0 11 Cyclosporin Cyclosporin NNP 12 13 A A NNP 14 22 inhibits inhibit VBZ 23 31 monocyte monocyte NN 32 38 tissue tissue NN 39 45 factor factor NN 46 56 activation activation NN 57 59 in in IN 60 67 cardiac cardiac JJ 68 78 transplant transplant NN 79 89 recipients recipient NNS 89 90 . . . 92 102 BACKGROUND background NN 102 103 : : : 104 110 Fibrin Fibrin NNP 111 121 deposition deposition NN 122 125 and and CC 126 136 thrombosis thrombosis NN 137 141 have have VBP 142 146 been be VBN 147 157 implicated implicate VBN 158 160 in in IN 161 165 both both CC 166 175 allograft allograft NN 176 185 rejection rejection NN 186 189 and and CC 190 202 vasculopathy vasculopathy NN 203 208 after after IN 209 216 cardiac cardiac JJ 217 232 transplantation transplantation NN 232 233 . . . 234 241 Because because IN 242 251 monocytes monocyte NNS 252 256 play play VBP 257 258 a a DT 259 266 pivotal pivotal JJ 267 271 role role NN 272 274 in in IN 275 278 the the DT 279 294 pathophysiology pathophysiology NN 295 297 of of IN 298 311 intravascular intravascular JJ 312 323 coagulation coagulation NN 324 334 activation activation NN 335 342 through through IN 343 348 their their PRP$ 349 356 ability ability NN 357 359 to to TO 360 370 synthesize synthesize VB 371 377 tissue tissue NN 378 384 factor factor NN 385 386 ( ( ( 386 388 TF TF NNP 388 389 ) ) ) 389 390 , , , 391 393 we we PRP 394 399 asked ask VBD 400 401 ( ( ( 401 402 1 1 LS 402 403 ) ) ) 404 411 whether whether IN 412 420 monocyte monocyte NN 421 423 TF TF NNP 424 434 activation activation NN 435 441 occurs occur VBZ 442 444 in in IN 445 452 cardiac cardiac JJ 453 463 transplant transplant NN 464 474 recipients recipient NNS 475 478 and and CC 479 480 ( ( ( 480 481 2 2 LS 481 482 ) ) ) 483 490 whether whether IN 491 499 monocyte monocyte NN 500 502 TF TF NNP 503 513 expression expression NN 514 516 is be VBZ 517 525 affected affect VBN 526 528 by by IN 529 538 treatment treatment NN 539 543 with with IN 544 555 cyclosporin cyclosporin NN 556 557 A A NNP 558 559 ( ( ( 559 562 CsA CsA NNP 562 563 ) ) ) 563 564 . . . 565 572 METHODS methods NNS 573 576 AND and CC 577 584 RESULTS results NNS 584 585 : : : 586 588 We we PRP 589 597 measured measure VBD 598 604 levels level NNS 605 607 of of IN 608 610 TF TF NNP 611 619 activity activity NN 620 622 in in IN 623 633 peripheral peripheral JJ 634 639 blood blood NN 640 651 mononuclear mononuclear JJ 652 657 cells cell NNS 658 661 and and CC 662 668 highly highly RB 669 677 purified purify VBN 678 699 monocytes/macrophages monocytes/macrophage NNS 700 704 from from IN 705 707 10 10 CD 708 719 consecutive consecutive JJ 720 727 cardiac cardiac JJ 728 738 transplant transplant NN 739 749 recipients recipient NNS 750 753 and and CC 754 756 10 10 CD 757 764 healthy healthy JJ 765 772 control control NN 773 781 subjects subject NNS 781 782 . . . 783 785 TF TF NNP 786 794 activity activity NN 795 804 generated generate VBN 805 807 by by IN 808 812 both both CC 813 825 unstimulated unstimulated JJ 826 829 and and CC 830 850 endotoxin-stimulated endotoxin-stimulated JJ 851 856 cells cell NNS 857 860 was be VBD 861 874 significantly significantly RB 875 881 higher high JJR 882 884 in in IN 885 895 transplant transplant NN 896 906 recipients recipient NNS 907 911 than than IN 912 914 in in IN 915 922 control control JJ 923 931 subjects subject NNS 932 933 ( ( ( 933 938 P<.05 p<.05 NN 938 939 ) ) ) 939 940 . . . 941 950 Increased increase VBN 951 959 monocyte monocyte NN 960 962 TF tf NN 963 973 expression expression NN 974 976 in in IN 977 987 transplant transplant NN 988 998 recipients recipient NNS 999 1002 was be VBD 1003 1008 shown show VBN 1009 1011 to to TO 1012 1014 be be VB 1015 1024 adversely adversely RB 1025 1033 affected affect VBN 1034 1036 by by IN 1037 1046 treatment treatment NN 1047 1051 with with IN 1052 1055 CsA CsA NNP 1055 1056 : : : 1057 1059 TF TF NNP 1060 1069 induction induction NN 1070 1073 was be VBD 1074 1082 markedly markedly RB 1083 1090 reduced reduce VBN 1091 1093 by by IN 1094 1097 CsA CsA NNP 1098 1103 serum serum NN 1104 1118 concentrations concentration NNS 1119 1127 reaching reach VBG 1128 1132 peak peak JJ 1133 1136 CsA CsA NNP 1137 1141 drug drug NN 1142 1148 levels level NNS 1148 1149 . . . 