Increase in bilirubin levels of patients with obstructive sleep apnea in the morning--a possible explanation of induced heme oxygenase-1.

STUDY OBJECTIVES: In the absence of heme oxygenase-1 (HO-1), which catalyzes the oxidation of heme to generate carbon monoxide and indirect bilirubin, hypoxia induces severe right ventricular dilation and infarction. Despite severe hypoxemia during sleep, patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) rarely die during sleep. We hypothesized that apnea-related hypoxemia would induce HO-1 and increase bilirubin levels in the morning in OSAHS patients. Therefore, bilirubin levels in OSAHS patients were analyzed before and after nasal continuous positive airway pressure (nCPAP) therapy. DESIGN: Bilirubin levels in the afternoon before sleep and in the morning immediately after sleep were determined before and after nCPAP treatment. SETTING: University Hospital in Kyoto, Japan. PATIENTS: The subjects were 22 patients with OSAHS (mean (SEM) apnea and hypopnea index of 60 (5)) who were treated with nCPAP and 13 controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Before nCPAP treatment, total after-sleep bilirubin level was significantly higher than the pre-sleep level (p<0.0001). The difference between the serum indirect bilirubin levels in the morning versus in the previous afternoon [D-(M-A)-IB] decreased significantly with nCPAP treatment (p<0.01). The magnitude of decrease in D-(M-A)-IB after nCPAP treatment correlated significantly with changes in the percent time spent with arterial O2 saturation below 90% (r=0.44; p=0.04) and 85% (r=0.49; p=0.02), respectively, during sleep after nCPAP treatment. CONCLUSIONS: The increase in bilirubin level by HO-1 might protect OSAHS patients from disorders related to hypoxemia.

Gene expression of the human prostaglandin E receptor EP4 subtype: differential regulation in monocytoid and lymphoid lineage cells by phorbol ester.

We isolated a cDNA clone encoding the human prostaglandin (PG) E receptor EP4 subtype and examined the gene expression in human blood cells. Northern blot analysis revealed that the EP4 gene is expressed at a high level in peripheral blood mononuclear cells, and at lower levels in cultured human blood cell lines, THP-1 and U937 (monocytoid cell lines), MOLT-4 and Jurkat (T-cell lines), and Raji (B-cell line). To examine regulation of the EP4 gene expression in the immune system, we studied the effects of phorbol 12-myristate 13-acetate (PMA) on these cell lines. Gene expression was upregulated in THP-1, U937, and Raji cells by PMA, and was downregulated in MOLT-4 and Jurkat cells. In THP-1 cells the effects of PMA were further analyzed, and the upregulation of the EP4 gene was shown to be followed by an increase in PGE2 binding sites and in PGE2-induced cAMP accumulation. In the striking contrast, other PGE receptor subtypes (EP1, EP2 and EP3) and other prostanoid receptors (IP and DP) were shown not to be upregulated by PMA. Therefore, this is the first demonstration of a highly specific upregulation of the EP4 subtype in THP-1 cells treated with PMA, suggesting the importance of the EP4 subtype in the immune system. In the present study we also clarified that EP4 gene expression is regulated differently among human monocytoid and lymphoid lineage cells, thus leading to the better understanding of the regulatory mechanisms for the human EP4 gene expression in the immune system.