Objective:This review focuses on the contribution of immune cell trafficking and activities during the initial phase of activation in the process of parturition. Although uterine contractile activity has been the predominant focus for the mechanism that initiates labor, significant cellular and biochemical chanes cause remodeling of the cervix well before term. A convergence of evidence suggests that inflammatory processes that involve prostaglandins, nitric oxide, cytokines, as well as systemic and paracrine endocrine mediators may enhance uterine contractility, promote ripening of the cervx, and thus constitute an integrative hypothesis for the initiation of labor.
Methods:Techniques to study the uterus and cervix of pregnant and virgin C3H/HeN mice included light and fluorescence microscopy. Tissues were processed by histochemistry and immunofluorescence. Analytic approaches to enumerae macrophages and assess activation included quantitative stereologic morphometry and laser scanning cytometry.
Results:The transition between relative quiescene of the uterus and enhanced contractility involed migration of macrophages from the uterine endometrium and activation of macrophages in the cervix. Before birth, macrophages migrae into the cervix and are activated in the myometrium.
Conclusion:Immune cell trafficking and activation are part of the initial mechanism that promotes ripening of the cervix, enhances uterine contractility, and initiates parturition. Markers for the conclusion of pregnancy may have diagnostic or therapeutic value to assess the normal progress of labor or identify women at risk of preterm labor.
1. Challis JR, Sloboda DM, Alfaidy N, et al. Prostaglandins and mechanisms of preterm birth. Reproduction2002;124(1):1-17.
2.
2. Creasy RK. Preventing preterm birth. N Engl J Med1991;325(1):727-729.
3.
3. Longo LD, Yellon S. Biological timekeeping during pregnancy and the role of circadian rhythms in parturition. In: Kunzel W, Jenson A, eds. The endocrine control of the fetus. Springer-Verlag: Berlin, 1988:173-191.
4.
4. Liggins GC, Fairclough RJ, Grieves SA, Forster CS, Knox BS. Parturition in the sheep. In: Knight J, O'Connor M, eds. The fetus and birth. Amsterdam: Elsevier, 1977:5-30.
5.
5. Gibb W, Challis JR. Mechanisms of term and preterm birth. J Obstet Gynaecol Can2002;24(11):874-883.
6.
6. Whittle WL, Patel FA, Alfaidy N, et al. Glucocorticoid regulation of human and ovine parturition: The relationship between fetal hypothalamic-pituitary-adrenal axis activation and intrauterine prostaglandin production. Biol Reprod2001;64(4):1019-1032.
7.
7. Casey ML, MacDonald PC. The endocrinology of human parturition. Ann N Y Acad Sci1988;825:273-284.
8.
8. Casey ML, MacDonald PC. Distinction between the initiation o parturition and the onset of labor. Semin Reprod Endocrinol1993;11:272-284.
9.
9. Haluska GJ, Wells TR, Hirst JJ, Brenner RM, Sadowsky DW, Novy MJ. Progesterone receptor localization and isoforms in myometrium, decidua, and fetal membrances from rhesus macques: Evidence for functional progesterone withdrawal at parturition. J Soc Gynecol Investig2002;9(3):125-136.
10.
10. Mesiano S, Chan EC, Fitter JT, Kwek K, Yeo G, Smith R. Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium. J Clin Endocrinol Metab2002;87(6):2924-2930.
11.
11. Reis FM, Fadalti M, Florio P, Petraglia F. Putative role of placental corticotropin-releasing factor in the mechanisms of human parturition. J So Gynecol Investig1999;6(3):109-119.
12.
12. Elovitz MA, Ascher-Landsberg J, Saunders T, Phillippe M. The mechanisms underlying the stimulatory effects of thrombin on myometrial smooth muscle. Am J Obstet Gynecol2000;183(3):674-681.
13.
13. Challis JR, Lye SL, Gibb W. Prostaglandins and parturition. Ann N y Acad Sci1997;828:254-267.
14.
14. Liggins GC. Initiation of spontaneous labor. Clin Obstet Gynecol1983;26(1):47-55.
15.
15. Liggins GC. Premature parturition after infusion of corticotrophin or cortisol into foetal lambs. J Endocrinol1968;42:323-329.
16.
16. Ligins GC. Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol1969;45:515-523.
17.
17. MacIsaac RJ, Carson RS, Horvath AP. Premature birth of live lambs induced by pulsatile infusion of ACTH. J Endocrinol1990;124:99-107.
18.
18. Nathanielsz PW, Buster JE, Jenkin G, Jorgensen G, Thorburn GD. Induction of premature delivery in sheep following infusion of cortisol to the fetus: The effect of maternal progestagen treatment on the C21-steroid-17 alpha-hydroxylase, C-17,20 lyase and aromatase pathways. J Dev Physiol1988;10(3):257-270.
19.
19. Apostolakis EM, Rice KE, Longo LD, Seron-ferre M, Yellon SM. Time of day of birth and absence of endocrine and uterine contractile activity rhythms in sheep. Am J Physiol1993;264(4 Pt 1):E534-E540.
20.
20. Jacobs RA, Young IR, Hollingworth SA, Thorburn GD. Chronic administration of low doses of adrenocorticotropin to hypophysectomized fetal sheep leads to normal term labor. Endocrinology1994;134(3):1389-1394.
21.
21. Lye SJ, Sprague CL, Mitchell BF, Challis JR. Activation of ovine fetal adrenal function by pulsatile or continuous administration of adrenocorticotropin-(1-24). I Effects on fetal plasma corticosteroids. Endocrinology1983;113(2):770-776.
22.
22. Fowden AL, Li J, Forhead AJ. Glucocorticoids and the preparation for life after birth: Are there long-term consequences of the life insurance?Proc Nutr Soc1998;57(1):113-122.
23.
23. Craddock CG. Corticosteroid-induced lymphopenia, immunosuppression, and body defense. Ann Intern Med1978;88(4):564-566.
24.
24. Cato AC, Wade E. Molecular mechanisms of anti-inflammatory action of glucocorticoids. Bioessays1996;18(5):371-378.
25.
25. Amsterdam A, Tajima K, Sasson R. Cell-specific regulation of apoptosis by glucocorticoids: Implication to their anti-inflammaory action. Biochem Pharmacol2002;64(5-6):843-850.
