0 2 In in FW 3 7 vivo vivo FW 8 18 modulation modulation NN 19 21 of of IN 22 36 glucocorticoid glucocorticoid NN 37 45 receptor receptor NN 46 50 mRNA mrna NN 51 53 by by IN 54 61 inhaled inhale VBN 62 73 fluticasone fluticasone NN 74 84 propionate propionate NN 85 87 in in IN 88 97 bronchial bronchial JJ 98 104 mucosa mucosa NN 105 108 and and CC 109 114 blood blood NN 115 126 lymphocytes lymphocyte NNS 127 129 in in IN 130 138 subjects subject NNS 139 143 with with IN 144 148 mild mild JJ 149 155 asthma asthma NN 155 156 . . . 158 168 BACKGROUND background NN 168 169 : : : 170 172 In in FW 173 177 vivo vivo FW 178 188 regulation regulation NN 189 191 of of IN 192 195 the the DT 196 210 glucocorticoid glucocorticoid NN 211 219 receptor receptor NN 220 221 ( ( ( 221 223 GR GR NNP 223 224 ) ) ) 225 227 by by IN 228 243 glucocorticoids glucocorticoid NNS 244 252 provides provide VBZ 253 254 a a DT 255 260 means means NN 261 263 of of IN 264 274 modulating modulate VBG 275 286 sensitivity sensitivity NN 287 289 of of IN 290 298 targeted target VBN 299 304 cells cell NNS 304 305 . . . 306 315 OBJECTIVE objective NN 315 316 : : : 317 319 We we PRP 320 326 sought seek VBD 327 329 to to TO 330 339 determine determine VB 340 343 the the DT 344 346 in in FW 347 351 vivo vivo FW 352 362 modulation modulation NN 363 365 of of IN 366 368 GR GR NNP 369 373 mRNA mrna NN 374 384 expression expression NN 385 387 by by IN 388 399 fluticasone fluticasone NN 400 410 propionate propionate NN 411 412 ( ( ( 412 414 FP FP NNP 414 415 ) ) ) 416 418 in in IN 419 427 subjects subject NNS 428 432 with with IN 433 437 mild mild JJ 438 444 asthma asthma NN 444 445 . . . 446 453 METHODS methods NNS 453 454 : : : 455 458 Ten ten CD 459 465 atopic atopic JJ 466 475 asthmatic asthmatic JJ 476 484 subjects subject NNS 485 489 were be VBD 490 497 treated treat VBN 498 502 with with IN 503 505 FP FP NNP 506 509 250 250 CD 510 516 microg microg NN 517 522 twice twice RB 523 528 daily daily RB 529 532 for for IN 533 534 4 4 CD 535 540 weeks week NNS 540 541 . . . 542 548 Before before IN 549 552 and and CC 553 558 after after IN 559 568 treatment treatment NN 568 569 , , , 570 573 the the DT 574 582 patients patient NNS 583 592 underwent undergo VBD 593 603 fiberoptic fiberoptic JJ 604 616 bronchoscopy bronchoscopy NN 617 621 with with IN 622 635 endobronchial endobronchial JJ 636 642 biopsy biopsy NN 643 646 and and CC 647 655 sampling sampling NN 656 658 of of IN 659 665 venous venous JJ 666 671 blood blood NN 672 675 for for IN 676 688 measurements measurement NNS 689 691 of of IN 692 694 GR GR NNP 695 699 mRNA mrna NN 700 706 levels level NNS 706 707 . . . 708 709 A a DT 710 718 solution solution NN 719 732 hybridization hybridization NN 733 738 assay assay NN 739 742 was be VBD 743 747 used use VBN 748 751 for for IN 752 764 quantitative quantitative JJ 765 773 analysis analysis NN 774 776 of of IN 777 779 GR GR NNP 780 784 mRNA mRNA NNP 784 785 . . . 786 788 In in IN 789 797 addition addition NN 797 798 , , , 799 800 a a DT 801 808 24-hour 24-hour JJ 809 816 urinary urinary JJ 817 825 cortisol cortisol NN 826 835 excretion excretion NN 836 839 and and CC 840 842 an an DT 843 862 adrenocorticotropic adrenocorticotropic JJ 863 870 hormone hormone NN 871 875 test test NN 876 882 before before IN 883 886 and and CC 887 892 after after IN 893 902 treatment treatment NN 903 907 with with IN 908 910 FP FP NNP 911 915 were be VBD 916 925 performed perform VBN 925 926 . . . 927 934 RESULTS results NNS 934 935 : : : 936 937 A a DT 938 942 high high JJ 943 958 interindividual interindividual JJ 959 968 variation variation NN 969 971 in in IN 972 974 GR GR NNP 975 979 mRNA mRNA NNP 980 990 expression expression NN 991 994 was be VBD 995 999 seen see VBN 999 1000 . . . 