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1.  A2B Adenosine Receptor Blockade Enhances Macrophage-Mediated Bacterial Phagocytosis and Improves Polymicrobial Sepsis Survival in Mice 
Antimicrobial treatment strategies must improve to reduce the high mortality rates in septic patients. In noninfectious models of acute inflammation, activation of A2B adenosine receptors (A2BR) in extracellular adenosine-rich microenvironments causes immunosuppression. We examined A2BR in antibacterial responses in the cecal ligation and puncture (CLP) model of sepsis. Antagonism of A2BR significantly increased survival, enhanced bacterial phagocytosis, and decreased IL-6 and MIP-2 (a CXC chemokine) levels after CLP in outbred (ICR/CD-1) mice. During the CLP-induced septic response in A2BR knockout mice, hemodynamic parameters were improved compared with wild-type mice in addition to better survival and decreased plasma IL-6 levels. A2BR deficiency resulted in a dramatic 4-log reduction in peritoneal bacteria. The mechanism of these improvements was due to enhanced macrophage phagocytic activity without augmenting neutrophil phagocytosis of bacteria. Following ex vivo LPS stimulation, septic macrophages from A2BR knockout mice had increased IL-6 and TNF-α secretion compared with wild-type mice. A therapeutic intervention with A2BR blockade was studied by using a plasma biomarker to direct therapy to those mice predicted to die. Pharmacological blockade of A2BR even 32 h after the onset of sepsis increased survival by 65% in those mice predicted to die. Thus, even the late treatment with an A2BR antagonist significantly improved survival of mice (ICR/CD-1) that were otherwise determined to die according to plasma IL-6 levels. Our findings of enhanced bacterial clearance and host survival suggest that antagonism of A2BRs offers a therapeutic target to improve macrophage function in a late treatment protocol that improves sepsis survival.
PMCID: PMC3708265  PMID: 21242513
2.  Comparison of daily glucose excursion by continuous glucose monitoring between type 2 diabetic patients receiving biphasic insulin aspart 30 or biphasic human insulin 30 
Aims/Introduction:  Biphasic insulin aspart 30 (BIAsp 30) has an earlier and stronger peak effect with a similar duration of action to biphasic human insulin 30 (BHI 30). However, direct comparison of daily glucose excursion during treatment with these two types of insulin has not been carried out.
Materials and Methods:  We carried out continuous glucose monitoring (CGM) and evaluated the 48‐h glucose profile during twice‐daily injections of BIAsp 30 or BHI 30 at the same dosage in 12 hospitalized patients with type 2 diabetes who participated in a randomized cross‐over trial.
Results:  The 48‐h average glucose level and mean amplitude of glucose excursion (MAGE) were lower during BIAsp 30 treatment than with BHI 30. The average glucose level during 2–3 h after breakfast and 2–4 h after dinner, and the incremental postprandial glucose from just before to 4 h after dinner were lower with BIAsp 30 treatment than with BHI 30. Furthermore, BIAsp 30 treatment reduced the SD from 30 min before to 4 h after breakfast and lunch compared with BHI 30. The average glucose level and SD during the 30 min before each meal and during the night were not different between the two insulin preparations, and hypoglycemia was not observed with either treatment.
Conclusions:  Twice‐daily BIAsp 30 reduced the 48‐h average glucose and MAGE, the postprandial glucose (after breakfast and dinner), and the SD of glucose excursion (after breakfast and lunch) compared with the same dosage of BHI 30, without causing hypoglycemia or deterioration of glycemic control before meals and at night. This trial was registered with UMIN (no. UMIN000005129). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00123.x, 2011)
PMCID: PMC4019310  PMID: 24843521
Biphasic insulin aspart 30; Biphasic human insulin 30; Continuous glucose monitoring
3.  In vivo T Cell Activation in Lymphoid Tissues is Inhibited in the Oxygen-Poor Microenvironment 
Activation of immune cells is under control of immunological and physiological regulatory mechanisms to ensure adequate destruction of pathogens with the minimum collateral damage to “innocent” bystander cells. The concept of physiological negative regulation of immune response has been advocated based on the finding of the critical immunoregulatory role of extracellular adenosine. Local tissue oxygen tension was proposed to function as one of such physiological regulatory mechanisms of immune responses. In the current study, we utilized in vivo marker of local tissue hypoxia pimonidazole hydrochloride (Hypoxyprobe-1) in the flowcytometric analysis of oxygen levels to which lymphocytes are exposed in vivo. The level of exposure to hypoxia in vivo was low in B cells and the levels increased in the following order: T cells < NKT cells < NK cells. The thymus was more hypoxic than the spleen and lymph nodes, suggesting the variation in the degree of oxygenation among lymphoid organs and cell types in normal mice. Based on in vitro studies, tissue hypoxia has been assumed to be suppressive to T cell activation in vivo, but there was no direct evidence demonstrating that T cells exposed to hypoxic environment in vivo are less activated. We tested whether the state of activation of T cells in vivo changes due to their exposure to hypoxic tissue microenvironments. The parallel analysis of more hypoxic and less hypoxic T cells in the same mouse revealed that the degree of T cell activation was significantly stronger in better-oxygenated T cells. These observations suggest that the extent of T cell activation in vivo is dependent on their localization and is decreased in environment with low oxygen tension.
PMCID: PMC3342240  PMID: 22566817
T cell; oxygen; hypoxia; hyperoxia; Hypoxyprobe-1; cytometry; tumor

Results 1-3 (3)