26.
26. Buhimschi C, Boyle MB, Garfield RE. Electrical activity of the human uterus during pregnancy as recorded from the abdominal surface. Obstet Gynecol1997;90(1):102-111.
27.
27. Buhimschi C, Garfield RE. Uterine contractility as assessed by abdominal surface recording of electromyographic activity in rats during pregnancy. Am J Obstet Gynecol1996;174(2):744-753.
28.
28. Towell ME, Liggins GC. The effect of labour on uterine blood flow in the pregnant ewe. Q J Exp Physiol Cogn Med Sci1976;61(1):23-33.
29.
29. Wolfs GM, van Leeuwen M. Electromyographic observations on the human uterus during labour. Acta Obstet Gynecol Scand1979;90Suppl:1-61.
30.
30. Harding R, Poore ER, Bailey A, Thorburn GD, Jansen CA, Nathanielsz PW. Electromyographic activity of the nonpregnant and pregnant sheep uterus. Am J Obstet Gynecol1982;142(4):448-457.
31.
31. Demianczuk N, Towell Me, Garfield RE. Myometrial electrophysiologic activity and gap junctions in the pregnant rabbit. Am J Obstet Gynecol1984;149(5):485-491.
32.
32. Verhoeff A, Garfield RE, Ramonkdt J, Wallenburg HC. Elecrical and mechanical uterine activity and gap junctions in peripartal sheep. Am J Obstet Gynecol1985;153(4):447-454.
33.
33. Garfield RE, Jain V, Saade GR. Uterine contraction. In: Knobil E, Neill JD, eds. Encyclopedia of Reproduction. New York: Academic Press, 1998;932-942 (Vol. 4).
34.
34. Korita D, Sagawa N, Itoh H, et al. Cyclic mechanical stretch augments prostacyclin production in cultured human uterine myometrial cells from pregnant women: Possible involvement of up-regulation of prostacyclin synthase expression. J Clin Endocrinol Metab2002;87(11):5209-5219.
35.
35. Eswaran H, Preissl H, Wilson JD, Murphy P, Robinson SE, Lowery CL. First magnetomyographic recordings of uterine activity with spatial-termporal information with a 151-channel sensor array. Am J Obstet Gynecol2002;187(1):145-151.
36.
36. Mackler AM, Ducsay CA, Veldhuis JD, Yellon SM. Maturation of spontaneous and agonist-induced uterine contractions in the peripartum mouse uterus. Biol Reprod1999;61(4):873-878.
37.
37. Iams JD, Newman RB, Thom EA, et al. Frequency of uterine contractions and the risk of spontaneous preterm delivery. N Engl J Med2002;346(4):250-255.
38.
38. Buhimschi C, Boyle MD, Saade GR, Garfield RE. Uterine activity during pregnancy and labor assessed by simultaneous recordings from the myometrium and abdominal surface in the rat. Am J Obstet Gynecol1998;178(4):881-822.
39.
39. Fuchs AR. Uterine activity in late pregnancy and during parturition in the rat. Biol Reprod1969;1(4):344-353
40.
40. Anderson GF, Kawarabayashi T, Marshall JM. Effect of indomethacin and aspirin on uterine activity in pregnant rats: Comparison of circular and longitudinal muscle. Biol Reprod1981;24(2):359-372.
41.
41. Benegtsson B, Chow EM, Marshall JM. Activity of circular muscle of rat uterus at different times in pregnancy. Am J Physiol1984;246(3 Pt 1):C216-C223.
42.
42. Izumi H, Byam Smith M, Garfield RE. Gestational changes in oxytocin-and endothelin-1-induced contractility of pregnant rat myometrium. Eur J Pharmacol1995;278(3):187-194.
43.
43. Gomez R, Ghezzi F, Romero R, Munoz H. Tolosa JE, Rojas I. Premature labor and intra-amniotic infection. Clinical aspects and role of the cytokines in diagnosis and pathophysiology. Clin Perinatol1995;22(2):281-342.
44.
44. Mitchell MD. The mechanism(s) of human parturition. J Dev Physiol1984;6(1):107-118.
45.
45. Novy MJ, Liggins GC. Role of prostaglandins, prostacyclin, and thromboxanes in the physiologic control of the uterus and in parturition. Semin Perinatol1980;4(1):45-66.
46.
46. Romero R, Mazor M, Wu YK, et all. Infection in the pathogenesis of preterm labor. Semin Perinatol1988;12(4):262-279.
48. TambyRaja RL, Salmon JA, Karim SM, Ratnam SS. F prostaglandin levels in amniotic fluid in premature labour. Prostaglandins1977;13(2):339-348.
49.
49. Willman EA, Collins WP. The metabolism of prostaglandin E2 by tissues from the human uterus and foeto-placental unit. Acta Endocrinol (Copenhagen)1978;87(3):632-642.
50.
50. Kinoshita K, Satoh H, Sakamoto S. Biosynthesis of prostaglandin in human decidua, amnion chorion, and villi. Endocrinol Jpn1977;24:343-350.
51.
51. Mitchell MD, Bibby J, Hicks BR, Turnbull AC. Specific production of prostaglandin E by human amnion in vitro. Prostaglandins1978;15(2):377-382.
52.
52. Van Meir CA, Ramirez MM, Matthews SG, Calder AA, Keirse MJ, Challis JR. Chorionic prostaglandin catabolism is decreased in the lower uterine segment with term labour. Placenta1997;18(2-3):109-114.
53.
53. Boquet M, Cebral E, Motta A, Beron DA, Gimeno MA. Relationship between mouse uterine contractility, nitric oxide and prostaglandim production in early pregnancy. Prostaglandins Leukot Essent Fatty Acids1998;59(3):163-167.
54.
54. Fuchs AR, Fuchs F. Endocrinology of human parturition: A review. Br J Obstet Gynaecol1984;91(10):948-967.
55.
55. Wu WX, Ma XH, Zhang Q, Nathanielsz PW. Characterization of topology-, gestation-and labor-related changes of a cassette of myometrial contraction-associated protein mRNA in the pregnant baboon myometrium. J Endocrinol2001;171(3):445-453.
56.
