Öz
Aim: This study investigated IL-6 expression in placentas of patients diagnosed with preterm and term premature rupture of membranes (PROM) via immunohistochemical and in silico analysis.
Materials and Methods: Placentas of 40 healthy patients and 40 preterm and 40 term patients diagnosed with term PROM who gave birth in Gynecology and Obstetrics Clinic of XXX University were subjected to histological tissue embedding protocol. IL-6 immunostaining was performed on tissues. Bioinformatic analysis was performed to explore the potential molecular mechanisms underlying role of IL-6 role in PROM.
Results: IL-6 expression was generally negative in control group however significantly higher in both preterm PROM and term PROM groups, but no significant difference in between preterm and term PROM groups. In preterm PROM group, IL-6 was recorded as positive in areas with cytotrophoblast, syncytiotrophoblast and fibrinoid accumulation, but was negative in villus connective tissue cells and vascular endothelium. In EMR group, intense IL-6 expression was observed in trophoblastic layer, syncytial nodes and fibrinoid accumulation, but was generally negative in villous stromal and vascular endothelial cells. Enrichment analysis of IL-6-associated potential PROM targets revealed significant pathways related to microbial responses such as cellular response to lipopolysaccharide, molecule of bacterial origin and biotic stimuli, indicating that IL-6 may modulate PROM predominantly through these pathways.
Conclusion: Compared to control group, significant histopathological changes and increased IL-6 expression were observed in preterm PROM and term PROM groups, with in-silico analysis, indicating PROM increased placental inflammation and damage via IL-6.
Anahtar Kelimeler
premature rupture of membrane term preterm histopathology IL-6
Etik Beyan
This study was conducted with the approval of the Ethics Committee of Dicle University Faculty of Medicine (date 20.12.2023 and number 2023/7).
Destekleyen Kurum
Dicle University
Proje Numarası
TIP.24.006
Kaynakça
- 1. Kaplan Ö, Özdemir Başaran S, Pala A, ve diğerleri. Investigation of aquaporin molecules in the placentas of pregnant women with premature rupture of membranes. Medical Records. 2024;6(2):456-461. [Crossref]
- 2.Garg A, Jaiswal A. Evaluation and management of premature rupture of membranes: a review article. Cureus. 2023;15(3):e36615. [Crossref]
- 3.Mercer BM. Preterm premature rupture of the membranes. Obstetrics and Gynecology. 2003;101(1):178-193. [Crossref]
- 4.Zaman F, Aşır F, Ermiş IS, ve diğerleri. Immunohistochemical analysis of vimentin and zonula occludens-1 in placentas of patients with PPROM. Clinical and Experimental Obstetrics & Gynecology. 2024;51(1):18-24. [Crossref]
- 5.Medina TM, Hill DA. Preterm premature rupture of membranes: diagnosis and management. American Family Physician. 2006;73(4):659-664.
