{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T11:54:28Z","timestamp":1792065268779,"version":"4.4.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,10,13]],"date-time":"2017-10-13T00:00:00Z","timestamp":1507852800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,10,13]],"date-time":"2017-10-13T00:00:00Z","timestamp":1507852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Preterm premature rupture of membrane (pPROM) is associated with 30\u201340% of preterm births. Infection is considered a leading cause of pPROM due to increased levels of proinflammatory cytokines in amniotic fluid. Only 30%, however, are positive for microbial organisms by amniotic fluid culture. Interestingly, in some pregnancies complicated by preterm premature rupture of membranes (pPROM), membranes heal spontaneously and pregnancy continues until term. Here, we investigated mechanisms of amnion healing. Using a preclinical mouse model, we found that small ruptures of the fetal membrane closed within 72\u2009h whereas healing of large ruptures was only 40%. Small rupture induced transient upregulation of cytokines whereas large ruptures elicited sustained upregulation of proinflammatory cytokines in the fetal membranes. Fetal macrophages from amniotic fluid were recruited to the wounded amnion where macrophage adhesion molecules were highly expressed. Recruited macrophages released limited and well-localized amounts of IL-1\u03b2 and TNF which facilitated epithelial-mesenchymal transition (EMT) and epithelial cell migration. Arg1\u2009+\u2009macrophages dominated within 24\u2009h. Migration and healing of the amnion mesenchymal compartment, however, remained compromised. These findings provide novel insights regarding unique healing mechanisms of amnion.<\/jats:p>","DOI":"10.1038\/s41598-017-13296-1","type":"journal-article","created":{"date-parts":[[2017,10,9]],"date-time":"2017-10-09T10:45:54Z","timestamp":1507545954000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Healing of Preterm Ruptured Fetal Membranes"],"prefix":"10.1038","volume":"7","author":[{"given":"Haruta","family":"Mogami","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annavarapu","family":"Hari Kishore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yucel","family":"Akgul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Ann","family":"Word","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,10,13]]},"reference":[{"key":"13296_CR1","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1056\/NEJM199803053381006","volume":"338","author":"S Parry","year":"1998","unstructured":"Parry, S. & Strauss, J. F. 3rd Premature rupture of the fetal membranes. N Engl J Med \n                           338, 663\u2013670, https:\/\/doi.org\/10.1056\/NEJM199803053381006 (1998).","journal-title":"N Engl J Med"},{"key":"13296_CR2","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/S0140-6736(08)60074-4","volume":"371","author":"RL Goldenberg","year":"2008","unstructured":"Goldenberg, R. L., Culhane, J. F., Iams, J. D. & Romero, R. Epidemiology and causes of preterm birth. Lancet \n                           371, 75\u201384, https:\/\/doi.org\/10.1016\/S0140-6736(08)60074-4 (2008).","journal-title":"Lancet"},{"key":"13296_CR3","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/S0002-9378(88)80030-9","volume":"159","author":"R Romero","year":"1988","unstructured":"Romero, R. et al. Intraamniotic infection and the onset of labor in preterm premature rupture of the membranes. Am J Obstet Gynecol \n                           159, 661\u2013666 (1988).","journal-title":"Am J Obstet Gynecol"},{"key":"13296_CR4","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/S0002-9378(98)70272-8","volume":"179","author":"R Gomez","year":"1998","unstructured":"Gomez, R. et al. The fetal inflammatory response syndrome. Am J Obstet Gynecol \n                           179, 194\u2013202 (1998).","journal-title":"Am J Obstet Gynecol"},{"key":"13296_CR5","doi-asserted-by":"crossref","unstructured":"Johnson, J. W., Egerman, R. S. & Moorhead, J. Cases with ruptured membranes that \u201creseal\u201d. Am