56. Lim H, Paria BC, Das SK, et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell1997;91(2):197-208.
57.
57. Tsuboi K, Sugimoto Y, Iwane A, Yamamoto K, Yamamoto S, Ichikawa A. Uterine expression of prostaglandin H2 synthase in late pregnancy and during parturition in prostaglandin F receptor-deficient mice. Endocrinology2000;141(1):315-324.
58.
58. Sugimoto Y, Yamasaki A, Segi E, et al. Failure of parturition in mice lacking the prostaglandin F receptor. Science1997;277(5326):681-683.
59.
59. Norwitz ER, Starkey PM, Lopez Bernal A, Turnbull AC. Identification by flow cytometry of the prostaglandin-producing cell populations of term human decidua. J Endocrinol1991;131(2):327-334.
60.
60. Norwitz ER, Lopez BA, Starkey PM. Tumor necrosis factoralpha selectively stijulates prostaglandin F2 alpha production by macrophages in human term decidua. Am J Obstet Gynecol1992;167(3):815-820.
61.
61. Matthews CJ, Searle RF. The role of prostaglandins in the immunosuppressive effects of supernatants from adherent cells of murine decidual tissue. J Reprod Immunol1987;12(2):109-124.
62.
62. Tawfik OW, Hunt JS, Wood GW. Implication of prostaglandin E2 in soluble factor-mediated immune suppression by murine decidual cells. Am J Reprod Immunol Microbiol1986;12(4):111-117.
63.
63. Chwalisz K, Benson M, Scholz P, Daum J, Beier HM, Hegele-Hartung C. Cervical ripening with the cytokines interleukin 8, interleukin 1 beta and tumour necrosis factor alpha in guineapigs. Hum Reprod1994;9(11):2173-2181.
64.
64. Opsjon S, Wathen NC, Tingulstad S, et al. Tumor necrosis factor, interleukin-1, and interleukin-6 in normal human pregnancy. Am J Obstet Gynecol1993;169(2 Pt 1):397-404.
65.
65. Romero R, Avila C, Santhanam U, Sehgal PB. Amniotic fluid interleukin 6 in preterm labor. Association with infection. J Clin Invest1990;85(5):1392-1400.
66.
66. Romero R, Ceska M, Avila C, Mazor M, Behnke E, Lindley I. Neutrophil attractant/activating peptide-1/interleukin-8 in term and preterm parturition. Am J Obstet Gynecol1991;165(4 Pt 1):813-820.
67.
67. Romero R, Parvizi ST, Oyarzun E, et al. Amniotic fluid interleukin-1 in spontaneous labor at term. J Reprod Med1990;35(3):235-238.
68.
68. Dudley DJ. Immunoendocrinology of preterm labor: The link between corticotropin-releasing hormone and inflammation. Am J Obstet Gynecol1999;180(1 Pt 3):S251-S256.
69.
69. Abbas AK, Lichtman AH, Pober JS. Activation of T lymphocytes. In: Schmitt W, Hacker HN, Ehlers J, eds. Cellular and molecular immunology. Philadelphia: W.B. Saunders Company, 2000:161-181.
70.
70. Janeway CA Jr, Travers P, Walport M, Capra JD. T-cell mediated immunity. In: Austin P, Lawrence E, eds. Immunobiology: The immune system in health and disease. New York: Garland Publishing, 1999:274-275.
71.
71. Allport VC, Pieber D, Slater DM, Newton R, White JO, Bennett PR. Human labour is associaed with nuclear factor-kappaB activity which mediates cyclo-oxygenase-2 expression and is involved with the “functional progesterone withdrawal.”Mol Hum Reprod2001;7(6):581-586.
72.
72. Elliott CL, Allport VC, Loudon JA, Wu GD, Bennett RP. Nuclear factor-kappa B is essential for up-regulation of interleukin-8 expression in human amnion and cervical epithelial cells. Mol Hum Reprod2001;7(8):787-790.
73.
73. Chen HL, Kamath R, Pace JL, Russell SW, Hunt JS. Expression of the interferon-gamma receptor gene in mouse placentas is related to stage of gestation and is restricted to specific subpopulations of trophoblast cells. Placenta1994;15(2):109-121.
74.
74. Fidel PL Jr, Romero R, Wolf N, et al. Systemic and local cytokine profiles in endotoxin-induced preterm parturition in mice. Am J Obstet Gynecol1994;170(5 pt 1):1467-1475.
75.
75. Bukovsky A, Caudle MR, Keenan JA, Wimalasena J, Upadhyaya NB, Van Meter SE. Is corpus luteum regression an immune-mediated event? Localization of immune system components and luteinizing hormone recptor in human corpora lutea. Biol Reprod1995;53(6):1373-1384.
76.
76. Zhao Y, Burbach JA, Roby KF, Terranova PF, Brannian JD. Macrophages are the major source of tumor necrosis factor alpha in the porcine corpus luteum. Biol Reprod1998;59(6):1385-1391.
77.
77. Cohen PE, Nishmura K, Zhu L, Pollard JW. Macrophages: Important accessory cells for reproductive function. J Leukoc Biol1999;66(5):765-772.
78.
78. Olson KK, Townson DH. Prolactin-induced expression of intercellular adhesion molecule-1 and the accumulation of monocytes/macrophages during regression of the rat corpus luteum. Biol Reprod2000;62(6):1571-1578.
79.
79. Paavola LG. The corpus luteum of the guinea pig. Fine structure at the time of maximum progesterone secretion and during regression. Am J Anat1977;150(4):565-603.
80.
80. Padykula HA, Tansey TR. The occurrence of uterine stromal and intraepithelial monocytes and heterophils during normal late pregnancy in the rat. Anat Rec1979;193(3):329-356.
81.
81. Sacks G, Sargent I, Redman C. An innate view of human pregnancy. Immunol Today1999;20(3):114-118.
82.
82. Salamonsen LA, Kovacs GT, Findlay JK. Current concepts of the mechanisms of menstruation. Baillieres Best Pract Res Clin Obstet Gynaecol1999;13(2):161-179.
83.
83. Kwak JY, Gilman-Sachs A, Moretti M, Beaman KD, Beer AE. Natural killer cell cytotoxicity and paternal lymphocyte immunization in women with recurrent spontaneous abortions. Am J Reprod Immunol1998;40(5):352-358.
