Compartmentalized profiling of amniotic fluid cytokines in women with preterm labor


Autoři: Gaurav Bhatti aff001;  Roberto Romero aff001;  Gregory Edward Rice aff008;  Wendy Fitzgerald aff009;  Percy Pacora aff001;  Nardhy Gomez-Lopez aff001;  Mahendra Kavdia aff002;  Adi L. Tarca aff001;  Leonid Margolis aff009
Působiště autorů: Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Beth aff001;  Department of Biomedical Engineering, Wayne State University College of Engineering, Detroit, Michigan, United States of America aff002;  Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, United States of America aff003;  Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, United States of America aff004;  Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, United States of America aff005;  Detroit Medical Center, Detroit, Michigan, United States of America aff006;  Department of Obstetrics and Gynecology, Florida International University, Miami, Florida, United States of America aff007;  Centre for Clinical Research, University of Queensland, Herston, Queensland, Australia aff008;  Section on Intercellular Interactions, National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, United States of America aff009;  Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, United States of America aff010;  Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, Michigan, United States of America aff011;  Department of Computer Science, Wayne State University College of Engineering, Detroit, Michigan, United States of America aff012
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227881

Souhrn

Objective

Amniotic fluid cytokines have been implicated in the mechanisms of preterm labor and birth. Cytokines can be packaged within or on the surface of extracellular vesicles. The main aim of this study was to test whether the protein abundance internal to and on the surface of extracellular vesicles changes in the presence of sterile intra-amniotic inflammation and proven intra-amniotic infection in women with preterm labor as compared to the women with preterm labor without either intra-amniotic inflammation or proven intra-amniotic infection.

Study design

Women who had an episode of preterm labor and underwent an amniocentesis for the diagnosis of intra-amniotic infection or intra-amniotic inflammation were classified into three groups: 1) preterm labor without either intra-amniotic inflammation or proven intra-amniotic infection, 2) preterm labor with sterile intra-amniotic inflammation, and 3) preterm labor with intra-amniotic infection. The concentrations of 38 proteins were determined on the extracellular vesicle surface, within the vesicles, and in the soluble fraction of amniotic fluid.

Results

1) Intra-amniotic inflammation, regardless of detected microbes, was associated with an increased abundance of amniotic fluid cytokines on the extracellular vesicle surface, within vesicles, and in the soluble fraction. These changes were most prominent in women with proven intra-amniotic infection. 2) Cytokine changes on the surface of extracellular vesicles were correlated with those determined in the soluble fraction; yet the magnitude of the increase was significantly different between these compartments. 3) The performance of prediction models of early preterm delivery based on measurements on the extracellular vesicle surface was equivalent to those based on the soluble fraction.

Conclusions

Differential packaging of amniotic fluid cytokines in extracellular vesicles during preterm labor with sterile intra-amniotic inflammation or proven intra-amniotic infection is reported herein for the first time. The current study provides insights into the biology of the intra-amniotic fluid ad may aid in the development of biomarkers for obstetrical disease.

Klíčová slova:

Amniotic fluid – Cytokines – Forecasting – Inflammation – Labor and delivery – Preterm birth – Vesicles – Preterm labor


Zdroje

1. Cole CR, Hansen NI, Higgins RD, Ziegler TR, Stoll BJ, Eunice Kennedy Shriver NNRN. Very low birth weight preterm infants with surgical short bowel syndrome: incidence, morbidity and mortality, and growth outcomes at 18 to 22 months. Pediatrics. 2008;122(3):e573–82. Epub 2008/09/03. doi: 10.1542/peds.2007-3449 18762491.

2. Beck S, Wojdyla D, Say L, Betran AP, Merialdi M, Requejo JH, et al. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ. 2010;88(1):31–8. Epub 2010/04/30. doi: 10.2471/BLT.08.062554 20428351.

3. Dong Y, Yu JL. An overview of morbidity, mortality and long-term outcome of late preterm birth. World J Pediatr. 2011;7(3):199–204. Epub 2011/08/09. doi: 10.1007/s12519-011-0290-8 21822987.

4. Ruegger C, Hegglin M, Adams M, Bucher HU, Swiss Neonatal N. Population based trends in mortality, morbidity and treatment for very preterm- and very low birth weight infants over 12 years. BMC Pediatr. 2012;12:17. Epub 2012/02/24. doi: 10.1186/1471-2431-12-17 22356724.

5. Yamakawa T, Itabashi K, Kusuda S, Neonatal Research Network of J. Mortality and morbidity risks vary with birth weight standard deviation score in growth restricted extremely preterm infants. Early Hum Dev. 2016;92:7–11. Epub 2015/11/30. doi: 10.1016/j.earlhumdev.2015.10.019 26615548.

6. Fritz T, Kallen K, Marsal K, Jacobsson B. Outcome of extremely preterm infants after iatrogenic or spontaneous birth. Acta Obstet Gynecol Scand. 2018. Epub 2018/05/26. doi: 10.1111/aogs.13387 29797737.

7. McGregor JA, French JI. Preterm Birth: The Role of Infection and Inflammation. Medscape Womens Health. 1997;2(8):1. Epub 1997/08/01. 9746700.

8. Klebanoff M, Searle K. The role of inflammation in preterm birth—focus on periodontitis. BJOG. 2006;113 Suppl 3:43–5. Epub 2007/01/09. doi: 10.1111/j.1471-0528.2006.01121.x 17206963.

9. Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel L, Hassan S. The role of inflammation and infection in preterm birth. Semin Reprod Med. 2007;25(1):21–39. Epub 2007/01/06. doi: 10.1055/s-2006-956773 17205421.

10. Catov JM, Bodnar LM, Ness RB, Barron SJ, Roberts JM. Inflammation and dyslipidemia related to risk of spontaneous preterm birth. Am J Epidemiol. 2007;166(11):1312–9. Epub 2007/10/02. doi: 10.1093/aje/kwm273 17906337.

11. Holst D, Garnier Y. Preterm birth and inflammation-The role of genetic polymorphisms. Eur J Obstet Gynecol Reprod Biol. 2008;141(1):3–9. Epub 2008/09/12. doi: 10.1016/j.ejogrb.2008.07.020 18783866.

12. Bastek JA, Gomez LM, Elovitz MA. The role of inflammation and infection in preterm birth. Clin Perinatol. 2011;38(3):385–406. Epub 2011/09/06. doi: 10.1016/j.clp.2011.06.003 21890015.

13. Nold C, Anton L, Brown A, Elovitz M. Inflammation promotes a cytokine response and disrupts the cervical epithelial barrier: a possible mechanism of premature cervical remodeling and preterm birth. Am J Obstet Gynecol. 2012;206(3):208.e1–7. Epub 2012/01/31. doi: 10.1016/j.ajog.2011.12.036 22285171.

14. Kemp MW. Preterm birth, intrauterine infection, and fetal inflammation. Front Immunol. 2014;5:574. Epub 2014/12/19. doi: 10.3389/fimmu.2014.00574 25520716.

15. Burdet J, Rubio AP, Salazar AI, Ribeiro ML, Ibarra C, Franchi AM. Inflammation, infection and preterm birth. Curr Pharm Des. 2014;20(29):4741–8. Epub 2014/03/05. doi: 10.2174/1381612820666140130202224 24588830.

16. Cappelletti M, Della Bella S, Ferrazzi E, Mavilio D, Divanovic S. Inflammation and preterm birth. J Leukoc Biol. 2016;99(1):67–78. Epub 2015/11/06. doi: 10.1189/jlb.3MR0615-272RR 26538528.