- 6.Menon R, Moore JJ. Fetal membranes, not a mere appendage of the placenta, but a critical part of the fetal-maternal interface controlling parturition. Obstetrics and Gynecology Clinics of North America. 2020;47(1):147-162. [Crossref]
- 7.Oyen ML, Calvin SE, Landers DV. Premature rupture of the fetal membranes: is the amnion the major determinant? American Journal of Obstetrics and Gynecology. 2006;195(2):510-515. [Crossref]
- 8.Wu D, Cao J, Xu M, ve diğerleri. Fetal membrane imaging: current and future perspectives-a review. Frontiers in Physiology. 2024;15:1330702. [Crossref]
- 9.Kilbride HW, Thibeault DW. Neonatal complications of preterm premature rupture of membranes: pathophysiology and management. Clinics in Perinatology. 2001;28(4):761-785. [Crossref]
- 10.Devlieger R, Millar LK, Bryant-Greenwood G, ve diğerleri. Fetal membrane healing after spontaneous and iatrogenic membrane rupture: a review of current evidence. American Journal of Obstetrics and Gynecology. 2006;195(6):1512-1520. [Crossref]
- 11.Zhang JM, An J. Cytokines, inflammation, and pain. International Anesthesiology Clinics. 2007;45(2):27-37. [Crossref]
- 12.Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Frontiers in Immunology. 2014;5:491-503. [Crossref]
- 13.Chang Y, Li W, Shen Y, ve diğerleri. Association between interleukin-6 and preterm birth: a meta-analysis. Annals of Medicine. 2023;55:2284384. [Crossref]
- 14.Gulbiniene V, Balciuniene G, Dumalakiene I, ve diğerleri. The significance of TNF-α and MMP-8 concentrations in non-invasively obtained amniotic fluid predicting fetal inflammatory response syndrome. International Journal of Gynecology & Obstetrics. 2023;160(2):476-482. [Crossref]
- 15.Romero R, Espinoza J, Gonçalves LF, ve diğerleri. The role of inflammation and infection in preterm birth. Seminars in Reproductive Medicine. 2007;25(1):21-39. [Crossref]
- 16.Herrera CL, Kadari PS, Pruszynski JE, ve diğerleri. Impact of maternal infection on outcomes in extremely preterm infants. Pediatric Research. 2024;95(2):573-578. [Crossref]
- 17.Ermiş IS, Deveci E, Aşır F. Effects of quince gel and hesperidin mixture on experimental endometriosis. Molecules. 2023;28(16):5945. [Crossref]
- 18.Keşim DA, Aşır F, Ayaz H, ve diğerleri. The effects of ellagic acid on experimental corrosive esophageal burn injury. Current Issues in Molecular Biology. 2024;46(2):1579-1592. [Crossref]
- 19.Cizkova K, Foltynkova T, Gachechiladze M, ve diğerleri. Comparative analysis of immunohistochemical staining intensity determined by light microscopy, ImageJ and QuPath in placental Hofbauer cells. Acta Histochemica et Cytochemica. 2021;54(1):21-29. [Crossref]
- 20.Ge SX, Jung D, Yao R. ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics. 2019;36(8):2628-2629. [Crossref]
- 21.Rose-John S, Winthrop K, Calabrese L. The role of IL-6 in host defence against infections: immunobiology and clinical implications. Nature Reviews Rheumatology. 2017;13(7):399-409. [Crossref]
- 22.Aşır F, Erdemci F, Çankırı Z, ve diğerleri. Zonisamide ameliorated the apoptosis and inflammation in cerebellar tissue of induced alcohol addiction animal model. Life. 2024;14(7):795. [Crossref]
- 23.Ermiş IS, Aşır F, Oğlak SC, ve diğerleri. The investigation of caspase-3 and tumor necrosis factor-alpha expression in placentas of patients with preterm premature rupture of membranes. Clinical and Experimental Obstetrics & Gynecology. 2023;50(8):173-180. [Crossref]
- 24.Mercer BM. Preterm premature rupture of the membranes: current approaches to evaluation and management. Obstetrics and Gynecology Clinics of North America. 2005;32(3):411-428. [Crossref]
- 25.Nunes V, Cross J, Speich JE, ve diğerleri. Fetal membrane imaging and the prediction of preterm birth: a systematic review, current issues, and future directions. BMC Pregnancy and Childbirth. 2016;16:387-397. [Crossref]