84.
84. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol1994;12:991-1045.
85.
85. Wood GW. Immunohistological identification of macrophages in murine placentgae, yolk-sac membranes and pregnant uteri. Placenta1980;1(4):309-317.
86.
86. De M, Wood GW. Analysis of the number and distribution of macrophages, lymphocytes, and granulocytes in the mouse uterus from implantation through parturition. J Leukoc Biol1991;50(4):381-392.
87.
87. Mackler AM, Barber EM, Takikawa O, Pollard JW. Indoleamine 2-3-dioxygenase is regulated by interferon-γ in the mouse placenta during Listeria monocytogenes infection. J Immunol. In press.
88.
88. Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science1998;281(5380):1191-1193.
89.
89. Hunt JS, Manning LS, Mitchell D, Selanders JR, Wood GW. Localization and characterization of macrophages in murine uterus. J Leukoc Biol1985;38(2):255-265.
90.
90. Kearns M, Lala PK. Bone marrow origin of decidual cell precursors in the pseudopregnant mouse uterus. J Exp Med1982;155(5):1537-1554.
91.
91. Kearns M, Lala PK. Radioautographic analysis of surface markers on decidual cells shared by cells of the lymphomyeloid tissues. Am J Reprod Immunol Microbiol1985;9(2):39-47.
92.
92. Huntg JS, Petroff MG, Burnett TG. Uterine leukocytes: Key players in pregnancy. Semin Cell Dev Biol2000;11(2):127-137.
93.
93. Hunt JS, Manning LS, Wood GW. Macrophages in murine uterus are immunosuppressive. Cell Immunol1984;85(2):499-510.
94.
94. Guleria I, Pollard JW. The trophoblast is a component of the innate immune system during pregnancy. Nat Med2000;6(5):589-593.
95.
95. Hunt JS. Immunologically relevant cells in the uterus. Biol Reprod1994;50(3):461-466.
96.
96. Huang J, Roby KF, Pace JL, Russell SW, Hunt JS. Cellular localization and hormonal regulation of inducible nitric oxide synthase in cycling mouse uterus. J Leukoc Biol1995;57(1):27-35.
97.
97. Goto M, Yamaguchi Y, Ichiguchi O, et al. Phenotype and localization of macrophages expressing inducible nitric oxide synthase in rat hepatic allograft rejection. Transplantation1997;64(2):303-310.
98.
98. Hunt JS, Miller L, Platt JS. Hormonal regulation of uterine macrophages. Dev Immunol1998;6(1-2):105-110.
99.
99. Jungi TW, Adler H, Adler B, Thony B, Thoney M, Krampe M, Peterhans E. Inducible nitric oxide synthase of macrophages. Present knowledge and evidence for species-specific regulation. Vet Immunol Immunopathol1996;54(1-4):323-330.
100.
100. MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol1997;15:323-350.
101.
101. Mason GL, Yang Z, Olchowy TW, Jian Z, Bochsler PN. Nitric oxide production and expression and expression of inducible nitric oxide synthase by bovine alveolar macrophages. Vet Immunol Immunopathoal1996;53(1-2):15-27.
102.
102. Bansal RK, Goldsmith PC, He Y, Zaloudek CJ, Ecker JL, Riemer RK. A declinein myometrial nitric oxide synthase expression is associated with labor and delivery. J Clin Invest1997;99(10):2502-2508.
103.
103. Heymann MA, Bootstaylor B, Roman C, et al. Glyceryl trinitrate stops active labor in sheep. In: Moncada S, Feelish M, Busse R, Higgs EA, eds. The biology of nitric oxide. London: Portland Press, 1993:201-203.
104.
104. Jennings RW, MacGillivray TE, Harrison MR. Nitric oxide ablates preterm labor in the rhesus monkey. J Matern Fetal Med1993;2:170-175.
105.
105. Riemer RK, Buscher C, Bansal RK, Black SM, He Y, Natuzzi ES. Increased expression of nitric oxide synthase in the myometrium of the pregnant rat uterus. Am J Physiol1997;272(6 Pt 1):E1008-E1015.
106.
106. Natuzzi ES, Ursell PC, Harrison M, Buscher C, Riemer RK. Nitric oxide synthase activity in the pregnant uterus decreases at parturition. Biochem Biophys Res Commun1993;194(1):1-8.
107.
107. Sladek SM, Regenstein AC, Lykins D, Roberts JM. Nitric oxide synthase activity in pregnant rabbit uterus decreases on the last day of pregnancy. Am J Obstet Gynecol1993;169(5):1285-1291.
108.
108. MacMicking JD, Nathan C, Hom G, et al. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell1995;81(4):641-650.
109.
109. Roh CR, Oh WJ, Yoon BK, Lee JH. Up-regulationof matrix matalloproteinase-9 in human myometrium during labour: A cytokine-mediated process in uterine smooth muscle cells. Mol Hum Reprod2000;6(1):96-102.
110.
110. Riley SC, Leask R, Chard T, Wathen NC, Calder AA, Howe DC. Secretion of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases into the intrauterine compartments during early pregnancy. Mol Hum Reprod1999;5(4):376-381.
111.
111. Thomson AJ, Telfer JF, Young A, et al. Leukocytes infiltrate the myometrium during human parturition: Further evidence that labour is an inflammatory process. Hum Reprod1999;14(1):229-236.
112.
112. Winkler M, Oberpichler A, Tschesche H, Ruck P, Fischer DC, Rath W. Collagenolysis in the lower uterine segment during parturition at term: Correlations with stage of cervical dilatation and duration of labor. Am J Obstet Gynecol1999;181(1):153-158.
113.
113. Junqueira LC, Zugaib M, Montes GS, Toledo OM, Krisztan RM, Shigihara KM. Morphologic and histochemical evidence for the occurrence of collagenolysis and for the role of neutrophilic polymorphonuclear leukocytes during cervical dilation. Am J Obstet Gynecol1980;138(3):273-281.
114.
114. Mackler Am, Iezza G, Akin MR, McMillan P, Yellon SM. Macrophage trafficking in the uterus and cervix precedes parturition in the mouse. Biol Reprod1999;61(4):879-883.