17. van der Krogt L, Ridout AE, Seed PT, Shennan AH. Placental inflammation and its relationship to cervicovaginal fetal fibronectin in preterm birth. Eur J Obstet Gynecol Reprod Biol. 2017;214:173–7. Epub 2017/05/24. doi: 10.1016/j.ejogrb.2017.05.001 28535404.

18. Romero R, Sirtori M, Oyarzun E, Avila C, Mazor M, Callahan R, et al. Infection and labor. V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol. 1989;161(3):817–24. Epub 1989/09/01. doi: 10.1016/0002-9378(89)90409-2 2675611.

19. Romero R, Shamma F, Avila C, Jimenez C, Callahan R, Nores J, et al. Infection and labor. VI. Prevalence, microbiology, and clinical significance of intraamniotic infection in twin gestations with preterm labor. Am J Obstet Gynecol. 1990;163(3):757–61. Epub 1990/09/01. doi: 10.1016/0002-9378(90)91063-i 2403156.

20. Mazor M, Hershkovitz R, Ghezzi F, Maymon E, Horowitz S, Leiberman JR. Intraamniotic infection in patients with preterm labor and twin pregnancies. Acta Obstet Gynecol Scand. 1996;75(7):624–7. Epub 1996/08/01. doi: 10.3109/00016349609054686 8822654.

21. Chaim W, Mazor M, Wiznitzer A. The prevalence and clinical significance of intraamniotic infection with Candida species in women with preterm labor. Arch Gynecol Obstet. 1992;251(1):9–15. Epub 1992/01/01. doi: 10.1007/bf02718273 1550392.

22. Mazor M, Kassis A, Horowitz S, Wiznitzer A, Kuperman O, Meril C, et al. Relationship between C-reactive protein levels and intraamniotic infection in women with preterm labor. J Reprod Med. 1993;38(10):799–803. Epub 1993/10/01. 8263870.

23. Gomez R, Romero R, Edwin SS, David C. Pathogenesis of preterm labor and preterm premature rupture of membranes associated with intraamniotic infection. Infect Dis Clin North Am. 1997;11(1):135–76. Epub 1997/03/01. doi: 10.1016/s0891-5520(05)70347-0 9067790.

24. Hsu CD, Aversa K, Meaddough E, Lee IS, Copel JA. Elevated amniotic fluid nitric oxide metabolites and cyclic guanosine 3',5'-monophosphate in pregnant women with intraamniotic infection. Am J Obstet Gynecol. 1997;177(4):793–6. Epub 1997/11/25. doi: 10.1016/s0002-9378(97)70270-9 9369821.

25. Newton ER, Piper J, Peairs W. Bacterial vaginosis and intraamniotic infection. Am J Obstet Gynecol. 1997;176(3):672–7. Epub 1997/03/01. doi: 10.1016/s0002-9378(97)70568-4 9077627.

26. Hsu CD, Meaddough E, Aversa K, Copel JA. The role of amniotic fluid L-selectin, GRO-alpha, and interleukin-8 in the pathogenesis of intraamniotic infection. Am J Obstet Gynecol. 1998;178(3):428–32. Epub 1998/04/16. doi: 10.1016/s0002-9378(98)70414-4 9539502.

27. Krohn MA, Germain M, Muhlemann K, Hickok D. Prior pregnancy outcome and the risk of intraamniotic infection in the following pregnancy. Am J Obstet Gynecol. 1998;178(2):381–5. Epub 1998/03/21. doi: 10.1016/s0002-9378(98)80029-x 9500503.

28. Mikamo H, Kawazoe K, Sato Y, Imai A, Tamaya T. Preterm labor and bacterial intraamniotic infection: arachidonic acid liberation by phospholipase A2 of Fusobacterium nucleatum. Am J Obstet Gynecol. 1998;179(6 Pt 1):1579–82. Epub 1998/12/17. doi: 10.1016/s0002-9378(98)70028-6 9855600.

29. Maymon E, Romero R, Pacora P, Gomez R, Mazor M, Edwin S, et al. A role for the 72 kDa gelatinase (MMP-2) and its inhibitor (TIMP-2) in human parturition, premature rupture of membranes and intraamniotic infection. J Perinat Med. 2001;29(4):308–16. Epub 2001/09/22. doi: 10.1515/JPM.2001.044 11565199.

30. Kim YM, Romero R, Oh SY, Kim CJ, Kilburn BA, Armant DR, et al. Toll-like receptor 4: a potential link between “danger signals,” the innate immune system, and preeclampsia? Am J Obstet Gynecol. 2005;193(3 Pt 2):921–7. Epub 2005/09/15. doi: 10.1016/j.ajog.2005.07.076 16157088.

31. Buhimschi IA, Zhao G, Pettker CM, Bahtiyar MO, Magloire LK, Thung S, et al. The receptor for advanced glycation end products (RAGE) system in women with intraamniotic infection and inflammation. Am J Obstet Gynecol. 2007;196(2):181.e1–13. Epub 2007/02/20. doi: 10.1016/j.ajog.2006.09.001 17306673.

32. Gravett MG, Adams KM, Sadowsky DW, Grosvenor AR, Witkin SS, Axthelm MK, et al. Immunomodulators plus antibiotics delay preterm delivery after experimental intraamniotic infection in a nonhuman primate model. Am J Obstet Gynecol. 2007;197(5):518.e1–8. Epub 2007/11/06. doi: 10.1016/j.ajog.2007.03.064 17980193.

33. Romero R, Schaudinn C, Kusanovic JP, Gorur A, Gotsch F, Webster P, et al. Detection of a microbial biofilm in intraamniotic infection. Am J Obstet Gynecol. 2008;198(1):135.e1–5. Epub 2008/01/02. doi: 10.1016/j.ajog.2007.11.026 18166328.

34. Allen-Daniels MJ, Serrano MG, Pflugner LP, Fettweis JM, Prestosa MA, Koparde VN, et al. Identification of a gene in Mycoplasma hominis associated with preterm birth and microbial burden in intraamniotic infection. Am J Obstet Gynecol. 2015;212(6):779.e1–e13. Epub 2015/02/01. doi: 10.1016/j.ajog.2015.01.032 25637842.

35. Gomez-Lopez N, Romero R, Xu Y, Leng Y, Garcia-Flores V, Miller D, et al. Are amniotic fluid neutrophils in women with intraamniotic infection and/or inflammation of fetal or maternal origin? Am J Obstet Gynecol. 2017;217(6):693.e1–e16. Epub 2017/10/02. doi: 10.1016/j.ajog.2017.09.013 28964823.

36. Romero R, Brody DT, Oyarzun E, Mazor M, Wu YK, Hobbins JC, et al. Infection and labor. III. Interleukin-1: a signal for the onset of parturition. Am J Obstet Gynecol. 1989;160(5 Pt 1):1117–23. Epub 1989/05/01. doi: 10.1016/0002-9378(89)90172-5 2786341.

37. Hoffman DR, Romero R, Johnston JM. Detection of platelet-activating factor in amniotic fluid of complicated pregnancies. Am J Obstet Gynecol. 1990;162(2):525–8. Epub 1990/02/01. doi: 10.1016/0002-9378(90)90423-5 2309839.

38. Romero R, Avila C, Santhanam U, Sehgal PB. Amniotic fluid interleukin 6 in preterm labor. Association with infection. J Clin Invest. 1990;85(5):1392–400. Epub 1990/05/01. doi: 10.1172/JCI114583 2332497.