J Obstet Gynecol \n                           163, 1024\u20131030; discussion 1030\u20131022 (1990).","DOI":"10.1016\/0002-9378(90)91117-U"},{"key":"13296_CR6","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1126\/science.276.5309.75","volume":"276","author":"P Martin","year":"1997","unstructured":"Martin, P. Wound healing\u2013aiming for perfect skin regeneration. Science \n                           276, 75\u201381 (1997).","journal-title":"Science"},{"key":"13296_CR7","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1146\/annurev-cellbio-092910-154251","volume":"27","author":"KJ Sonnemann","year":"2011","unstructured":"Sonnemann, K. J. & Bement, W. M. Wound repair: toward understanding and integration of single-cell and multicellular wound responses. Annu Rev Cell Dev Biol \n                           27, 237\u2013263, https:\/\/doi.org\/10.1146\/annurev-cellbio-092910-154251 (2011).","journal-title":"Annu Rev Cell Dev Biol"},{"key":"13296_CR8","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/nri978","volume":"3","author":"S Gordon","year":"2003","unstructured":"Gordon, S. Alternative activation of macrophages. Nat Rev Immunol \n                           3, 23\u201335, https:\/\/doi.org\/10.1038\/nri978 (2003).","journal-title":"Nat Rev Immunol"},{"key":"13296_CR9","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.immuni.2010.05.007","volume":"32","author":"S Gordon","year":"2010","unstructured":"Gordon, S. & Martinez, F. O. Alternative activation of macrophages: mechanism and functions. Immunity \n                           32, 593\u2013604, https:\/\/doi.org\/10.1016\/j.immuni.2010.05.007 (2010).","journal-title":"Immunity"},{"key":"13296_CR10","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1038\/nri3073","volume":"11","author":"PJ Murray","year":"2011","unstructured":"Murray, P. J. & Wynn, T. A. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol \n                           11, 723\u2013737, https:\/\/doi.org\/10.1038\/nri3073 (2011).","journal-title":"Nat Rev Immunol"},{"key":"13296_CR11","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1038\/sj.jp.7211290","volume":"25","author":"MA Underwood","year":"2005","unstructured":"Underwood, M. A., Gilbert, W. M. & Sherman, M. P. Amniotic fluid: not just fetal urine anymore. J Perinatol \n                           25, 341\u2013348, https:\/\/doi.org\/10.1038\/sj.jp.7211290 (2005).","journal-title":"J Perinatol"},{"key":"13296_CR12","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1136\/jmg.11.2.190","volume":"11","author":"GR Sutherland","year":"1974","unstructured":"Sutherland, G. R., Bauld, R. & Bain, A. D. Observations on human amniotic fluid cell strains in serial culture. J Med Genet \n                           11, 190\u2013195 (1974).","journal-title":"J Med Genet"},{"key":"13296_CR13","first-page":"103","volume":"49","author":"L Sutton","year":"1983","unstructured":"Sutton, L., Mason, D. Y. & Redman, C. W. HLA-DR positive cells in the human placenta. Immunology \n                           49, 103\u2013112 (1983).","journal-title":"Immunology"},{"key":"13296_CR14","doi-asserted-by":"publisher","first-page":"3209","DOI":"10.1242\/jcs.031187","volume":"122","author":"TJ Shaw","year":"2009","unstructured":"Shaw, T. J. & Martin, P. Wound repair at a glance. J Cell Sci \n                           122, 3209\u20133213, https:\/\/doi.org\/10.1242\/jcs.031187 (2009).","journal-title":"J Cell Sci"},{"key":"13296_CR15","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1038\/nri1375","volume":"4","author":"BA Imhof","year":"2004","unstructured":"Imhof, B. A. & Aurrand-Lions, M. Adhesion mechanisms regulating the migration of monocytes. Nat Rev Immunol \n                           4, 432\u2013444, https:\/\/doi.org\/10.1038\/nri1375 (2004).","journal-title":"Nat Rev Immunol"},{"key":"13296_CR16","doi-asserted-by":"publisher","first-page":"2247","DOI":"10.2353\/ajpath.2010.090048","volume":"176","author":"C Yan","year":"2010","unstructured":"Yan, C. et al. Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol \n                           176, 2247\u20132258, https:\/\/doi.org\/10.2353\/ajpath.2010.090048 (2010).","journal-title":"Am J Pathol"},{"key":"13296_CR17","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1067\/mob.2000.108872","volume":"183","author":"AF Borgida","year":"2000","unstructured":"Borgida, A. F., Mills, A. A., Feldman, D. M., Rodis, J. F. & Egan, J. F. Outcome of pregnancies complicated by ruptured membranes after genetic amniocentesis. Am J Obstet Gynecol \n                           183, 937\u2013939, https:\/\/doi.org\/10.1067\/mob.2000.108872 (2000).","journal-title":"Am J Obstet Gynecol"},{"key":"13296_CR18","doi-asserted-by":"publisher","first-page":"142","DOI":"10.5966\/sctm.2011-0018","volume":"1","author":"S Maxson","year":"2012","unstructured":"Maxson, S., Lopez, E. A., Yoo, D., Danilkovitch-Miagkova, A. & Leroux, M. A. Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Transl Med \n                           1, 142\u2013149, https:\/\/doi.org\/10.5966\/sctm.2011-0018 (2012).","journal-title":"Stem Cells Transl Med"},{"key":"13296_CR19","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1098\/rstb.2004.1466","volume":"359","author":"MJ Redd","year":"2004","unstructured":"Redd, M. J., Cooper, L., Wood, W., Stramer, B. & Martin, P. Wound healing and inflammation: embryos reveal the way to perfect repair. Philos Trans R Soc Lond B Biol Sci \n                           359, 777\u2013784, https:\/\/doi.org\/10.1098\/rstb.2004.1466 (2004).","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"13296_CR20","first-page":"240","volume":"51","author":"D Sopher","year":"1972","unstructured":"Sopher, D. The response of rat fetal membranes to injury. Ann R Coll Surg Engl \n                           51, 240\u2013249 (1972).","journal-title":"Ann R Coll Surg Engl"},{"key":"13296_CR21","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1016\/j.placenta.2005.03.008","volume":"27","author":"E Gratacos","year":"2006","unstructured":"Gratacos, E. et al. A histological study of fetoscopic membrane defects to document membrane healing. Placenta \n                           27, 452\u2013456, https:\/\/doi.org\/10.1016\/j.placenta.2005.03.008 (2006).","journal-title":"Placenta"},{"key":"13296_CR22","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/j.jsgi.2005.08.008","volume":"12","author":"CY Cheung","year":"2005","unstructured":"Cheung, C. Y. & Brace, R. A. Amniotic fluid volume and composition in mouse pregnancy. 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Proc Natl Acad Sci USA \n                           101, 4978\u20134983, https:\/\/doi.org\/10.1073\/pnas.0401124101 (2004).","journal-title":"Proc Natl Acad Sci USA"},{"key":"13296_CR27","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1095\/biolreprod.110.087577","volume":"84","author":"K Kobayashi","year":"2011","unstructured":"Kobayashi, K., Umezawa, K. & Yasui, M. Apoptosis in mouse amniotic epithelium is induced by activated macrophages through the TNF receptor type 1\/TNF pathway. Biol Reprod \n                           84, 248\u2013254, https:\/\/doi.org\/10.1095\/biolreprod.110.087577 (2011).","journal-title":"Biol Reprod"},{"key":"13296_CR28","doi-asserted-by":"publisher","first-page":"L911","DOI":"10.1152\/ajplung.00025.2009","volume":"296","author":"ML North","year":"2009","unstructured":"North, M. L., Khanna, N., Marsden, P. A., Grasemann, H. & Scott, J. A. Functionally important role for arginase 1 in the airway hyperresponsiveness of asthma. Am J Physiol Lung Cell Mol Physiol \n                           296, L911\u2013920, https:\/\/doi.org\/10.1152\/ajplung.00025.2009 (2009).","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"13296_CR29","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/S0002-9440(10)63811-4","volume":"162","author":"D Bruch-Gerharz","year":"2003","unstructured":"Bruch-Gerharz, D. et al. Arginase 1 overexpression in psoriasis: limitation of inducible nitric oxide synthase activity as a molecular mechanism for keratinocyte hyperproliferation. Am J Pathol \n                           162, 203\u2013211, https:\/\/doi.org\/10.1016\/S0002-9440(10)63811-4 (2003).","journal-title":"Am J Pathol"},{"key":"13296_CR30","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.1038\/jid.2013.164","volume":"133","author":"L Campbell","year":"2013","unstructured":"Campbell, L., Saville, C. R., Murray, P. J., Cruickshank, S. M. & Hardman, M. J. Local arginase 1 activity is required for cutaneous wound healing. J Invest Dermatol \n                           133, 2461\u20132470, https:\/\/doi.org\/10.1038\/jid.2013.164 (2013).","journal-title":"J Invest Dermatol"},{"key":"13296_CR31","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1172\/JCI39104","volume":"119","author":"R Kalluri","year":"2009","unstructured":"Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J Clin Invest \n                           119, 1420\u20131428, https:\/\/doi.org\/10.1172\/JCI39104 (2009).","journal-title":"J Clin Invest"},{"key":"13296_CR32","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1242\/jcs.000455","volume":"121","author":"MJ Wheelock","year":"2008","unstructured":"Wheelock, M. J., Shintani, Y., Maeda, M., Fukumoto, Y. & Johnson, K. R. Cadherin switching. J Cell Sci \n                           121, 727\u2013735, https:\/\/doi.org\/10.1242\/jcs.000455 (2008).","journal-title":"J Cell Sci"},{"key":"13296_CR33","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3009337","volume":"6","author":"SA Eming","year":"2014","unstructured":"Eming, S. A., Martin, P. & Tomic-Canic, M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med \n                           6, 265sr266, https:\/\/doi.org\/10.1126\/scitranslmed.3009337 (2014).","journal-title":"Sci Transl Med"},{"key":"13296_CR34","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1146\/annurev.immunol.19.1.683","volume":"19","author":"KW Moore","year":"2001","unstructured":"Moore, K. W., de W Malefyt, R., Coffman, R. L. & O\u2019Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol \n                           19, 683\u2013765, https:\/\/doi.org\/10.1146\/annurev.immunol.19.1.683 (2001).","journal-title":"Annu Rev Immunol"},{"key":"13296_CR35","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1006\/bbrc.1999.1455","volume":"265","author":"Y Sato","year":"1999","unstructured":"Sato, Y., Ohshima, T. & Kondo, T. Regulatory role of endogenous interleukin-10 in cutaneous inflammatory response of murine wound healing. Biochem Biophys Res Commun \n                           265, 194\u2013199, https:\/\/doi.org\/10.1006\/bbrc.1999.1455 (1999).","journal-title":"Biochem Biophys Res Commun"},{"key":"13296_CR36","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1095\/biolreprod55.6.1253","volume":"55","author":"ML Casey","year":"1996","unstructured":"Casey, M. L. & MacDonald, P. C. Interstitial collagen synthesis and processing in human amnion: a property of the mesenchymal cells. Biol Reprod \n                           55, 1253\u20131260 (1996).","journal-title":"Biol Reprod"},{"key":"13296_CR37","doi-asserted-by":"publisher","first-page":"2427","DOI":"10.1182\/blood-2007-07-101261","volume":"111","author":"E Miyata","year":"2008","unstructured":"Miyata, E. et al. Hematopoietic origin of hepatic stellate cells in the adult liver. Blood \n                           111, 2427\u20132435, https:\/\/doi.org\/10.1182\/blood-2007-07-101261 (2008).","journal-title":"Blood"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-13296-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-13296-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-13296-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T12:01:57Z","timestamp":1671796917000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-13296-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,13]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["13296"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-13296-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,13]]},"assertion":[{"value":"13 June 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 September 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 October 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"13139"}}