115.
115. Pollard JW, Hunt JS, Wiktor Jedrzejczak W, Stanley ER. A pregnancy defect in the osteopetrotic (op/op) mouse demonstrates the requirement for CSF-1 in female fertility. Dev Biol1991;148(1):273-283.
116.
116. Mackler AM, Green LM, McMillan PJ, Yellon SM. Distribution and activation of uterine mononuclear phagocytes in peripartum endometrium and myometrium of the mouse. Biol Reprod2000;62(5):1193-1200.
117.
117. Pollard JW. Role of cytokines in the pregnant uterus of interstitial implanting species. In: Bazer FW, ed. The endocrinology of pregnancy. Totowa: Humana Press, Inc., 1998:59-82.
118.
118. Bernatchez SF, Atkinson MR, Parks PJ. Expression of intercellular adhesion molecule-1 on macrophages in vitro as a marker of activation. Biomaterials1997;18(20):1371-1378.
119.
119. Leenen PJ, de Bruijn MF, Voerman JS, Campbell PA, van Ewijk W. Markers of mouse macrophage development detected by monoclonal antibodies. J Immunol Methods1994;174(1-2):5-19.
120.
120. Goebeler M, Roth J, Kunz M, Sorg C. Expression of intercellular adhesion molecule-1 by murine macrophages is up-regulated during differentiation and inflammatory activation. Immunobiology1993;188(1-2):159-171.
122. Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol1993;11:767-804.
123.
123. Losa Garcia JE, Rodriguez FM, Martin de Cabo MR, et al. Evaluation of inflammatory cytokine secretion by human alveolar macrophages. Mediators Inflamm1999;8(1):43-51.
124.
124. Hammermann R, Dreissig MD, Mossner J, et al. Nuclear factor-kappaB mediates simultaneous inductionof inducible nitricoxide synthase and up-regulation of the cationic amino acid transporter CAT-2B in rat alveolar macrophages. Mol Pharmacol2000;58(6):1294-1302.
125.
125. Werb Z, Gordon S. Secretion of a specific collagenase by stimulated macrophages. J Exp Med1975;142(2):346-360.
126.
126. Buhimschi I, Ali M, Jain V, Chwalisz K, Garfield RE. Differential regulation ofnitric oxide in the rat uterus and cervix during pregnancy and labour. Hum Reprod1996;11(8):1755-1766.
127.
127. Guo CB, Kagey-Sobotka A, Lichtenstein LM, Bochner BS. Immunophenotyping and functional analysis of purified human uterine mast cells. Blood1992;79(3):708-712.
128.
128. Slukvin II, Chernyshov VP, Merkulova AA, Vodyanik MA, Kalinovsky AK. Differential expression of adhesion and homing molecules by human decidual and peripheral blood lymphocytes in early pregnancy. Cell Immunol1994;158(1):29-45.
129.
129. Calatayud S, Vivier E, Bernaud J, Merieux Y, Rigal D. Expression of a NK cell-restricted epitope on decidual large granular lymphocytes. Int Immunol1996;8(10):1637-1642.
130.
130. Ruck P, Marzusch K, Kaiserling E, et al. Distribution of cell adhesion molecules in decidua of early human pregnancy. An immunohistochemical study. Lab Invest1994;171(1):94-101.
131.
131. Ledingham MA, Thomson AJ, Jordan F, Young A, Crawford M, Norman JE. Cell adhesion molecule expression in the cervix and myometrium during pregnancy and parturition. Obstet Gynecol2001;97(2):235-242.
132.
132. Hendricks CH, Brenner WE, Kraus G. Normal cervical dilatation pattern in late pregnancy and labor. Am J Obstet Gynecol1970;106(7):1065-1082.
133.
133. Danforth DN, Veis A, Breen M, Weinstein HG, Buckingham JC, Manalo P. The effect of pregnancy and labor on the human cervix: Changes in collagen, glycoproteins, and glycosaminoglycans. Am J Obstet Gynecol1974;120(5):641-651.
134.
134. Leppi TJ, Kinnison PA. The connective tissue ground substance in the mouse uterine cervix: An electron microscopic histochemical study. Anat Rec1971;170(1):97-117.
135.
135. Rimmer DM. The effect of pregnancy on the collagen of the uterine cervix of the mouse. J Endocrinol. 1973;57(3):413-418.
136.
136. Uldbjerg N, Ekman G, Malmstrom A, Olsson K, Ulmsten U. Ripening of the human uterine cervix related to changes in collagen, glycosaminoglycans, and collagenolytic activity. Am J Obstet Gynecol1983;147(6):662-666.
137.
137. Kitamura K, Ito A, Mori Y, Hirakawa S. Changes in he human uterine cervical collagenase with special reference to cervical ripening. Biochem Med1979;22(3):332-338.
138.
138. Minamoto T, Arai K, Hirakawa S, Nagai Y. Immunohistopregnant and nonpregnant states. Am J Obstet Gynecol1987;156(1):138-144.
139.
139. Rajabi MR, Dean DD, Beydoun SN, Woessner JF Jr. Elevated tissue levels of collagenase during dilation of uterine cervix in human parturition. Am J Obstet Gynecol1988;159(4):971-976.
140.
140. Limvarapuss C, Kanayama N, Terao T. Elastase activity of endocervical mucus in normal pregnancy. Asia Oceania J Obstet Gynaecol1992;18(2):147-153.
141.
141. Yu SY, Tozzi CA, Babiarz J, Leppert PC. Collagen changes in rat cervix in pregnancy—polarized light microscopic and electron microscopic studies. Proc Soc Exp Biol Med1995;209(4):360-368.
142.
142. O'Brien WF. Cervical ripening and labor induction: Progress and challenges. Clin Obstet Gynecol1995;38(2):221-223.
143.
143. Yoshida M, Sagawa N, Itoh H, et al. Prostaglandin F(2alpha), cytokines and cyclic mechanical stretch augment matrix metalloproteinase-1 secretion from cultured human uterine cervical fibroblast cells. Mol Hum Reprod2002;8(7):681-687.
144.