39. Romero R, Parvizi ST, Oyarzun E, Mazor M, Wu YK, Avila C, et al. Amniotic fluid interleukin-1 in spontaneous labor at term. J Reprod Med. 1990;35(3):235–8. Epub 1990/03/01. 2325034.

40. Santhanam U, Avila C, Romero R, Viguet H, Ida N, Sakurai S, et al. Cytokines in normal and abnormal parturition: elevated amniotic fluid interleukin-6 levels in women with premature rupture of membranes associated with intrauterine infection. Cytokine. 1991;3(2):155–63. Epub 1991/03/01. doi: 10.1016/1043-4666(91)90037-e 1888885.

41. Romero R, Mazor M, Sepulveda W, Avila C, Copeland D, Williams J. Tumor necrosis factor in preterm and term labor. Am J Obstet Gynecol. 1992;166(5):1576–87. Epub 1992/05/01. doi: 10.1016/0002-9378(92)91636-o 1595815.

42. Romero R, Mazor M, Brandt F, Sepulveda W, Avila C, Cotton DB, et al. Interleukin-1 alpha and interleukin-1 beta in preterm and term human parturition. Am J Reprod Immunol. 1992;27(3–4):117–23. Epub 1992/04/01. doi: 10.1111/j.1600-0897.1992.tb00737.x 1418402.

43. Romero R, Sepulveda W, Kenney JS, Archer LE, Allison AC, Sehgal PB. Interleukin 6 determination in the detection of microbial invasion of the amniotic cavity. Ciba Found Symp. 1992;167:205–20; discussion 20–3. Epub 1992/01/01. doi: 10.1002/9780470514269.ch13 1425014.

44. Cherouny PH, Pankuch GA, Romero R, Botti JJ, Kuhn DC, Demers LM, et al. Neutrophil attractant/activating peptide-1/interleukin-8: association with histologic chorioamnionitis, preterm delivery, and bioactive amniotic fluid leukoattractants. Am J Obstet Gynecol. 1993;169(5):1299–303. Epub 1993/11/01. doi: 10.1016/0002-9378(93)90297-v 8238198.

45. Romero R, Yoon BH, Mazor M, Gomez R, Diamond MP, Kenney JS, et al. The diagnostic and prognostic value of amniotic fluid white blood cell count, glucose, interleukin-6, and gram stain in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 1993;169(4):805–16. Epub 1993/10/01. doi: 10.1016/0002-9378(93)90009-8 7694461.

46. Romero R, Yoon BH, Kenney JS, Gomez R, Allison AC, Sehgal PB. Amniotic fluid interleukin-6 determinations are of diagnostic and prognostic value in preterm labor. Am J Reprod Immunol. 1993;30(2–3):167–83. Epub 1993/09/01. doi: 10.1111/j.1600-0897.1993.tb00618.x 8311926.

47. Laham N, Rice GE, Bishop GJ, Ransome C, Brennecke SP. Interleukin 8 concentrations in amniotic fluid and peripheral venous plasma during human pregnancy and parturition. Acta Endocrinol (Copenh). 1993;129(3):220–4. Epub 1993/09/01. doi: 10.1530/acta.0.1290220 8212986.

48. Greig PC, Ernest JM, Teot L, Erikson M, Talley R. Amniotic fluid interleukin-6 levels correlate with histologic chorioamnionitis and amniotic fluid cultures in patients in premature labor with intact membranes. Am J Obstet Gynecol. 1993;169(4):1035–44. Epub 1993/10/01. doi: 10.1016/0002-9378(93)90050-s 8238116.

49. Laham N, Brennecke SP, Bendtzen K, Rice GE. Tumour necrosis factor alpha during human pregnancy and labour: maternal plasma and amniotic fluid concentrations and release from intrauterine tissues. Eur J Endocrinol. 1994;131(6):607–14. Epub 1994/12/01. doi: 10.1530/eje.0.1310607 7804444.

50. Allbert JR, Naef RW 3rd, Perry KG Jr., Magann EF, Whitworth NS, Morrison JC. Amniotic fluid interleukin-6 and interleukin-8 levels predict the success of tocolysis in patients with preterm labor. J Soc Gynecol Investig. 1994;1(4):264–8. Epub 1994/10/01. doi: 10.1177/107155769400100404 9419782.

51. Waring PM, Romero R, Laham N, Gomez R, Rice GE. Leukemia inhibitory factor: association with intraamniotic infection. Am J Obstet Gynecol. 1994;171(5):1335–41. Epub 1994/11/01. doi: 10.1016/0002-9378(94)90157-0 7977543.

52. Greig PC, Herbert WN, Robinette BL, Teot LA. Amniotic fluid interleukin-10 concentrations increase through pregnancy and are elevated in patients with preterm labor associated with intrauterine infection. Am J Obstet Gynecol. 1995;173(4):1223–7. Epub 1995/10/01. doi: 10.1016/0002-9378(95)91358-0 7485325.

53. Dudley DJ, Hunter C, Varner MW, Mitchell MD. Elevation of amniotic fluid interleukin-4 concentrations in women with preterm labor and chorioamnionitis. Am J Perinatol. 1996;13(7):443–7. Epub 1996/10/01. doi: 10.1055/s-2007-994385 8960615.

54. Dudley DJ, Hunter C, Mitchell MD, Varner MW. Amniotic fluid interleukin-10 (IL-10) concentrations during pregnancy and with labor. J Reprod Immunol. 1997;33(2):147–56. Epub 1997/06/01. doi: 10.1016/s0165-0378(97)00020-x 9234213.

55. Rivero-Marcotegui A, Larranaga-Azcarate C, Ceres-Ruiz R, Garcia-Merlo S. Polymorphonuclear elastase and interleukin-6 in amniotic fluid in preterm labor. Clin Chem. 1997;43(5):857–9. Epub 1997/05/01. 9166251.

56. Veith GL, Rice GE. Interferon gamma expression during human pregnancy and in association with labour. Gynecol Obstet Invest. 1999;48(3):163–7. Epub 1999/11/05. doi: 10.1159/000010165 10545738.

57. Kemp B, Winkler M, Maas A, Maul H, Ruck P, Reineke T, et al. Cytokine concentrations in the amniotic fluid during parturition at term: correlation to lower uterine segment values and to labor. Acta Obstet Gynecol Scand. 2002;81(10):938–42. Epub 2002/10/09. doi: 10.1034/j.1600-0412.2002.811007.x 12366484.

58. Jacobsson B, Mattsby-Baltzer I, Andersch B, Bokstrom H, Holst RM, Wennerholm UB, et al. Microbial invasion and cytokine response in amniotic fluid in a Swedish population of women in preterm labor. Acta Obstet Gynecol Scand. 2003;82(2):120–8. Epub 2003/03/22. doi: 10.1034/j.1600-0412.2003.00047.x 12648172.

59. Holst RM, Mattsby-Baltzer I, Wennerholm UB, Hagberg H, Jacobsson B. Interleukin-6 and interleukin-8 in cervical fluid in a population of Swedish women in preterm labor: relationship to microbial invasion of the amniotic fluid, intra-amniotic inflammation, and preterm delivery. Acta Obstet Gynecol Scand. 2005;84(6):551–7. Epub 2005/05/20. doi: 10.1111/j.0001-6349.2005.00708.x 15901266.