1001 1008 However however RB 1008 1009 , , , 1010 1012 we we PRP 1013 1021 detected detect VBD 1022 1023 a a DT 1024 1035 significant significant JJ 1036 1045 reduction reduction NN 1046 1048 of of IN 1049 1052 the the DT 1053 1055 GR GR NNP 1056 1060 mRNA mrna NN 1061 1067 levels level NNS 1068 1070 in in IN 1071 1074 the the DT 1075 1088 endobronchial endobronchial JJ 1089 1095 biopsy biopsy NN 1096 1105 specimens specimen NNS 1106 1111 after after IN 1112 1114 FP FP NNP 1115 1124 treatment treatment NN 1125 1126 ( ( ( 1126 1130 36.6 36.6 CD 1131 1134 +/- +/- CC 1135 1139 23.1 23.1 CD 1140 1143 and and CC 1144 1148 25.0 25.0 CD 1149 1152 +/- +/- SYM 1153 1157 10.9 10.9 CD 1158 1162 amol amol NN 1163 1165 GR gr NN 1166 1177 mRNA/microg mrna/microg NN 1178 1181 RNA RNA NNP 1181 1182 , , , 1183 1195 respectively respectively RB 1195 1196 ; ; : 1197 1198 P p NN 1199 1203 <.01 <.01 NN 1203 1204 ) ) ) 1204 1205 . . . 1206 1208 In in IN 1209 1212 the the DT 1213 1223 peripheral peripheral JJ 1224 1229 blood blood NN 1230 1241 lymphocytes lymphocyte NNS 1242 1244 an an DT 1245 1249 even even RB 1250 1254 more more RBR 1255 1263 striking striking JJ 1264 1278 downregulation downregulation NN 1279 1281 of of IN 1282 1285 the the DT 1286 1288 GR gr NN 1289 1291 by by IN 1292 1295 its its PRP$ 1296 1303 cognate cognate JJ 1304 1310 ligand ligand NN 1311 1314 was be VBD 1315 1325 documented document VBN 1326 1327 ( ( ( 1327 1331 30.3 30.3 CD 1332 1335 +/- +/- CC 1336 1340 26.5 26.5 CD 1341 1344 and and CC 1345 1348 8.8 8.8 CD 1349 1352 +/- +/- SYM 1353 1354 5 5 CD 1355 1359 amol amol NN 1360 1362 GR gr NN 1363 1374 mRNA/microg mrna/microg NN 1375 1378 RNA RNA NNP 1378 1379 , , , 1380 1392 respectively respectively RB 1392 1393 ; ; : 1394 1395 P p NN 1396 1401 <.001 <.001 CD 1401 1402 ) ) ) 1402 1403 , , , 1404 1412 possibly possibly RB 1413 1423 reflecting reflect VBG 1424 1435 differences difference NNS 1436 1438 in in IN 1439 1453 glucocorticoid glucocorticoid NN 1454 1465 sensitivity sensitivity NN 1466 1473 between between IN 1474 1481 tissues tissue NNS 1481 1482 . . . 1483 1484 A a DT 1485 1490 small small JJ 1491 1494 but but CC 1495 1506 significant significant JJ 1507 1516 reduction reduction NN 1517 1519 of of IN 1520 1523 the the DT 1524 1531 24-hour 24-hour JJ 1532 1539 urinary urinary JJ 1540 1548 cortisol cortisol NN 1549 1558 excretion excretion NN 1559 1562 was be VBD 1563 1571 observed observe VBN 1572 1573 ( ( ( 1573 1576 233 233 CD 1577 1580 +/- +/- CC 1581 1584 109 109 CD 1585 1588 and and CC 1589 1592 157 157 CD 1593 1596 +/- +/- SYM 1597 1599 66 66 CD 1600 1606 nmol/L nmol/l NN 1606 1607 , , , 1608 1620 respectively respectively RB 1620 1621 ; ; : 1622 1623 P p NN 1624 1628 <.01 <.01 NN 1628 1629 ) ) ) 1629 1630 , , , 1631 1638 whereas whereas IN 1639 1642 the the DT 1643 1651 feedback feedback NN 1652 1662 regulation regulation NN 1663 1665 of of IN 1666 1680 glucocorticoid glucocorticoid NN 1681 1690 synthesis synthesis NN 1691 1693 by by IN 1694 1699 means mean NNS 1700 1702 of of IN 1703 1706 the the DT 1707 1737 hypothalamic-pituitary-adrenal hypothalamic-pituitary-adrenal JJ 1738 1742 axis axis NN 1743 1745 as as IN 1746 1754 assessed assess VBN 1755 1757 by by IN 1758 1761 the the DT 1762 1781 adrenocorticotropic adrenocorticotropic JJ 1782 1789 hormone hormone NN 1790 1794 test test NN 1795 1803 remained remain VBD 1804 1810 normal normal JJ 1811 1816 after after IN 1817 1826 treatment treatment NN 1827 1831 with with IN 1832 1834 FP FP NNP 1834 1835 . . . 1836 1846 CONCLUSION conclusion NN 1846 1847 : : : 1848 1851 The the DT 1852 1859 results result NNS 1860 1862 in in IN 1863 1867 this this DT 1868 1873 study study NN 1874 1881 confirm confirm VBP 1882 1885 the the DT 1886 1893 potency potency NN 1894 1896 of of IN 1897 1900 the the DT 1901 1908 inhaled inhale VBN 1909 1923 corticosteroid corticosteroid NN 1924 1926 FP FP NNP 1927 1930 and and CC 1931 1938 provide provide VBP 1939 1947 evidence evidence NN 1948 1951 for for IN 1952 1953 a a DT 1954 1966 considerable considerable JJ 1967 1982 tissue-specific tissue-specific JJ 1983 1998 interindividual interindividual JJ 1999 2008 variation variation NN 2009 2011 in in IN 2012 2015 the the DT 2016 2026 expression expression NN 2027 2029 of of IN 2030 2033 the the DT 2034 2036 GR gr NN 2036 2037 . . .