144. Terakawa k, Itoh H, Sagawa N, et al. Site-specific augmentation of amnion cyclooxygenase-2 and decidua vera phospholipase-A2 expression in labor: Possible contribution of mechanical stretch and inerleukin-1 to amnion prostaglandin synthesis. J Soc Gynecol Investig2002;9(2):68-74.
145.
145. Ou CW, Chen ZQ, Qi S, Lye SJ. Expression and regulation of the messenger ribonucleic acid encoding the prostaglandin F(2alpha) receptor in the rat myometrium during pregnancy and labor. Am J Obstet Gynecol2000;182(4):919-925.
146.
146. Winkler M, Kemp B, Fischer DC, Maul H, Hlubek M, Rath W. Tissue concentrations of cytokines in the lower uterine segment during preterm parturition. J Perinat Med2001;29(6):519-527.
147.
147. Smith GC, Wu WX, Nathanielsz PW. Effects of gestational age and labor on the expression of prostanoid receptor genes in pregnant baboon cervix. Prostaglandins Other Lipid Mediat2001;63(4):153-163.
148.
148. Mahendroo MS, Porter A, Russell DW, Word RA. The parturition defect in steroid 5alpha-reductase type 1 knockout mice is due to impaired cervical ripening. Mol Endocrinol1999;13(6):981-992.
149.
149. Minjarez D, Konda V, Word RA. Regulation of uterine 5 alpha-reductase type 1 in mice. Biol Reprod2001;65(5):1378-1382.
150.
150. Osmers R, Rath W, Adelmann-Grill BC, et al. Origin of cervical collagenase during parturition. Am J Obstet Gynecol1992;166(6):1455-1460.
151.
151. Ito A, Nakamura T, Uchiyama T, et al. Stimulation of the biosynthesis of interleukin 8 by interleukin 1 and tumor necrosis factor alpha in cultural human chorionic cells. Biol Pharm Bull1994;17(11):1463-1467.
152.
152. Rotten D, Gavignet C, Colin MC, Robert AM, Godeau G. Evolution of he elastic fiber network of the human uterine cervix before, during and after pregnancy. A quantitative evaluation by automated image analysis. Clin Physiol Biochem1988;6(5):285-292.
153.
153. Watari M, Watari H, DiSanto ME, Chacko S, Shi GP, Strauss JF II. Pro-inflammatory cytokines induce expression of matrix-metabolizing enzymes in human cervical smooth muscle cells. Am J Pathol1999;154(6):1755-1762.
154.
154. Bokstrom H, Brannstrom M, Alexandersson M. Norstrom A. Leukocyte subpopulations in the human uterine cervical stroma aat early and term pregnancy. Hum Reprod1997;12(3):586-590.
155.
155. Collins JJ, Usip S, McCarson KE, Papka RE. Snsory nerves and neuropeptides in uterine cervical ripening. Petides2002;23(1):167-183.
156.
156. Knudsen UB, Uldbjerg N, Rechberger T, Fredens K. Kosinophils in human cervical ripening. Eur J Obstet Gynecol Reprod Biol1997;72(2):165-168.
157.
157. Owiny JR, Gilbert RO, Wahl CH, Nathanielsz PW. Leukocytic invasion of the ovine cervix at parturition. J Soc Gynecol Investig1995;2(4):593-596.
158.
158. Spanggaard H, Knudsen UB, Uldbjerg N, Jeziorska M, Woolley DE, Danielsen CC. Mast cells in cervical ripening—an immunohistochemical and biomechanical study in rats. Eur J Obstet Gynecol Reprod Biol1997;73(1):91-97.
159.
159. Stjernholm Y, Sennstrom M, Granstrom L, Ekman G, Johansson O. Protein gene product 9.5-immunoreactive nerve fibers and cells in human cervix of late pregnant, postparal and non-pregnant women. Acta Obstet Gynecol Scand1999;78(4):299-304.
160.
160. Mori Y, Ito A. Cervical ripening: Biochemical regulation. In: Leppert PC, Woessner JE, eds. The extracellular matrix of the uterus, cervix and fetal membrances. Ithaca: Perinatology Press, 1991:77-86.
161.
161. Fosang AJ, Handley CJ, Santer V, Lowther DA. Thorburn GD. Pregnancy-related changes in the connective tissue of the ovine cervix. Biol Reprod1984;30(5):1223-1235.
162.
162. Kuijpers TW, Hakkert BC, Hart MH, Roos D. Neutrophil migration across monolayers of cytokine-pre-stimulated endothelial cells: A role for platelete-activating factor and IL-8. J Cell Biol1992;117(3):565-572.
163.
163. El Maradny E, Kanayama N, Halim A, Machara K, Sumimoto K, Terao T. Interleukin-8 induces cervical ripening in rabbis. Am J Obstet Gynecol1994;171(1):77-83.
164.
164. Winkler M, Fischer DC, Hlubek M, van de LE, Haubeck HD, Rath W. Interleukin-1beta and interleukin-8 concentrations in the lower uterine segment during parturiton at term. Obstet Gynecol1998;91(6):945-949.
165.
165. Sennstrom MB, Ekman G, Westergren-Thorsson G, et al. Human cervical ripening, an inflammatory process mediated by cytokines. Mol Hum Reprod2000;6(4):375-381.
166.
166. Tanaka Y, Narahara H, Takai N, Yoshimatsu J, Anai T, Miyakawa I, Interleukin-1beta and interleukin-8 in cervicovaginal fluid during pregnancy. Am J Obstet Gynecol1998;179(3 Pt 1):644-649.
167.
167. Stjernholm Y, Sennstrom M, Granstrom L, Ekman G, Liang Y, Johansson O. Neurochemical and cellular markers in human cervix of late pregnant, postparal and non-pregnant women. Acta Obstet Gynecol Scand2000;79(7):528-537.
168.
168. Kelly RW. Inflammatory mediaors and cervical ripening. J Reprod Immunol2002;57(1-2):217-217.
169.
169. Ito A, Goshowaki H, Sato T, et al. Human recombinant interleukin-1 alpha-mediated stimulation of procollagenase production and suppression of biosynthesis of tissue inhibitor of metalloproteinases in rabbit uterine cervical fibroblasts. FEBS Lett1988;234(2):326-330.
170.