60. Combs CA, Gravett M, Garite TJ, Hickok DE, Lapidus J, Porreco R, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014;210(2):125.e1–e15. Epub 2013/11/28. doi: 10.1016/j.ajog.2013.11.032 24274987.

61. Romero R, Grivel JC, Tarca AL, Chaemsaithong P, Xu Z, Fitzgerald W, et al. Evidence of perturbations of the cytokine network in preterm labor. Am J Obstet Gynecol. 2015;213(6):836.e1–e18. Epub 2015/08/02. doi: 10.1016/j.ajog.2015.07.037 26232508.

62. Tarca AL, Fitzgerald W, Chaemsaithong P, Xu Z, Hassan SS, Grivel JC, et al. The cytokine network in women with an asymptomatic short cervix and the risk of preterm delivery. Am J Reprod Immunol. 2017;78(3). doi: 10.1111/aji.12686 28585708.

63. Rieckmann P, D'Alessandro F, Nordan RP, Fauci AS, Kehrl JH. IL-6 and tumor necrosis factor-alpha. Autocrine and paracrine cytokines involved in B cell function. J Immunol. 1991;146(10):3462–8. Epub 1991/05/15. 2026875.

64. Cassatella MA, Meda L, Bonora S, Ceska M, Constantin G. Interleukin 10 (IL-10) inhibits the release of proinflammatory cytokines from human polymorphonuclear leukocytes. Evidence for an autocrine role of tumor necrosis factor and IL-1 beta in mediating the production of IL-8 triggered by lipopolysaccharide. J Exp Med. 1993;178(6):2207–11. Epub 1993/12/01. doi: 10.1084/jem.178.6.2207 8245792.

65. Arzt E, Stalla GK. Cytokines: autocrine and paracrine roles in the anterior pituitary. Neuroimmunomodulation. 1996;3(1):28–34. Epub 1996/01/01. doi: 10.1159/000097224 8892358.

66. Kaplan D. Autocrine secretion and the physiological concentration of cytokines. Immunol Today. 1996;17(7):303–4. Epub 1996/07/01. doi: 10.1016/0167-5699(96)30017-0 8763813.

67. Renner U, Pagotto U, Arzt E, Stalla GK. Autocrine and paracrine roles of polypeptide growth factors, cytokines and vasogenic substances in normal and tumorous pituitary function and growth: a review. Eur J Endocrinol. 1996;135(5):515–32. Epub 1996/11/01. doi: 10.1530/eje.0.1350515 8980150.

68. Rothwell NJ. The endocrine significance of cytokines. J Endocrinol. 1991;128(2):171–3. Epub 1991/02/01. doi: 10.1677/joe.0.1280171 1900883.

69. Vassilopoulou-Sellin R. Endocrine effects of cytokines. Oncology (Williston Park). 1994;8(10):43–6, 9; discussion 9–50. Epub 1994/10/01. 7528526.

70. Silva CM, Isgaard J, Thorner MO. Cytokines in endocrine function. Adv Protein Chem. 1998;52:199–221. Epub 1999/01/26. doi: 10.1016/s0065-3233(08)60436-2 9917921.

71. Konadu KA, Chu J, Huang MB, Amancha PK, Armstrong W, Powell MD, et al. Association of Cytokines With Exosomes in the Plasma of HIV-1-Seropositive Individuals. J Infect Dis. 2015;211(11):1712–6. Epub 2014/12/17. doi: 10.1093/infdis/jiu676 25512626.

72. Tokarz A, Szuscik I, Kusnierz-Cabala B, Kapusta M, Konkolewska M, Zurakowski A, et al. Extracellular vesicles participate in the transport of cytokines and angiogenic factors in diabetic patients with ocular complications. Folia Med Cracov. 2015;55(4):35–48. Epub 2016/02/13. 26867118.

73. Kovach MA, Singer BH, Newstead MW, Zeng X, Moore TA, White ES, et al. IL-36gamma is secreted in microparticles and exosomes by lung macrophages in response to bacteria and bacterial components. J Leukoc Biol. 2016;100(2):413–21. Epub 2016/02/13. doi: 10.1189/jlb.4A0315-087R 26864267.

74. Fitzgerald W, Gomez-Lopez N, Erez O, Romero R, Margolis L. Extracellular vesicles generated by placental tissues ex vivo: A transport system for immune mediators and growth factors. Am J Reprod Immunol. 2018:e12860. Epub 2018/05/05. doi: 10.1111/aji.12860 29726582.

75. Keller S, Rupp C, Stoeck A, Runz S, Fogel M, Lugert S, et al. CD24 is a marker of exosomes secreted into urine and amniotic fluid. Kidney Int. 2007;72(9):1095–102. Epub 2007/08/19. 17700640.

76. Asea A, Jean-Pierre C, Kaur P, Rao P, Linhares IM, Skupski D, et al. Heat shock protein-containing exosomes in mid-trimester amniotic fluids. J Reprod Immunol. 2008;79(1):12–7. Epub 2008/08/22. doi: 10.1016/j.jri.2008.06.001 18715652.

77. Xiao GY, Cheng CC, Chiang YS, Cheng WT, Liu IH, Wu SC. Exosomal miR-10a derived from amniotic fluid stem cells preserves ovarian follicles after chemotherapy. Sci Rep. 2016;6:23120. Epub 2016/03/17. doi: 10.1038/srep23120 26979400.

78. Sedrakyan S, Villani V, Da Sacco S, Tripuraneni N, Porta S, Achena A, et al. Amniotic fluid stem cell-derived vesicles protect from VEGF-induced endothelial damage. Sci Rep. 2017;7(1):16875. Epub 2017/12/06. doi: 10.1038/s41598-017-17061-2 29203902.

79. Mellows B, Mitchell R, Antonioli M, Kretz O, Chambers D, Zeuner MT, et al. Protein and Molecular Characterization of a Clinically Compliant Amniotic Fluid Stem Cell-Derived Extracellular Vesicle Fraction Capable of Accelerating Muscle Regeneration Through Enhancement of Angiogenesis. Stem Cells Dev. 2017;26(18):1316–33. Epub 2017/07/07. doi: 10.1089/scd.2017.0089 28679310.

80. Hell L, Wisgrill L, Ay C, Spittler A, Schwameis M, Jilma B, et al. Procoagulant extracellular vesicles in amniotic fluid. Transl Res. 2017;184:12–20 e1. Epub 2017/02/27. doi: 10.1016/j.trsl.2017.01.003 28236427.

81. Balbi C, Piccoli M, Barile L, Papait A, Armirotti A, Principi E, et al. First Characterization of Human Amniotic Fluid Stem Cell Extracellular Vesicles as a Powerful Paracrine Tool Endowed with Regenerative Potential. Stem Cells Transl Med. 2017;6(5):1340–55. Epub 2017/03/09. doi: 10.1002/sctm.16-0297 28271621.

82. Radeghieri A, Savio G, Zendrini A, Di Noto G, Salvi A, Bergese P, et al. Cultured human amniocytes express hTERT, which is distributed between nucleus and cytoplasm and is secreted in extracellular vesicles. Biochem Biophys Res Commun. 2017;483(1):706–11. Epub 2016/12/19. doi: 10.1016/j.bbrc.2016.12.077 27988335.

83. Zhao B, Zhang Y, Han S, Zhang W, Zhou Q, Guan H, et al. Exosomes derived from human amniotic epithelial cells accelerate wound healing and inhibit scar formation. J Mol Histol. 2017;48(2):121–32. Epub 2017/02/24. doi: 10.1007/s10735-017-9711-x 28229263.

