Additional file 1: of Arginase impairs hypoxic pulmonary vasoconstriction in murine endotoxemia

Up-regulated genes in the lungs of endotoxemic wild-type, but not NOS2-deficient mice. We previously showed that HPV is preserved in endotoxemic NOS2-deficient (NOS2−/−) mice. [2]. The objective of this study was to identify gene products that may contribute to endotoxin-induced impairment of HPV in wild-type mice. Transcription profiling was performed on homogenized lung tissue from wild-type mice 22 h after LPS administration (N = 3) and compared to the profile produced by the lungs of wild-type mice challenged with saline LPS (N = 4). Transcription profiling was also performed on homogenized lung tissue from NOS2−/− mice 22 h after LPS administration (N = 3) and was compared to the profile produced by the lungs of NOS2−/− mice challenged with saline (N = 1). The microarray assessed the expression of 22,690 genes. A subset of 59 genes (shown in this table) was increased greater than three-fold in wild-type mice challenged with endotoxin, but was not enhanced three-fold in the lungs of NOS2−/− mice challenged with endotoxin. The microarray results indicated that Arg1 was the most highly expressed gene in endotoxemic wild-type mice, and that Arg1 expression was not increased in the lungs of endotoxemic NOS2−/− mice. (DOCX 1424 kb

Additional file 3: of Arginase impairs hypoxic pulmonary vasoconstriction in murine endotoxemia

Up-regulated genes in the lungs of endotoxemic NOS2−/− mice, but not in endotoxemic wild-type mice. Expression of 155 genes was increased more than three-fold by endotoxin in NOS2−/− mice, but was not similarly increased by endotoxin in wild-type mice. (DOCX 3039 kb

Additional file 2: of Arginase impairs hypoxic pulmonary vasoconstriction in murine endotoxemia

Down-regulated genes in the lungs of endotoxemic wild-type mice, but not endotoxemic NOS2-deficient mice. Expression of 72 genes was decreased to 0.3-fold or less by endotoxin in wild-type mice, but was not decreased by endotoxin in NOS2−/− mice. (DOCX 2071 kb

Additional file 4: of Arginase impairs hypoxic pulmonary vasoconstriction in murine endotoxemia

Down-regulated genes in the lungs of endotoxemic NOS2−/− mice, but not in endotoxemic wild-type mice. Ninety-three genes were decreased to 0.3-fold or less by endotoxin in NOS2−/− mice, but were not decreased by endotoxin in wild-type mice. (DOCX 2346 kb

A Triazole Disulfide Compound Increases the Affinity of Hemoglobin for Oxygen and Reduces the Sickling of Human Sickle Cells

Sickle cell disease is an inherited disorder of hemoglobin (Hb). During a sickle cell crisis, deoxygenated sickle hemoglobin (deoxyHbS) polymerizes to form fibers in red blood cells (RBCs), causing the cells to adopt “sickled” shapes. Using small molecules to increase the affinity of Hb for oxygen is a potential approach to treating sickle cell disease, because oxygenated Hb interferes with the polymerization of deoxyHbS. We have identified a triazole disulfide compound (4,4′-di­(1,2,3-triazolyl)­disulfide, designated TD-3), which increases the affinity of Hb for oxygen. The crystal structures of carboxy- and deoxy-forms of human adult Hb (HbA), each complexed with TD-3, revealed that one molecule of the monomeric thiol form of TD-3 (5-mercapto-1H-1,2,3-triazole, designated MT-3) forms a disulfide bond with β-Cys93, which inhibits the salt-bridge formation between β-Asp94 and β-His146. This inhibition of salt bridge formation stabilizes the R-state and destabilizes the T-state of Hb, resulting in reduced magnitude of the Bohr effect and increased affinity of Hb for oxygen. Intravenous administration of TD-3 (100 mg/kg) to C57BL/6 mice increased the affinity of murine Hb for oxygen, and the mice did not appear to be adversely affected by the drug. TD-3 reduced in vitro hypoxia-induced sickling of human sickle RBCs. The percentage of sickled RBCs and the <i>P</i>₅₀ of human SS RBCs by TD-3 were inversely correlated with the fraction of Hb modified by TD-3. Our study shows that TD-3, and possibly other triazole disulfide compounds that bind to Hb β-Cys93, may provide new treatment options for patients with sickle cell disease