Maternal Serum Gasdermin D Concentrations in Pregnancies Complicated by Isolated Intrauterine Growth Restriction

Abstract

Objective We aimed to investigate the relationship between the isolated intrauterine growth restriction (IUGR) and maternal serum gasdermin D (GSDMD) concentration.

Materials and methods This cross-sectional study was conducted with 80 pregnant women who applied to the Umraniye Training and Research Hospital Gynecology and Obstetrics Clinic between January 2022 and May 2022. The IUGR group consisted of 40 pregnant women diagnosed with IUGR in the third trimester, and the control group consisted of 40 healthy pregnant women matched with the IUGR group in terms of age and BMI. Demographic characteristics, ultrasound findings, and neonatal outcomes were noted. The two groups were compared in terms of maternal serum GSDMD concentrations.

Results Both groups were similar in terms of demographic characteristics. Fetal biometric measurements were found to be significantly lower in the IUGR group compared to the control group, and umbilical artery Doppler PI and SD were found to be higher. Gestational age, newborn birth weight, birth height, and Apgar scores were significantly lower and NICU admission rate was higher in the IUGR group. Gestational age at blood sampling for GSDMD was similar in both groups (p=0.805). While maternal serum GSDMD concentration was 11.14 ng/ml in the IUGR group, it was 6.66 ng/ml in the control group (p=0.000). ROC analysis was performed to determine the value of GSDMD concentration in terms of IUGR estimation. AUC analysis of GSDMD for IUGR estimation was 0.88 (p<.001, 95% CI=0.80–0.95). The optimal cutoff value for GSDMD concentration was determined as 8.84 ng/ml with 80% sensitivity and 75% specificity.

Conclusion Maternal serum GSDMD concentrations were found to be higher in pregnant women whose pregnancy was complicated by isolated IUGR. We think that high GSDMD concentrations may be a reflection of increased GSDMD-mediated pyroptosis in placental tissue in isolated IUGR cases.