84. Sheller-Miller S, Urrabaz-Garza R, Saade G, Menon R. Damage-Associated molecular pattern markers HMGB1 and cell-Free fetal telomere fragments in oxidative-Stressed amnion epithelial cell-Derived exosomes. J Reprod Immunol. 2017;123:3–11. Epub 2017/09/01. doi: 10.1016/j.jri.2017.08.003 28858636.

85. Song JE, Park SJ, Lee KY, Lee WJ. Amniotic fluid HIF1alpha and exosomal HIF1alpha in cervical insufficiency patients with physical examination-indicated cerclage. J Matern Fetal Neonatal Med. 2018:1–8. Epub 2018/01/24. doi: 10.1080/14767058.2018.1432037 29357727.

86. Dixon CL, Sheller-Miller S, Saade GR, Fortunato SJ, Lai A, Palma C, et al. Amniotic Fluid Exosome Proteomic Profile Exhibits Unique Pathways of Term and Preterm Labor. Endocrinology. 2018;159(5):2229–40. Epub 2018/04/11. doi: 10.1210/en.2018-00073 29635386.

87. Beretti F, Zavatti M, Casciaro F, Comitini G, Franchi F, Barbieri V, et al. Amniotic fluid stem cell exosomes: Therapeutic perspective. Biofactors. 2018;44(2):158–67. Epub 2018/01/18. doi: 10.1002/biof.1407 29341292.

88. Farhadihosseinabadi B, Farahani M, Tayebi T, Jafari A, Biniazan F, Modaresifar K, et al. Amniotic membrane and its epithelial and mesenchymal stem cells as an appropriate source for skin tissue engineering and regenerative medicine. Artif Cells Nanomed Biotechnol. 2018:1–10. Epub 2018/04/25. doi: 10.1080/21691401.2018.1458730 29687742.

89. Tan JL, Lau SN, Leaw B, Nguyen HPT, Salamonsen LA, Saad MI, et al. Amnion Epithelial Cell-Derived Exosomes Restrict Lung Injury and Enhance Endogenous Lung Repair. Stem Cells Transl Med. 2018;7(2):180–96. Epub 2018/01/04. doi: 10.1002/sctm.17-0185 29297621.

90. Sheller S, Papaconstantinou J, Urrabaz-Garza R, Richardson L, Saade G, Salomon C, et al. Amnion-Epithelial-Cell-Derived Exosomes Demonstrate Physiologic State of Cell under Oxidative Stress. PLoS One. 2016;11(6):e0157614. Epub 2016/06/23. doi: 10.1371/journal.pone.0157614 27333275.

91. American College of O, Gynecology Committee on Practice B-O. ACOG Practice Bulletin Number 49, December 2003: Dystocia and augmentation of labor. Obstet Gynecol. 2003;102(6):1445–54. Epub 2003/12/10. doi: 10.1016/j.obstetgynecol.2003.10.011 14662243.

92. Yoon BH, Romero R, Moon JB, Shim SS, Kim M, Kim G, et al. Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Obstet Gynecol. 2001;185(5):1130–6. Epub 2001/11/22. doi: 10.1067/mob.2001.117680 11717646.

93. Romero R, Chaemsaithong P, Chaiyasit N, Docheva N, Dong Z, Kim CJ, et al. CXCL10 and IL-6: Markers of two different forms of intra-amniotic inflammation in preterm labor. Am J Reprod Immunol. 2017;78(1). Epub 2017/05/26. doi: 10.1111/aji.12685 28544362.

94. Romero R, Ghidini A, Mazor M, Behnke E. Microbial invasion of the amniotic cavity in premature rupture of membranes. Clin Obstet Gynecol. 1991;34(4):769–78. Epub 1991/12/01. doi: 10.1097/00003081-199112000-00013 1778019.

95. Romero R, Nores J, Mazor M, Sepulveda W, Oyarzun E, Parra M, et al. Microbial invasion of the amniotic cavity during term labor. Prevalence and clinical significance. J Reprod Med. 1993;38(7):543–8. Epub 1993/07/01. 8410850.

96. Romero R, Miranda J, Chaiworapongsa T, Korzeniewski SJ, Chaemsaithong P, Gotsch F, et al. Prevalence and clinical significance of sterile intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Reprod Immunol. 2014;72(5):458–74. Epub 2014/08/01. doi: 10.1111/aji.12296 25078709.

97. Romero R, Miranda J, Chaemsaithong P, Chaiworapongsa T, Kusanovic JP, Dong Z, et al. Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2015;28(12):1394–409. Epub 2014/09/06. doi: 10.3109/14767058.2014.958463 25190175.

98. Romero R, Miranda J, Chaiworapongsa T, Chaemsaithong P, Gotsch F, Dong Z, et al. Sterile intra-amniotic inflammation in asymptomatic patients with a sonographic short cervix: prevalence and clinical significance. J Matern Fetal Neonatal Med. 2015;28(11):1343–59. Epub 2014/09/06. doi: 10.3109/14767058.2014.954243 25123515.

99. Gomez-Lopez N, Romero R, Panaitescu B, Leng Y, Xu Y, Tarca AL, et al. Inflammasome activation during spontaneous preterm labor with intra-amniotic infection or sterile intra-amniotic inflammation. Am J Reprod Immunol. 2018;80(5):e13049. Epub 2018/11/10. doi: 10.1111/aji.13049 30225853.

100. Gomez-Lopez N, Romero R, Tarca AL, Miller D, Panaitescu B, Schwenkel G, et al. Gasdermin D: Evidence of Pyroptosis in Spontaneous Preterm Labor with Sterile Intra-amniotic Inflammation or Intra-amniotic Infection. Am J Reprod Immunol. 2019. Epub 2019/08/29. doi: 10.1111/aji.13184 31461796.

101. Gomez-Lopez N, Romero R, Maymon E, Kusanovic JP, Panaitescu B, Miller D, et al. Clinical chorioamnionitis at term IX: in vivo evidence of intra-amniotic inflammasome activation. J Perinat Med. 2019;47(3):276–87. Epub 2018/11/10. doi: 10.1515/jpm-2018-0271 30412466.

102. Romero R, Quintero R, Nores J, Avila C, Mazor M, Hanaoka S, et al. Amniotic fluid white blood cell count: a rapid and simple test to diagnose microbial invasion of the amniotic cavity and predict preterm delivery. Am J Obstet Gynecol. 1991;165(4 Pt 1):821–30. Epub 1991/10/01. doi: 10.1016/0002-9378(91)90423-o 1951538.

103. Martinez-Varea A, Romero R, Xu Y, Miller D, Ahmed AI, Chaemsaithong P, et al. Clinical chorioamnionitis at term VII: the amniotic fluid cellular immune response. J Perinat Med. 2017;45(5):523–38. Epub 2016/10/21. doi: 10.1515/jpm-2016-0225 27763883.

104. Romero R, Jimenez C, Lohda AK, Nores J, Hanaoka S, Avila C, et al. Amniotic fluid glucose concentration: a rapid and simple method for the detection of intraamniotic infection in preterm labor. Am J Obstet Gynecol. 1990;163(3):968–74. Epub 1990/09/01. doi: 10.1016/0002-9378(90)91106-m 1698338.

105. Romero R, Emamian M, Quintero R, Wan M, Hobbins JC, Mazor M, et al. The value and limitations of the Gram stain examination in the diagnosis of intraamniotic infection. Am J Obstet Gynecol. 1988;159(1):114–9. Epub 1988/07/01. doi: 10.1016/0002-9378(88)90503-0 2456013.