- 26.Menon R, Richardson LS. Preterm prelabor rupture of the membranes: a disease of the fetal membranes. Seminars in Perinatology. 2017;41(7):409-419. [Crossref]
- 27.van der Ham DP, van Melick MJGJ, Smits L, ve diğerleri. Methods for the diagnosis of rupture of the fetal membranes in equivocal cases: a systematic review. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2011;157(2):123-127. [Crossref]
- 28.Chatterjee P, Chiasson VL, Bounds KR, ve diğerleri. Regulation of the anti-inflammatory cytokines interleukin-4 and interleukin-10 during pregnancy. Frontiers in Immunology. 2014;5:253-259. [Crossref]
- 29.Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. New England Journal of Medicine. 2000;342(20):1500-1507. [Crossref]
- 30.Balciuniene G, Gulbiniene V, Dumalakiene I, ve diğerleri. Prognostic markers for chorioamnionitis: IL-6, TNF-α, and MMP-8 in vaginally obtained amniotic fluid. Journal of Clinical Medicine. 2021;10(5):1136-1146. [Crossref]
- 31.Sayed Ahmed WA, Ahmed MR, Mohamed ML, ve diğerleri. Maternal serum interleukin-6 in the management of patients with preterm premature rupture of membranes. Journal of Maternal-Fetal & Neonatal Medicine. 2016;29(19):3162-3166. [Crossref]
- 32.Osanyin GE, Adegbola O. Maternal serum interleukin 6 levels and fetomaternal outcomes in women with preterm premature rupture of membranes in Lagos, South-western Nigeria. Journal of Maternal-Fetal & Neonatal Medicine. 2016;29(21):3506-3510. [Crossref]
- 33.Romero R, Chaiworapongsa T, Espinoza J. Micronutrients and intrauterine infection, preterm birth and the fetal inflammatory response syndrome. Journal of Nutrition. 2003;133(5):1668S-1673S. [Crossref]
- 34.Hatzidaki E, Gourgiotis D, Manoura A, ve diğerleri. Interleukin-6 in preterm premature rupture of membranes as an indicator of neonatal outcome. Acta Obstetricia et Gynecologica Scandinavica. 2005;84(7):632-638. [Crossref]
- 35.Chen J-L, Liu L, Peng X-R, ve diğerleri. Role of the GalNAc-galectin pathway in the healing of premature rupture of membranes. Molecular Medicine. 2024;30:138-149. [Crossref]
- 36.Wu Y, Wang M, Zhu Y, ve diğerleri. Serum interleukin-6 in the diagnosis of bacterial infection in cirrhotic patients: a meta-analysis. Medicine (Baltimore). 2016;95(41):e5127. [Crossref]
- 37.Schmitz T, Sentilhes L, Lorthe E, ve diğerleri. Preterm premature rupture of the membranes: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF). European Journal of Obstetrics & Gynecology and Reproductive Biology. 2019;236:1-6. [Crossref]
- 38.Oh KJ, Park KH, Kim SN, ve diğerleri. Predictive value of intra-amniotic and serum markers for inflammatory lesions of preterm placenta. Placenta. 2011;32(10):732-736. [Crossref]
- 39.Zhang W, Wang L, Zhao Y, ve diğerleri. Changes in cytokine (IL-8, IL-6 and TNF-alpha) levels in the amniotic fluid and maternal serum in patients with premature rupture of the membranes. Zhonghua Yi Xue Za Zhi (Taipei). 2000;63(4):311-315.
- 40.Li W, Zhao X, Li S, ve diğerleri. Upregulation of TNF-α and IL-6 induces preterm premature rupture of membranes by activation of ADAMTS-9 in embryonic membrane cells. Life Sciences. 2020;260:118237. [Crossref]
- 41.Chaemsaithong P, Romero R, Korzeniewski SJ, ve diğerleri. A rapid interleukin-6 bedside test for the identification of intra-amniotic inflammation in preterm labor with intact membranes. Journal of Maternal-Fetal & Neonatal Medicine. 2016;29(3):349-359. [Crossref]
- 42.Martinez-Portilla RJ, Hawkins-Villarreal A, Alvarez-Ponce P, ve diğerleri. Maternal serum interleukin-6: a non-invasive predictor of histological chorioamnionitis in women with preterm-prelabor rupture of membranes. Fetal Diagnosis and Therapy. 2019;45(3):168-175. [Crossref]
Öz
Amaç: Bu çalışmada, preterm ve term prematüre membran rüptürü (EMR) tanısı almış hastaların plasentalarındaki IL-6 ekspresyonu immünohistokimyasal ve in silico analiz yoluyla araştırılmıştır.