170. Baggiolini M, Bretz U, Dewald B, Feigensom ME. The polymorphonuclear leukocyte. Agents Actions1978;8(1-2):3-10.
171.
171. Peveri P, Walz A, Dewald B, Baggiolini M. A novel neutrophilactivating factor produced by human mononuclear phagocytes. J Exp Med1988;167(5):1547-1559.
172.
172. Unkeless JC, Gordon S, Reich E. Secretion of plasminogen activator by stimulated macrophages. J Exp Med1974;139(4):834-850.
173.
173. Wahl LM, Wahl SM, Mergenhagen SE, Martin GR. Collagenase production by lymphokine-activated macrophages. Science1975;187(4173):261-263.
174.
174. Huybrechts-Godin G, Peeters-Joris C, Vaes G. Partial characterization of the macrophage factor that stimulates fibroblasts to produce collagenase and to degrade collagen. Biochim Biophys Acta1985;846(1):51-54.
175.
175. Pandis GK, Papageorphiou At, Ramanathan VG, Thompson MO, Nicolaides KH. Preinduction sonographic measurement of cervical length in the prediction of successful induction of labor. Ultrasound Obstet Gynecol2001;18(6):623-628.
176.
176. Goldenberg RL, Iams JD. Mercer BM, et al. The preterm prediction study: The value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network. Am J Public Health1998;88(2):233-238.
177.
177. Newman RB. The preterm prediction study: Comparison of the cervical score and Bishop score for the prediction of spontaneous preterm. J Soc Gynecol Invest1997;4:152-A.
178.
178. Goldenberg RL, Mercer BM, Meis PJ, Copper RL, Das A, McNelis D. The preterm prediction study: Fetal fibronectin testing and spontaneous preterm birth. NICHD Maternal Fetal Medicine Units Network. Obstet Gynecol1996;87(5 Pt 1):643-648.
179.
179. Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med1996;334(9):567-572.
180.
180. Ledingham MA, Thomason AJ, Young A, Macara LM, Greer IA, Norman JE. Chanes in the expression of nitric oxide synthase in the human uterine cervix during pregnancy and parturition. Mol Hum Reprod2000;6(11):1041-1048.
181.
181. Tschugguel W, Schneeberger C, Lass H, et al. Human cervical ripening is association with an increase in cervical inducible nitric oxide synthase expression. Biol Reprod1999;60(6):1367-1372.
182.
182. Nakaya Y, Yamamoto S. Hamada Y, Kamada M, Aono T, Niwa M. Inducible nitric oxide synthase in uterine smooth muscle. LifeSci1996;58(13):L249-L255.
183.
183. Ali M, Buhimschi I, Chwalisz K, Garfield RE. Changes in expression of the nitric oxide synthase isoforms in rat uterus and cervix during pregnancy and parturition. Mol Hum Reprod1997;3(11):995-1003.
184.
184. Bao S, Rai J, Schreiber J. Brain nitric oxide synthase expression is enhanced in the human cervix in labor. J Soc Gynecol Investig2001;8(3):158-164.
185.
185. Marshall JM. Effects of ovarian steroids and pregnancy on adrenergic nerves of uterus and oviduct. Am J Physiol1981;240(5):C165-C174.
186.
186. Arkinstall SJ, Moye I, Jones CT. Alpha 2-adrenergic receptors in guinea pig myometrium in late pregnancy: Evidence for a predominantly postjunctional location. Am J Obstet Gynecol1990;162(3):831-836.
187.
187. Alm P, Owman C, Sjoberg NO, Stjernquist M, Sundler F. Histochemical demonstration of a concomitant reduction in neural vasoactive intestinal polypeptide, acetylcholinesterase, and noradrenaline of cat uterus during pregnancy. Neuroscience1996;18(3):713-726.
188.
188. Dong YL, Gangula PR, Vallampalli C. Nitric oxide synthase isoforms in the rat uterus: Differential regulation during pregnancy and labory. J Reprod Fertil1996;107(2):249-254.
189.
189. Elmer M, Alm P, Thorbert G. Electrical field stimulation of myometrial strips from non-pregnant and pregnant guinea-pigs. Acta Physiol Scaqnd1980;108(3):209-213.
190.
190. Brauer MM, Lincoln J, Sarner S, et all. Maturational changes in sympathetic and sensory innervation of the rat uterus: Effects of neonatal capsaicin treatment. Int J Dev Neurosci1994;12(2):157-171.
191.
191. Papka RE, Cotton JP, Traurig HH. Comparative distribution of neuropeptide tyrosine-, vosoactive intestinal polypetide-, substance P-immunoreactive, acetylcolinesterase-postive and noradrenergic nerves in the reproductive tract of the female rat. Cell Tissue Res1985;242(3):475-490.
192.
192. Papka RE. Some nerve endings in the rat pelvic paracervical autonomic ganglia and varicosities in the uterus contain calcitonin gene-related peptide and originate from dorsal root ganglia. Neuroscience1990;39(2):459-470.
193.
193. Papka RE, Traug HH. Distribution of subgroups of neuropeptide Y-immunoreactive and noradrenergic nerves in the female rat uterine cervix. Cell Tissue Res1988;252(3):533-541.
194.
194. Traurig HH, Papka RE, Rush ME. Effects of capsaicin on reproductive function in he female rat: Role of peptide-containing primary afferent nerves innervating the uterine cervix in the neuroendocrine copulatory response. Cell Tissue Res1988;253(3):573-581.
195.
195. Collins JJ. Lin CE, Berthoud HR, Papka RE. Vagal afferents from the uterus and cervix provide direct connections to the brainstem. Cell Tissue Res1999;295(1):43-54.
196.
196. Lee JW, Erskine MS. Pseudorabies virus tracing of neural pathways between the uterine cervix and CNS: Effects of survival time, estrogen treatment, rhizotomy, and pelvic nerve transection. J Comp Neurol2000;418(4):484-503.
197.
197. Vera PL, Haase EB, Schramm LP. Origins of the sympathetic innervation of the cervical end of the uterus in the rat. Brain Res1997;747(1):140-143.
198.
198. Maggi Ca, Patacchini R, Giuliani S, Santicioli P, Meli A. Evidence for wo independent modes of activation of the `efferent' function of capsaicin-sensitive nerves. Eur J Pharmacol1988;156(3):367-373.