106. Welch BL. On the Comparison of Several Mean Values: An Alternative Approach. Biometrika. 1951;38(3/4):330–6. doi: 10.2307/2332579

107. Bartlett MS. The Use of Transformations. Biometrics. 1947;3(1):39–52. doi: 10.2307/3001536 20240416

108. Koenker R. Quantile regression for longitudinal data. Journal of Multivariate Analysis. 2004;91(1):74–89. https://doi.org/10.1016/j.jmva.2004.05.006

109. Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society Series B (Methodological). 1995;57(1):289–300.

110. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2019.

111. Chen C, Liaw A, Breiman L. Using random forest to learn imbalanced data. Technical report. Berkeley: University of California, 2004.

112. Martin JA, Hamilton BE, Osterman MJK, Driscoll AK, Drake P. Births: Final Data for 2017. National Vital Statistics Reports. 2018;67(8). 30707672

113. Romero R, Espinoza J, Kusanovic JP, Gotsch F, Hassan S, Erez O, et al. The preterm parturition syndrome. BJOG. 2006;113 Suppl 3:17–42. Epub 2007/01/09. doi: 10.1111/j.1471-0528.2006.01120.x 17206962.

114. Romero R. Prenatal medicine: the child is the father of the man. 1996. J Matern Fetal Neonatal Med. 2009;22(8):636–9. Epub 2009/09/09. doi: 10.1080/14767050902784171 19736614.

115. Di Renzo GC. The great obstetrical syndromes. J Matern Fetal Neonatal Med. 2009;22(8):633–5. Epub 2009/09/09. doi: 10.1080/14767050902866804 19736613.

116. Gravett MG, Novy MJ, Rosenfeld RG, Reddy AP, Jacob T, Turner M, et al. Diagnosis of intra-amniotic infection by proteomic profiling and identification of novel biomarkers. Jama. 2004;292(4):462–9. Epub 2004/07/29. doi: 10.1001/jama.292.4.462 15280344.

117. Romero R, Kusanovic JP, Gotsch F, Erez O, Vaisbuch E, Mazaki-Tovi S, et al. Isobaric labeling and tandem mass spectrometry: a novel approach for profiling and quantifying proteins differentially expressed in amniotic fluid in preterm labor with and without intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med. 2010;23(4):261–80. Epub 2009/08/12. doi: 10.3109/14767050903067386 19670042.

118. Romero R, Chaiworapongsa T, Savasan ZA, Hussein Y, Dong Z, Kusanovic JP, et al. Clinical chorioamnionitis is characterized by changes in the expression of the alarmin HMGB1 and one of its receptors, sRAGE. J Matern Fetal Neonatal Med. 2012;25(6):558–67. Epub 2012/05/15. doi: 10.3109/14767058.2011.599083 22578261.

119. Romero R, Chaemsaithong P, Korzeniewski SJ, Tarca AL, Bhatti G, Xu Z, et al. Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response. J Perinat Med. 2016;44(1):5–22. Epub 2015/05/06. doi: 10.1515/jpm-2015-0045 25938217.

120. Maddipati KR, Romero R, Chaiworapongsa T, Chaemsaithong P, Zhou SL, Xu Z, et al. Clinical chorioamnionitis at term: the amniotic fluid fatty acyl lipidome. Journal of lipid research. 2016;57(10):1906–16. Epub 2016/08/20. doi: 10.1194/jlr.P069096 27538821.

121. Maddipati KR, Romero R, Chaiworapongsa T, Chaemsaithong P, Zhou SL, Xu Z, et al. Lipidomic analysis of patients with microbial invasion of the amniotic cavity reveals up-regulation of leukotriene B4. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2016;30(10):3296–307. Epub 2016/06/18. doi: 10.1096/fj.201600583R 27312808.

122. Romero R, Chaemsaithong P, Docheva N, Korzeniewski SJ, Kusanovic JP, Yoon BH, et al. Clinical chorioamnionitis at term VI: acute chorioamnionitis and funisitis according to the presence or absence of microorganisms and inflammation in the amniotic cavity. J Perinat Med. 2016;44(1):33–51. Epub 2015/09/10. doi: 10.1515/jpm-2015-0119 26352071.

123. Romero R, Chaemsaithong P, Docheva N, Korzeniewski SJ, Tarca AL, Bhatti G, et al. Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response. J Perinat Med. 2016;44(1):53–76. Epub 2015/09/12. doi: 10.1515/jpm-2015-0121 26360486.

124. Gomez-Lopez N, Romero R, Xu Y, Plazyo O, Unkel R, Leng Y, et al. A Role for the Inflammasome in Spontaneous Preterm Labor With Acute Histologic Chorioamnionitis. Reprod Sci. 2017;24(10):1382–401. Epub 2017/01/27. doi: 10.1177/1933719116687656 28122480.

125. Chaiyasit N, Romero R, Chaemsaithong P, Docheva N, Bhatti G, Kusanovic JP, et al. Clinical chorioamnionitis at term VIII: a rapid MMP-8 test for the identification of intra-amniotic inflammation. J Perinat Med. 2017;45(5):539–50. Epub 2017/07/05. doi: 10.1515/jpm-2016-0344 28672752.

126. Gomez-Lopez N, Romero R, Xu Y, Miller D, Unkel R, Shaman M, et al. Neutrophil Extracellular Traps in the Amniotic Cavity of Women with Intra-Amniotic Infection: A New Mechanism of Host Defense. Reprod Sci. 2017;24(8):1139–53. Epub 2017/07/05. doi: 10.1177/1933719116678690 27884950.

127. Gomez-Lopez N, Romero R, Leng Y, Xu Y, Slutsky R, Levenson D, et al. The origin of amniotic fluid monocytes/macrophages in women with intra-amniotic inflammation or infection. J Perinat Med. 2019. Epub 2019/09/09. doi: 10.1515/jpm-2019-0262 31494640.

128. Para R, Romero R, Miller D, Panaitescu B, Varrey A, Chaiworapongsa T, et al. Human beta-defensin-3 participates in intra-amniotic host defense in women with labor at term, spontaneous preterm labor and intact membranes, and preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2019:1–16. Epub 2019/04/20. doi: 10.1080/14767058.2019.1597047 30999788.

129. Pitt JM, Kroemer G, Zitvogel L. Extracellular vesicles: masters of intercellular communication and potential clinical interventions. J Clin Invest. 2016;126(4):1139–43. doi: 10.1172/JCI87316 27035805.

130. Meldolesi J. Exosomes and Ectosomes in Intercellular Communication. Curr Biol. 2018;28(8):R435–R44. Epub 2018/04/25. doi: 10.1016/j.cub.2018.01.059 29689228.

131. Soler N, Marguet E, Verbavatz JM, Forterre P. Virus-like vesicles and extracellular DNA produced by hyperthermophilic archaea of the order Thermococcales. Res Microbiol. 2008;159(5):390–9. Epub 2008/07/16. doi: 10.1016/j.resmic.2008.04.015 18625304.

132. Schorey JS, Cheng Y, Singh PP, Smith VL. Exosomes and other extracellular vesicles in host-pathogen interactions. EMBO Rep. 2015;16(1):24–43. Epub 2014/12/10. doi: 10.15252/embr.201439363 25488940.