Gereç ve Yöntemler: XXX Üniversitesi Kadın Hastalıkları ve Doğum Kliniği'nde doğum yapan 40 sağlıklı hasta ve 40 preterm ve 40 term EMR tanısı almış hastanın plasentaları histolojik doku gömme protokolüne tabi tutulmuştur. Dokularda IL-6 immün boyama yapılmıştır. IL-6'nın EMR’deki rolünün altında yatan olası moleküler mekanizmaları araştırmak için biyoinformatik analiz yapılmıştır.
Sonuç: IL-6 ekspresyonu kontrol grubunda genel olarak negatifti ancak hem preterm EMR hem de term EMR gruplarında anlamlı olarak daha yüksekti ancak preterm ve term PROM grupları arasında anlamlı bir fark yoktu. Preterm EMR grubunda, IL-6 sitotrofoblast, sinsitiyotrofoblast ve fibrinoid birikimi olan alanlarda pozitif olarak kaydedildi ancak villus bağ dokusu hücrelerinde ve vasküler endotelde negatifti. EMR grubunda, trofoblastik tabaka, sinsitiyal düğümler ve fibrinoid birikiminde yoğun IL-6 ekspresyonu gözlendi, ancak villöz stromal ve vasküler endotel hücrelerinde genellikle negatifti. IL-6 ile ilişkili potansiyel EMR hedeflerinin zenginleştirme analizi, lipopolisakkarit, bakteri kökenli molekül ve biyotik uyaranlara hücresel yanıt gibi mikrobiyal yanıtlarla ilgili önemli yollar ortaya koydu ve IL-6'nın EMR’yi baskın olarak bu yollar aracılığıyla modüle edebileceğini gösterdi.
Sonuç: Kontrol grubuyla karşılaştırıldığında, preterm PROM ve term PROM gruplarında önemli histopatolojik değişiklikler ve artmış IL-6 ekspresyonu gözlendi ve in-silico analiz, EMR’nin IL-6 yoluyla plasenta iltihabını ve hasarını artırdığını gösterdi.
Anahtar Kelimeler
Proje Numarası
TIP.24.006
Kaynakça
- 1. Kaplan Ö, Özdemir Başaran S, Pala A, ve diğerleri. Investigation of aquaporin molecules in the placentas of pregnant women with premature rupture of membranes. Medical Records. 2024;6(2):456-461. [Crossref]
- 2.Garg A, Jaiswal A. Evaluation and management of premature rupture of membranes: a review article. Cureus. 2023;15(3):e36615. [Crossref]
- 3.Mercer BM. Preterm premature rupture of the membranes. Obstetrics and Gynecology. 2003;101(1):178-193. [Crossref]
- 4.Zaman F, Aşır F, Ermiş IS, ve diğerleri. Immunohistochemical analysis of vimentin and zonula occludens-1 in placentas of patients with PPROM. Clinical and Experimental Obstetrics & Gynecology. 2024;51(1):18-24. [Crossref]
- 5.Medina TM, Hill DA. Preterm premature rupture of membranes: diagnosis and management. American Family Physician. 2006;73(4):659-664.