1150 1160 Inhibition Inhibition NNP 1161 1163 of of IN 1164 1166 TF TF NNP 1167 1176 induction induction NN 1177 1179 in in IN 1180 1183 the the DT 1184 1192 presence presence NN 1193 1195 of of IN 1196 1200 high high JJ 1201 1204 CsA CsA NNP 1205 1210 blood blood NN 1211 1225 concentrations concentration NNS 1226 1229 was be VBD 1230 1234 also also RB 1235 1243 observed observe VBN 1244 1248 when when WRB 1249 1260 stimulation stimulation NN 1261 1263 of of IN 1264 1269 cells cell NNS 1270 1273 was be VBD 1274 1283 performed perform VBN 1284 1288 with with IN 1289 1305 interferon-gamma interferon-gamma NN 1306 1308 or or CC 1309 1326 interleukin-1beta interleukin-1beta NN 1326 1327 . . . 1328 1330 As as IN 1331 1336 shown show VBN 1337 1339 by by IN 1340 1347 reverse reverse JJ 1348 1372 transcription-polymerase transcription-polymerase NN 1373 1378 chain chain NN 1379 1387 reaction reaction NN 1388 1391 and and CC 1392 1407 electrophoretic electrophoretic JJ 1408 1416 mobility mobility NN 1417 1422 shift shift NN 1423 1428 assay assay NN 1428 1429 , , , 1430 1442 respectively respectively RB 1442 1443 , , , 1444 1453 treatment treatment NN 1454 1458 with with IN 1459 1462 CsA CsA NNP 1463 1468 leads lead VBZ 1469 1471 to to TO 1472 1481 decreased decrease VBN 1482 1484 TF TF NNP 1485 1489 mRNA mrna NN 1490 1500 expression expression NN 1501 1504 and and CC 1505 1512 reduced reduce VBN 1513 1523 activation activation NN 1524 1526 of of IN 1527 1530 the the DT 1531 1540 NF-kappaB NF-kappaB NNP 1541 1554 transcription transcription NN 1555 1561 factor factor NN 1561 1562 , , , 1563 1568 which which WDT 1569 1571 is be VBZ 1572 1577 known know VBN 1578 1580 to to TO 1581 1591 contribute contribute VB 1592 1594 to to TO 1595 1598 the the DT 1599 1608 induction induction NN 1609 1611 of of IN 1612 1615 the the DT 1616 1618 TF TF NNP 1619 1627 promotor promotor NN 1628 1630 in in IN 1631 1636 human human JJ 1637 1646 monocytes monocyte NNS 1646 1647 . . . 1648 1659 CONCLUSIONS conclusions NNS 1659 1660 : : : 1661 1665 This this DT 1666 1671 study study NN 1672 1684 demonstrates demonstrate VBZ 1685 1689 that that IN 1690 1692 TF TF NNP 1693 1703 activation activation NN 1703 1704 , , , 1705 1714 occurring occur VBG 1715 1717 in in IN 1718 1729 mononuclear mononuclear JJ 1730 1735 cells cell NNS 1736 1738 of of IN 1739 1746 cardiac cardiac JJ 1747 1757 transplant transplant NN 1758 1768 recipients recipient NNS 1768 1769 , , , 1770 1772 is be VBZ 1773 1782 inhibited inhibit VBN 1783 1785 by by IN 1786 1795 treatment treatment NN 1796 1800 with with IN 1801 1804 CsA CsA NNP 1804 1805 . . . 1806 1816 Inhibition Inhibition NNP 1817 1819 of of IN 1820 1828 monocyte monocyte NN 1829 1831 TF tf NN 1832 1841 induction induction NN 1842 1844 by by IN 1845 1848 CsA CsA NNP 1849 1852 may may MD 1853 1863 contribute contribute VB 1864 1866 to to TO 1867 1870 its its PRP$ 1871 1881 successful successful JJ 1882 1885 use use NN 1886 1888 in in IN 1889 1896 cardiac cardiac JJ 1897 1907 transplant transplant NN 1908 1916 medicine medicine NN 1917 1920 and and CC 1921 1926 might might MD 1927 1929 be be VB 1930 1936 useful useful JJ 1937 1939 in in IN 1940 1948 managing manage VBG 1949 1956 further further JJ 1957 1965 settings setting NNS 1966 1968 of of IN 1969 1977 vascular vascular JJ 1978 1987 pathology pathology NN 1988 1992 also also RB 1993 1998 known know VBN 1999 2001 to to TO 2002 2009 involve involve VB 2010 2012 TF TF NNP 2013 2023 expression expression NN 2024 2027 and and CC 2028 2037 NF-kappaB nf-kappab NN 2038 2048 activation activation NN 2048 2049 . . .