133. Halperin W, Jensen WA. Ultrastructural changes during growth and embryogenesis in carrot cell cultures. J Ultrastruct Res. 1967;18(3):428–43. Epub 1967/05/01. doi: 10.1016/s0022-5320(67)80128-x 6025110.

134. Meyer D, Pajonk S, Micali C, O'Connell R, Schulze-Lefert P. Extracellular transport and integration of plant secretory proteins into pathogen-induced cell wall compartments. Plant J. 2009;57(6):986–99. Epub 2008/11/13. doi: 10.1111/j.1365-313X.2008.03743.x 19000165.

135. Regente M, Corti-Monzon G, Maldonado AM, Pinedo M, Jorrin J, de la Canal L. Vesicular fractions of sunflower apoplastic fluids are associated with potential exosome marker proteins. FEBS Lett. 2009;583(20):3363–6. Epub 2009/10/03. doi: 10.1016/j.febslet.2009.09.041 19796642.

136. Rutter BD, Innes RW. Extracellular Vesicles Isolated from the Leaf Apoplast Carry Stress-Response Proteins. Plant Physiol. 2017;173(1):728–41. Epub 2016/11/12. doi: 10.1104/pp.16.01253 27837092.

137. Regente M, Pinedo M, San Clemente H, Balliau T, Jamet E, de la Canal L. Plant extracellular vesicles are incorporated by a fungal pathogen and inhibit its growth. J Exp Bot. 2017;68(20):5485–95. Epub 2017/11/18. doi: 10.1093/jxb/erx355 29145622.

138. Cocucci E, Meldolesi J. Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. 2015;25(6):364–72. Epub 2015/02/17. doi: 10.1016/j.tcb.2015.01.004 25683921.

139. Margolis L, Sadovsky Y. The biology of extracellular vesicles: The known unknowns. PLoS Biol. 2019;17(7):e3000363–e. doi: 10.1371/journal.pbio.3000363 31318874.

140. Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10(12):1470–6. Epub 11/16. doi: 10.1038/ncb1800 19011622.

141. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9. Epub 2007/05/09. doi: 10.1038/ncb1596 17486113.

142. Thakur BK, Zhang H, Becker A, Matei I, Huang Y, Costa-Silva B, et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 2014;24(6):766–9. Epub 04/08. doi: 10.1038/cr.2014.44 24710597.

143. Eken C, Gasser O, Zenhaeusern G, Oehri I, Hess C, Schifferli JA. Polymorphonuclear neutrophil-derived ectosomes interfere with the maturation of monocyte-derived dendritic cells. J Immunol. 2008;180(2):817–24. Epub 2008/01/08. doi: 10.4049/jimmunol.180.2.817 18178820.

144. Sadallah S, Eken C, Schifferli JA. Erythrocyte-derived ectosomes have immunosuppressive properties. J Leukoc Biol. 2008;84(5):1316–25. Epub 2008/08/08. doi: 10.1189/jlb.0108013 18685086.

145. Eken C, Martin PJ, Sadallah S, Treves S, Schaller M, Schifferli JA. Ectosomes released by polymorphonuclear neutrophils induce a MerTK-dependent anti-inflammatory pathway in macrophages. J Biol Chem. 2010;285(51):39914–21. Epub 2010/10/21. doi: 10.1074/jbc.M110.126748 20959443.

146. Sadallah S, Eken C, Martin PJ, Schifferli JA. Microparticles (ectosomes) shed by stored human platelets downregulate macrophages and modify the development of dendritic cells. J Immunol. 2011;186(11):6543–52. Epub 2011/04/29. doi: 10.4049/jimmunol.1002788 21525379.

147. Sadallah S, Eken C, Schifferli JA. Ectosomes as immunomodulators. Semin Immunopathol. 2011;33(5):487–95. Epub 2010/12/08. doi: 10.1007/s00281-010-0232-x 21136061.

148. Eken C, Sadallah S, Martin PJ, Treves S, Schifferli JA. Ectosomes of polymorphonuclear neutrophils activate multiple signaling pathways in macrophages. Immunobiology. 2013;218(3):382–92. Epub 2012/07/04. doi: 10.1016/j.imbio.2012.05.021 22749214.

149. Dujardin S, Begard S, Caillierez R, Lachaud C, Delattre L, Carrier S, et al. Ectosomes: a new mechanism for non-exosomal secretion of tau protein. PLoS One. 2014;9(6):e100760. Epub 2014/06/28. doi: 10.1371/journal.pone.0100760 24971751.

150. Ti D, Hao H, Tong C, Liu J, Dong L, Zheng J, et al. LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J Transl Med. 2015;13:308. Epub 2015/09/21. doi: 10.1186/s12967-015-0642-6 26386558.

151. Essandoh K, Yang L, Wang X, Huang W, Qin D, Hao J, et al. Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction. Biochim Biophys Acta. 2015;1852(11):2362–71. Epub 2015/08/25. doi: 10.1016/j.bbadis.2015.08.010 26300484.

152. Li X, Liu L, Yang J, Yu Y, Chai J, Wang L, et al. Exosome Derived From Human Umbilical Cord Mesenchymal Stem Cell Mediates MiR-181c Attenuating Burn-induced Excessive Inflammation. EBioMedicine. 2016;8:72–82. Epub 2016/07/20. doi: 10.1016/j.ebiom.2016.04.030 27428420.

153. Sadallah S, Schmied L, Eken C, Charoudeh HN, Amicarella F, Schifferli JA. Platelet-Derived Ectosomes Reduce NK Cell Function. J Immunol. 2016;197(5):1663–71. Epub 2016/07/28. doi: 10.4049/jimmunol.1502658 27448586.

154. Alexander M, Ramstead AG, Bauer KM, Lee SH, Runtsch MC, Wallace J, et al. Rab27-Dependent Exosome Production Inhibits Chronic Inflammation and Enables Acute Responses to Inflammatory Stimuli. J Immunol. 2017;199(10):3559–70. Epub 2017/10/06. doi: 10.4049/jimmunol.1700904 28978688.

155. Tan DBA, Armitage J, Teo TH, Ong NE, Shin H, Moodley YP. Elevated levels of circulating exosome in COPD patients are associated with systemic inflammation. Respir Med. 2017;132:261–4. Epub 2017/05/10. doi: 10.1016/j.rmed.2017.04.014 28476471.

156. Olmos-Ortiz LM, Barajas-Mendiola MA, Barrios-Rodiles M, Castellano LE, Arias-Negrete S, Avila EE, et al. Trichomonas vaginalis exosome-like vesicles modify the cytokine profile and reduce inflammation in parasite-infected mice. Parasite Immunol. 2017;39(6). Epub 2017/03/28. doi: 10.1111/pim.12426 28345149.

157. Li P, Liu Z, Xie Y, Gu H, Dai Q, Yao J, et al. Serum Exosomes Attenuate H2O2-Induced Apoptosis in Rat H9C2 Cardiomyocytes via ERK1/2. J Cardiovasc Transl Res. 2018. Epub 2018/02/07. doi: 10.1007/s12265-018-9791-3 29404859.

158. Li Y, Liu Y, Xiu F, Wang J, Cong H, He S, et al. Characterization of exosomes derived from Toxoplasma gondii and their functions in modulating immune responses. Int J Nanomedicine. 2018;13:467–77. Epub 2018/02/07. doi: 10.2147/IJN.S151110 29403276.

159. Keller S, Ridinger J, Rupp AK, Janssen JW, Altevogt P. Body fluid derived exosomes as a novel template for clinical diagnostics. J Transl Med. 2011;9:86. Epub 2011/06/10. doi: 10.1186/1479-5876-9-86 21651777.