199.
199. Papka RE, McNeill DL. Light-and electron-microscopic study of synaptic connections in the paracervical ganglion of the female rat: Special reference to calcitonin gene-related peptide-, galanin-and tachykinin (substance P and neurokinin A)-immunoreactive nerve fibers and terminals. Cell Tissue Res1993;271(3):417-428.
200.
200. Traurig HH, Papka RE, Shew RL. Substance P and related peptides associated with the afferent and autonomic innervation of the uterus. Ann N Y Acad Sci1991;632:304-313.
201.
201. Holzer P. Local effector functions of capsaicin-sensitive sensory nerve endings; Involvement of tachykinins, calcitonin generelated peptide and other neuropeptides. Neuroscience1988;24(3):739-768.
202.
202. Papka RE, Hafemeister J, Puder BA, Usip S, Storey-Workely M. Strogen receptor-alpha and neural circuits to the spinal cord during pregnancy. J Neurosci Res2002;70(6):808-816.
203.
203. Carlson RR, De Feo VJ. Role of the pelvic nerve vs. the abdominal sympathetic nerves in the reproductive function of the female rat. Endocrinology1965;77(6):1014-1022.
204.
204. Renegar RH, Steel M, Burden HW, Hodson CA. Endocrine parameters associated with disruption of parturition after bilateral pelvic neurectomy. Proc Soc Exp Biol Med1992;201(1):28-33.
205.
205. Spies HG, Forbes VM, Clegg MT. The influence of coitus, sucking, and prolactin injections on pregnancy in pelvic neurectomized rats. Proc Soc Exp Biol Med1971;138:470-474.
206.
206. Thompson RJ, Doran JF, Jackson P, Dhillon AP, Rode J. PGP 9.5-a new marker for vertebrate neurons and neuroendocrine cells. Brain Res1983;278(1-2):224-228.
207.
207. Iams JD, Johnson FF, Creasy RK. Prevention of preterm birth. Clin Obstet Gynecol1988;31(3):599-615.
208.
208. Goldenberg RL. The management o preterm labor. Obstet Gynecol2002;100(5 Pt 1):1020-1037.
209.
209. Gupta SK. The immunology of reproduction: Update 1998. Immunol Today1998;19(10):433-434.
210.
210. Martius J, Roos T. The role of urogenital tract infections in the etiology of preterm birth: A review. Arch Gynecol Obstet1996;258(1):1-19.
211.
211. Vigneswaran R. Infection and preterm birth: Evidence of a common causal relationship with bronchopulmonary dysplasia and cerebral palsy. J Paediatr Child Health2000;36(4):293-296.
212.
212. Goldenberg RL, Jobe AH. Prospects for research in reproductive health and birth outcomes. JAMA2001;285(5):633-639.
213.
213. Saji F,Samekuma Y, Kamiura S, Sawai K, Shimoya K, Kimura T. Cytokine production in chorioamnionitis. J Reprod Immunol2000;47(2):185-196.
214.
214. Hirsch E, Saotome I, Hirsh D. A model of intrauterine infection and preterm delivery in mice. Am J Obstet Gynecol1995;172(5):1598-1603.
215.
215. Knox IC Jr, Hoerner JK. The role of of infection in premature rupture of the membrances. 1950. Am J Obstet Gynecol1995;173(3 Pt 1):951-951.
216.
216. Reznikoc LL, Fantuzzi G, Selzman CH, et al. Utilization of endoscopic inoculation in a mouse model of intrauterine infection-induced preterm birth: Role of interleukin 1beta. Biol Reprod1999;60(5):1231-1238.
217.
217. Romero R, Sirtori M, Oyarzun E, et al. Infection and labor. V. Prevalence,microbiology, and clinical significanceof intraamniotic infection in women with preterm labor and intact membrances. Am J Obstet Gynecol1989;161(3):817-824.
218.
218. Romero R, Mazor M, Tartakosky B. Systemic administratioon of interleukin-1 induces preterm parturition in mice. Am J Obstet Gynecol1991;165(4 Pt 1):969-971.
219.
219. Romero R, Avila C, Brekus CA, Morotti R. The role of systemic and intrauterine infection in preterm parturition. Ann N Y Acad Sci1991;622:355-375.
220.
220. Hebisch G. Cytokine levels in five different fluid compartments during amniotic fluid infection and labour. Adv Exp Med Biol1997;433:87-90.
221.
221. Fidel PI Jr, Romero R, Maymon E, Hertelendy F. Bacteriainduced or bacterial product-induced preterm parturition in mice and rabbits is preceded by a significant fall in serum progesterone concentrations. J Matern Fetal Med1998;7(5):222-226.
222.
222. Kaga N, Katsuki Y, Obata M, Shibutani Y. Repeated administration of low-dose lipopolysaccharide induces preterm delivery in mice: A model for human preterm parturition and for assessment of the therapeutic abilityof drugs against preterm delivery. Am J Obstet Gynecol1996;174(2):754-759.
223.
223. McGregor JA, French JI, Bacterial vaginosis in pregnancy. Obstet Gynecol Surv2000;55(5 Suppl 1):S1-S19.
224.
224. Armer TL, Duff P. Intraamniotic infection in patients with intact membranes and preterm labor. Obstet Gynecol Surv1991;46(9):589-593.
225.
225. Guinn DA, Goldenberg RL, Cliver SP, Owen J. Relationship of gestational age and cervical dilation to the timing of delivery. Int J Gynaecol Obstet1999;64(3):233-237.
226.
226. The Canadian Preterm Labor Investigators Group. Treatment of perterm labor with the beta-adrengergic agonist ritodrine. N Engl J Med1992;327(5):308-312.
227.
227. King JF, Grant A Keirse MJ, Chalmers I. Beta-mimetics in preterm labour: An overview of he randomized controlled trials. Br J Obstet Gynaecol1988;95(3):211-222.
228.
228. Romero R, Sibai B, Caritis S, et al. Antibiotic treatment of preterm labor with inact membranes: A multicenter, randomized, double-blinded, placebo-controlled trial. Am J Obstet Gynecol1993;169:764-774.
