalized by melatonin. Additionally, infarct size of isolated hearts with regional I/R was substantial in the hypoxic group treated with vehicle but not in the melatonin-treated group. Moreover, melatonin treatment mitigated the SR-Ca(2+) homeostasis in the cardiomyocyte during I/R with (i) Ca(2+) overloading, (ii) decreased SR-Ca(2+) content, (iii) lowered expression and activity of Ca(2+) -handling proteins (SERCA2a and NCX1),and (iv) decreased expressions of CAMKII and phosphorylated eNOS(ser1177). Furthermore, melatonin ameliorated the level of expression of antioxidant enzymes (CAT and MnSOD) and NADPH oxidase (p22 and NOX2). Results support a prophylactic usage of melatonin in OSA patients, which protects against CIH-induced myocardial inflammation and fibrosis with impaired SR-Ca(2+) handling and exacerbated I/R injury.