160. Bretz NP, Ridinger J, Rupp AK, Rimbach K, Keller S, Rupp C, et al. Body fluid exosomes promote secretion of inflammatory cytokines in monocytic cells via Toll-like receptor signaling. J Biol Chem. 2013;288(51):36691–702. Epub 2013/11/15. doi: 10.1074/jbc.M113.512806 24225954.

161. Sheller-Miller S, Lei J, Saade G, Salomon C, Burd I, Menon R. Feto-Maternal Trafficking of Exosomes in Murine Pregnancy Models. Front Pharmacol. 2016;7:432. Epub 2016/11/30. doi: 10.3389/fphar.2016.00432 27895585.

162. Hirsch E, Wang H. The molecular pathophysiology of bacterially induced preterm labor: insights from the murine model. J Soc Gynecol Investig. 2005;12(3):145–55. Epub 2005/03/24. doi: 10.1016/j.jsgi.2005.01.007 15784499.

163. Hargreaves DC, Medzhitov R. Innate Sensors of Microbial Infection. Journal of Clinical Immunology. 2005;25(6):503–10. doi: 10.1007/s10875-005-8065-4 16380814

164. Ilievski V, Lu SJ, Hirsch E. Activation of toll-like receptors 2 or 3 and preterm delivery in the mouse. Reprod Sci. 2007;14(4):315–20. Epub 2007/07/24. doi: 10.1177/1933719107302959 17644803.

165. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81(1):1–5. Epub 2006/10/13. doi: 10.1189/jlb.0306164 17032697.

166. Gillaux C, Mehats C, Vaiman D, Cabrol D, Breuiller-Fouche M. Functional screening of TLRs in human amniotic epithelial cells. J Immunol. 2011;187(5):2766–74. Epub 2011/07/22. doi: 10.4049/jimmunol.1100217 21775685.

167. Triantafilou M, De Glanville B, Aboklaish AF, Spiller OB, Kotecha S, Triantafilou K. Synergic activation of toll-like receptor (TLR) 2/6 and 9 in response to Ureaplasma parvum & urealyticum in human amniotic epithelial cells. PLoS One. 2013;8(4):e61199. doi: 10.1371/journal.pone.0061199 23593431.

168. Lotze MT, Zeh HJ, Rubartelli A, Sparvero LJ, Amoscato AA, Washburn NR, et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol Rev. 2007;220:60–81. Epub 2007/11/06. doi: 10.1111/j.1600-065X.2007.00579.x 17979840.

169. Bianchi R, Adami C, Giambanco I, Donato R. S100B binding to RAGE in microglia stimulates COX-2 expression. J Leukoc Biol. 2007;81(1):108–18. Epub 2006/10/07. doi: 10.1189/jlb.0306198 17023559.

170. Romero R, Espinoza J, Hassan S, Gotsch F, Kusanovic JP, Avila C, et al. Soluble receptor for advanced glycation end products (sRAGE) and endogenous secretory RAGE (esRAGE) in amniotic fluid: modulation by infection and inflammation. J Perinat Med. 2008;36(5):388–98. doi: 10.1515/JPM.2008.076 18593373.

171. Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10(12):826–37. doi: 10.1038/nri2873 21088683.

172. Eigenbrod T, Park JH, Harder J, Iwakura Y, Nunez G. Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1 alpha released from dying cells. J Immunol. 2008;181(12):8194–8. doi: 10.4049/jimmunol.181.12.8194 19050234.

173. Foell D, Wittkowski H, Vogl T, Roth J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol. 2007;81(1):28–37. Epub 2006/09/01. doi: 10.1189/jlb.0306170 16943388.

174. Gomez-Lopez N, Romero R, Plazyo O, Panaitescu B, Furcron AE, Miller D, et al. Intra-Amniotic Administration of HMGB1 Induces Spontaneous Preterm Labor and Birth. Am J Reprod Immunol. 2016;75(1):3–7. Epub 2016/01/20. doi: 10.1111/aji.12443 26781934.

175. Gomez-Lopez N, Romero R, Garcia-Flores V, Leng Y, Miller D, Hassan SS, et al. Inhibition of the NLRP3 inflammasome can prevent sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomesdagger. Biology of reproduction. 2019;100(5):1306–18. Epub 2019/01/01. doi: 10.1093/biolre/ioy264 30596885.

176. Gotsch F, Romero R, Chaiworapongsa T, Erez O, Vaisbuch E, Espinoza J, et al. Evidence of the involvement of caspase-1 under physiologic and pathologic cellular stress during human pregnancy: a link between the inflammasome and parturition. J Matern Fetal Neonatal Med. 2008;21(9):605–16. Epub 2008/10/02. doi: 10.1080/14767050802212109 18828051.

177. Plazyo O, Romero R, Unkel R, Balancio A, Mial TN, Xu Y, et al. HMGB1 Induces an Inflammatory Response in the Chorioamniotic Membranes That Is Partially Mediated by the Inflammasome. Biology of reproduction. 2016;95(6):130. Epub 2016/11/04. doi: 10.1095/biolreprod.116.144139 27806943.

178. Gomez-Lopez N, Romero R, Tarca AL, Miller D, Panaitescu B, Schwenkel G, et al. Gasdermin D: Evidence of pyroptosis in spontaneous preterm labor with sterile intra-amniotic inflammation or intra-amniotic infection. Am J Reprod Immunol. 2019;82(6):e13184. Epub 2019/08/29. doi: 10.1111/aji.13184 31461796.

179. Gomez-Lopez N, Motomura K, Miller D, Garcia-Flores V, Galaz J, Romero R. Inflammasomes: Their Role in Normal and Complicated Pregnancies. J Immunol. 2019;203(11):2757–69. Epub 2019/11/20. doi: 10.4049/jimmunol.1900901 31740550.

180. Gervasi MT, Romero R, Bracalente G, Erez O, Dong Z, Hassan SS, et al. Midtrimester amniotic fluid concentrations of interleukin-6 and interferon-gamma-inducible protein-10: evidence for heterogeneity of intra-amniotic inflammation and associations with spontaneous early (<32 weeks) and late (>32 weeks) preterm delivery. J Perinat Med. 2012;40(4):329–43. Epub 2012/07/04. doi: 10.1515/jpm-2012-0034 22752762.

181. Son GH, You YA, Kwon EJ, Lee KY, Kim YJ. Comparative Analysis of Midtrimester Amniotic Fluid Cytokine Levels to Predict Spontaneous Very Pre-term Birth in Patients with Cervical Insufficiency. Am J Reprod Immunol. 2016;75(2):155–61. Epub 2015/11/22. doi: 10.1111/aji.12451 26589553.

182. Maritati M, Comar M, Zanotta N, Seraceni S, Trentini A, Corazza F, et al. Influence of vaginal lactoferrin administration on amniotic fluid cytokines and its role against inflammatory complications of pregnancy. J Inflamm (Lond). 2017;14:5. Epub 2017/03/16. doi: 10.1186/s12950-017-0152-9 28289333.

183. Fitzgerald W, Freeman ML, Lederman MM, Vasilieva E, Romero R, Margolis L. A System of Cytokines Encapsulated in ExtraCellular Vesicles. Sci Rep. 2018;8(1):8973. Epub 2018/06/14. doi: 10.1038/s41598-018-27190-x 29895824.


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2020 Číslo 1