- 6.Menon R, Moore JJ. Fetal membranes, not a mere appendage of the placenta, but a critical part of the fetal-maternal interface controlling parturition. Obstetrics and Gynecology Clinics of North America. 2020;47(1):147-162. [Crossref]
- 7.Oyen ML, Calvin SE, Landers DV. Premature rupture of the fetal membranes: is the amnion the major determinant? American Journal of Obstetrics and Gynecology. 2006;195(2):510-515. [Crossref]
- 8.Wu D, Cao J, Xu M, ve diğerleri. Fetal membrane imaging: current and future perspectives-a review. Frontiers in Physiology. 2024;15:1330702. [Crossref]
- 9.Kilbride HW, Thibeault DW. Neonatal complications of preterm premature rupture of membranes: pathophysiology and management. Clinics in Perinatology. 2001;28(4):761-785. [Crossref]
- 10.Devlieger R, Millar LK, Bryant-Greenwood G, ve diğerleri. Fetal membrane healing after spontaneous and iatrogenic membrane rupture: a review of current evidence. American Journal of Obstetrics and Gynecology. 2006;195(6):1512-1520. [Crossref]
- 11.Zhang JM, An J. Cytokines, inflammation, and pain. International Anesthesiology Clinics. 2007;45(2):27-37. [Crossref]
- 12.Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Frontiers in Immunology. 2014;5:491-503. [Crossref]
- 13.Chang Y, Li W, Shen Y, ve diğerleri. Association between interleukin-6 and preterm birth: a meta-analysis. Annals of Medicine. 2023;55:2284384. [Crossref]
- 14.Gulbiniene V, Balciuniene G, Dumalakiene I, ve diğerleri. The significance of TNF-α and MMP-8 concentrations in non-invasively obtained amniotic fluid predicting fetal inflammatory response syndrome. International Journal of Gynecology & Obstetrics. 2023;160(2):476-482. [Crossref]
- 15.Romero R, Espinoza J, Gonçalves LF, ve diğerleri. The role of inflammation and infection in preterm birth. Seminars in Reproductive Medicine. 2007;25(1):21-39. [Crossref]
- 16.Herrera CL, Kadari PS, Pruszynski JE, ve diğerleri. Impact of maternal infection on outcomes in extremely preterm infants. Pediatric Research. 2024;95(2):573-578. [Crossref]
- 17.Ermiş IS, Deveci E, Aşır F. Effects of quince gel and hesperidin mixture on experimental endometriosis. Molecules. 2023;28(16):5945. [Crossref]
- 18.Keşim DA, Aşır F, Ayaz H, ve diğerleri. The effects of ellagic acid on experimental corrosive esophageal burn injury. Current Issues in Molecular Biology. 2024;46(2):1579-1592. [Crossref]
- 19.Cizkova K, Foltynkova T, Gachechiladze M, ve diğerleri. Comparative analysis of immunohistochemical staining intensity determined by light microscopy, ImageJ and QuPath in placental Hofbauer cells. Acta Histochemica et Cytochemica. 2021;54(1):21-29. [Crossref]
- 20.Ge SX, Jung D, Yao R. ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics. 2019;36(8):2628-2629. [Crossref]
- 21.Rose-John S, Winthrop K, Calabrese L. The role of IL-6 in host defence against infections: immunobiology and clinical implications. Nature Reviews Rheumatology. 2017;13(7):399-409. [Crossref]
- 22.Aşır F, Erdemci F, Çankırı Z, ve diğerleri. Zonisamide ameliorated the apoptosis and inflammation in cerebellar tissue of induced alcohol addiction animal model. Life. 2024;14(7):795. [Crossref]
- 23.Ermiş IS, Aşır F, Oğlak SC, ve diğerleri. The investigation of caspase-3 and tumor necrosis factor-alpha expression in placentas of patients with preterm premature rupture of membranes. Clinical and Experimental Obstetrics & Gynecology. 2023;50(8):173-180. [Crossref]
- 24.Mercer BM. Preterm premature rupture of the membranes: current approaches to evaluation and management. Obstetrics and Gynecology Clinics of North America. 2005;32(3):411-428. [Crossref]
- 25.Nunes V, Cross J, Speich JE, ve diğerleri. Fetal membrane imaging and the prediction of preterm birth: a systematic review, current issues, and future directions. BMC Pregnancy and Childbirth. 2016;16:387-397. [Crossref]