Key words

intrauterine growth restriction - gasdermin D - placenta - pyroptosis

Publication History

Received: 05 July 2022

Accepted after revision: 13 October 2022

Article published online:
18 November 2022

• References

• 1 Lees CC, Romero R, Stampalija T. et al. The diagnosis and management of suspected fetal growth restriction: an evidence-based approach. Am J Obstet Gynecol 2022; 226: 366-378 DOI: 10.1016/j.ajog.2021.11.1357.
• 2 Nardozza LMM, Caetano ACR, Zamarian ACP. et al. Fetal growth restriction: current knowledge. Arch Gynecol Obstet 2017; 295: 1061-1077 DOI: 10.1007/s00404-017-4341-9.
• 3 Lees CC, Stampalija T, Baschat AA. et al. ISUOG Practice Guidelines: diagnosis and management of small-for-gestational-age fetus and fetal growth restriction. Ultrasound Obstet Gynecol 2020; 56: 298-312 DOI: 10.1002/uog.22134.
• 4 Figueras F, Gratacós E. Update on the diagnosis and classification of fetal growth restriction and proposal of a stage-based management protocol. Fetal Diagn Ther 2014; 36: 86-98 DOI: 10.1159/000357592.
• 5 Tamura M, Tanaka S, Fujii T. et al. Members of a novel gene family, Gsdm, are expressed exclusively in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner. Genomics 2007; 89: 618-629 DOI: 10.1016/j.ygeno.2007.01.003.
• 6 Liu X, Xia S, Zhang Z. et al. Channelling inflammation: gasdermins in physiology and disease. Nat Rev Drug Discov 2021; 20: 384-405 DOI: 10.1038/s41573-021-00154-z.
• 7 Katoh M, Katoh M. Identification and characterization of human DFNA5L, mouse Dfna5l, and rat Dfna5l genes in silico. Int J Oncol 2004; 25: 765-770
• 8 Saeki N, Usui T, Aoyagi K. et al. Distinctive expression and function of four GSDM family genes (GSDMA-D) in normal and malignant upper gastrointestinal epithelium. Genes Chromosomes Cancer 2009; 48: 261-271 DOI: 10.1002/gcc.20636.
• 9 Shi J, Gao W, Shao F. Pyroptosis: Gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci 2017; 42: 245-254 DOI: 10.1016/j.tibs.2016.10.004.
• 10 Liu X, Lieberman J. Knocking ’em dead: pore-forming proteins in ımmune defense. Annu Rev Immunol 2020; 38: 455-485 DOI: 10.1146/annurev-immunol-111319-023800.
• 11 Zanoni I, Tan Y, Di Gioia M. et al. By capturing ınflammatory lipids released from dying cells, the receptor CD14 ınduces ınflammasome-dependent phagocyte hyperactivation. Immunity 2017; 47: 697-709.e3 DOI: 10.1016/j.immuni.2017.09.010.
• 12 Zanoni I, Tan Y, Di Gioia M. et al. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science 2016; 352: 1232-1236 DOI: 10.1126/science.aaf3036.
• 13 Cheng S-B, Nakashima A, Huber WJ. et al. Pyroptosis is a critical inflammatory pathway in the placenta from early onset preeclampsia and in human trophoblasts exposed to hypoxia and endoplasmic reticulum stressors. Cell Death Dis 2019; 10: 927 DOI: 10.1038/s41419-019-2162-4.
• 14 Gomez-Lopez N, Romero R, Tarca AL. 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 DOI: 10.1111/aji.13184.
• 15 Bhide A, Acharya G, Bilardo CM. et al. ISUOG Practice Guidelines: use of Doppler ultrasonography in obstetrics. Ultrasound Obstet Gynecol 2013; 41: 233-239 DOI: 10.1002/uog.12371.
• 16 Shi J, Zhao Y, Wang K. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 2015; 526: 660-665 DOI: 10.1038/nature15514.
• 17 Chen X, He W, Hu L. et al. Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res 2016; 26: 1007-1020 DOI: 10.1038/cr.2016.100.
• 18 Dubois H, Sorgeloos F, Sarvestani ST. et al. Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection. PLoS Pathog 2019; 15: e1007709 DOI: 10.1371/journal.ppat.1007709.
• 19 Liu T, Zhou YT, Wang LQ. et al. NOD-like receptor family, pyrin domain containing 3 (NLRP3) contributes to inflammation, pyroptosis, and mucin production in human airway epithelium on rhinovirus infection. J Allergy Clin Immunol 2019; 144: 777-787.e9 DOI: 10.1016/j.jaci.2019.05.006.
• 20 Yang X, Cheng X, Tang Y. et al. Bacterial endotoxin activates the coagulation cascade through gasdermin D-dependent phosphatidylserine exposure. Immunity 2019; 51: 983-996.e6 DOI: 10.1016/j.immuni.2019.11.005.
• 21 Wu C, Lu W, Zhang Y. et al. Inflammasome activation triggers blood clotting and host death through pyroptosis. Immunity 2019; 50: 1401-1411.e4 DOI: 10.1016/j.immuni.2019.04.003.
• 22 Gao J, Qiu X, Xi G. et al. Downregulation of GSDMD attenuates tumor proliferation via the intrinsic mitochondrial apoptotic pathway and inhibition of EGFR/Akt signaling and predicts a good prognosis in non‑small cell lung cancer. Oncol Rep 2018; 40: 1971-1984 DOI: 10.3892/or.2018.6634.
• 23 Gomez-Lopez N, Romero R, Panaitescu B. et al. Gasdermin D: in vivo evidence of pyroptosis in spontaneous labor at term. J Matern Fetal Neonatal Med 2021; 34: 569-579 DOI: 10.1080/14767058.2019.1610740.
• 24 Banerjee S, Huang Z, Wang Z. et al. Etiological value of sterile ınflammation in preeclampsia: ıs ıt a non-ınfectious pregnancy complication?. Front Cell Infect Microbiol 2021; 11: 694298 DOI: 10.3389/fcimb.2021.694298.
• 25 Socha MW, Malinowski B, Puk O. et al. The NLRP3 ınflammasome role in the pathogenesis of pregnancy ınduced hypertension and preeclampsia. Cells 2020; 9: 1642 DOI: 10.3390/cells9071642.
• 26 De Miguel C, Pelegrín P, Baroja-Mazo A. et al. Emerging role of the ınflammasome and pyroptosis in hypertension. Int J Mol Sci 2021; 22: 1064 DOI: 10.3390/ijms22031064.
• 27 Abrahams VM, Tang Z, Mor G. et al. NLRP3 inflammasome function and pyroptotic cell death in human placental Hofbauer cells. J Reprod Immunol 2020; 142: 103214 DOI: 10.1016/j.jri.2020.103214.