- 26.Menon R, Richardson LS. Preterm prelabor rupture of the membranes: a disease of the fetal membranes. Seminars in Perinatology. 2017;41(7):409-419. [Crossref]
- 27.van der Ham DP, van Melick MJGJ, Smits L, ve diğerleri. Methods for the diagnosis of rupture of the fetal membranes in equivocal cases: a systematic review. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2011;157(2):123-127. [Crossref]
- 28.Chatterjee P, Chiasson VL, Bounds KR, ve diğerleri. Regulation of the anti-inflammatory cytokines interleukin-4 and interleukin-10 during pregnancy. Frontiers in Immunology. 2014;5:253-259. [Crossref]
- 29.Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. New England Journal of Medicine. 2000;342(20):1500-1507. [Crossref]
- 30.Balciuniene G, Gulbiniene V, Dumalakiene I, ve diğerleri. Prognostic markers for chorioamnionitis: IL-6, TNF-α, and MMP-8 in vaginally obtained amniotic fluid. Journal of Clinical Medicine. 2021;10(5):1136-1146. [Crossref]
- 31.Sayed Ahmed WA, Ahmed MR, Mohamed ML, ve diğerleri. Maternal serum interleukin-6 in the management of patients with preterm premature rupture of membranes. Journal of Maternal-Fetal & Neonatal Medicine. 2016;29(19):3162-3166. [Crossref]
- 32.Osanyin GE, Adegbola O. Maternal serum interleukin 6 levels and fetomaternal outcomes in women with preterm premature rupture of membranes in Lagos, South-western Nigeria. Journal of Maternal-Fetal & Neonatal Medicine. 2016;29(21):3506-3510. [Crossref]
- 33.Romero R, Chaiworapongsa T, Espinoza J. Micronutrients and intrauterine infection, preterm birth and the fetal inflammatory response syndrome. Journal of Nutrition. 2003;133(5):1668S-1673S. [Crossref]
- 34.Hatzidaki E, Gourgiotis D, Manoura A, ve diğerleri. Interleukin-6 in preterm premature rupture of membranes as an indicator of neonatal outcome. Acta Obstetricia et Gynecologica Scandinavica. 2005;84(7):632-638. [Crossref]
- 35.Chen J-L, Liu L, Peng X-R, ve diğerleri. Role of the GalNAc-galectin pathway in the healing of premature rupture of membranes. Molecular Medicine. 2024;30:138-149. [Crossref]
- 36.Wu Y, Wang M, Zhu Y, ve diğerleri. Serum interleukin-6 in the diagnosis of bacterial infection in cirrhotic patients: a meta-analysis. Medicine (Baltimore). 2016;95(41):e5127. [Crossref]
- 37.Schmitz T, Sentilhes L, Lorthe E, ve diğerleri. Preterm premature rupture of the membranes: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF). European Journal of Obstetrics & Gynecology and Reproductive Biology. 2019;236:1-6. [Crossref]
- 38.Oh KJ, Park KH, Kim SN, ve diğerleri. Predictive value of intra-amniotic and serum markers for inflammatory lesions of preterm placenta. Placenta. 2011;32(10):732-736. [Crossref]
- 39.Zhang W, Wang L, Zhao Y, ve diğerleri. Changes in cytokine (IL-8, IL-6 and TNF-alpha) levels in the amniotic fluid and maternal serum in patients with premature rupture of the membranes. Zhonghua Yi Xue Za Zhi (Taipei). 2000;63(4):311-315.
- 40.Li W, Zhao X, Li S, ve diğerleri. Upregulation of TNF-α and IL-6 induces preterm premature rupture of membranes by activation of ADAMTS-9 in embryonic membrane cells. Life Sciences. 2020;260:118237. [Crossref]
- 41.Chaemsaithong P, Romero R, Korzeniewski SJ, ve diğerleri. A rapid interleukin-6 bedside test for the identification of intra-amniotic inflammation in preterm labor with intact membranes. Journal of Maternal-Fetal & Neonatal Medicine. 2016;29(3):349-359. [Crossref]
- 42.Martinez-Portilla RJ, Hawkins-Villarreal A, Alvarez-Ponce P, ve diğerleri. Maternal serum interleukin-6: a non-invasive predictor of histological chorioamnionitis in women with preterm-prelabor rupture of membranes. Fetal Diagnosis and Therapy. 2019;45(3):168-175. [Crossref]
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Klinik Tıp Bilimleri (Diğer) |
| Bölüm | Makaleler |
| Yazarlar | |
| Proje Numarası | TIP.24.006 |
| Yayımlanma Tarihi | 30 Haziran 2025 |
| Gönderilme Tarihi | 12 Ocak 2025 |
| Kabul Tarihi | 13 Mayıs 2025 |
| Yayımlandığı Sayı | Yıl 2025 Cilt: 8 Sayı: 2 |
