Nardhy Gomez-Lopez1,2,3, Roberto Romero1,4,5,6, Bogdan Panaitescu1,2, Derek Miller1,2, Chengrui Zou1,2, Dereje W Gudicha1,2, Adi L Tarca1,2, Robert Para1,2, Percy Pacora1,2, Sonia S Hassan1,2,7, Chaur-Dong Hsu1,2,7. 1. Department of Obstetrics and Maternal Fetal Medicine, Division of Intramural Research, Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA. 2. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA. 3. Department of Immunology, Microbiology and Biochemistry, Wayne State University School of Medicine, Detroit, MI, USA. 4. Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA. 5. Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA. 6. Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA. 7. Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA.
Abstract
Objective: Pyroptosis is an inflammatory form of programmed cell death that is mediated by the activation of the inflammasome and depends on the pore-forming function of gasdermin D. Therefore, the detection of gasdermin D represents in vivo evidence of pyroptosis. We recently showed that there is intra-amniotic inflammasome activation in spontaneous labor at term; however, evidence of pyroptosis is lacking. The objectives of this study were to investigate (1) whether gasdermin D is detectable in the amniotic fluid of women who delivered at term; (2) whether amniotic fluid gasdermin D concentrations are associated with the process of spontaneous labor at term; and (3) whether gasdermin D is expressed in the chorioamniotic membranes from these patients. Methods: This retrospective cross-sectional study included amniotic fluid samples from 41 women who underwent spontaneous labor at term (n = 17) or delivered at term without labor (n = 24). As a readout of pyroptosis, gasdermin D was determined in amniotic fluid samples using a specific and sensitive ELISA kit. The 90th percentile of amniotic fluid gasdermin D concentrations was calculated among women without spontaneous labor at term (reference group). The association between high amniotic fluid gasdermin D concentrations (≥90th percentile in the reference group) and spontaneous labor at term was tested using the Fisher's exact test. A p value <.05 was considered significant. Multiplex immunofluorescence staining and phenoptics (multispectral imaging) were performed to determine gasdermin D expression in the chorioamniotic membranes and to colocalize this protein with the inflammasome-related molecules caspase-1 and interleukin-1β. Results: (1) Gasdermin D is present in the amniotic fluid of women who delivered at term; (2) the 90th percentile of amniotic fluid gasdermin D concentrations in women who delivered at term without spontaneous labor was 3.4 ng/mL; (3) the proportion of women with amniotic fluid gasdermin D concentrations above the threshold was higher in those who underwent term labor than in those who delivered at term without labor; (4) amniotic fluid concentrations of gasdermin D > 3.4 ng/mL were significantly associated with the presence of spontaneous labor in women who delivered at term (odds ratio 6.0, p-value .048); and (5) the protein expression of gasdermin D is increased in the chorioamniotic membranes of women who underwent spontaneous labor at term and is colocalized with caspase-1 and IL-1β.Conclusions: Gasdermin D is increased in the amniotic fluid and chorioamniotic membranes of women who underwent spontaneous labor at term compared to those without labor. These data provide evidence implicating pyroptosis in the mechanisms that lead to the sterile inflammatory process of term parturition.
Objective: Pyroptosis is an inflammatory form of programmed cell death that is mediated by the activation of the inflammasome and depends on the pore-forming function of gasdermin D. Therefore, the detection of gasdermin D represents in vivo evidence of pyroptosis. We recently showed that there is intra-amniotic inflammasome activation in spontaneous labor at term; however, evidence of pyroptosis is lacking. The objectives of this study were to investigate (1) whether gasdermin D is detectable in the amniotic fluid of women who delivered at term; (2) whether amniotic fluid gasdermin D concentrations are associated with the process of spontaneous labor at term; and (3) whether gasdermin D is expressed in the chorioamniotic membranes from these patients. Methods: This retrospective cross-sectional study included amniotic fluid samples from 41 women who underwent spontaneous labor at term (n = 17) or delivered at term without labor (n = 24). As a readout of pyroptosis, gasdermin D was determined in amniotic fluid samples using a specific and sensitive ELISA kit. The 90th percentile of amniotic fluid gasdermin D concentrations was calculated among women without spontaneous labor at term (reference group). The association between high amniotic fluid gasdermin D concentrations (≥90th percentile in the reference group) and spontaneous labor at term was tested using the Fisher's exact test. A p value <.05 was considered significant. Multiplex immunofluorescence staining and phenoptics (multispectral imaging) were performed to determine gasdermin D expression in the chorioamniotic membranes and to colocalize this protein with the inflammasome-related molecules caspase-1 and interleukin-1β. Results: (1) Gasdermin D is present in the amniotic fluid of women who delivered at term; (2) the 90th percentile of amniotic fluid gasdermin D concentrations in women who delivered at term without spontaneous labor was 3.4 ng/mL; (3) the proportion of women with amniotic fluid gasdermin D concentrations above the threshold was higher in those who underwent term labor than in those who delivered at term without labor; (4) amniotic fluid concentrations of gasdermin D > 3.4 ng/mL were significantly associated with the presence of spontaneous labor in women who delivered at term (odds ratio 6.0, p-value .048); and (5) the protein expression of gasdermin D is increased in the chorioamniotic membranes of women who underwent spontaneous labor at term and is colocalized with caspase-1 and IL-1β.Conclusions: Gasdermin D is increased in the amniotic fluid and chorioamniotic membranes of women who underwent spontaneous labor at term compared to those without labor. These data provide evidence implicating pyroptosis in the mechanisms that lead to the sterile inflammatory process of term parturition.
Authors: Chia-Ling Nhan-Chang; Roberto Romero; Adi L Tarca; Pooja Mittal; Juan Pedro Kusanovic; Offer Erez; Shali Mazaki-Tovi; Tinnakorn Chaiworapongsa; John Hotra; Nandor Gabor Than; Jung-Sun Kim; Sonia S Hassan; Chong Jai Kim Journal: Am J Obstet Gynecol Date: 2010-05 Impact factor: 8.661
Authors: A J Thomson; J F Telfer; A Young; S Campbell; C J Stewart; I T Cameron; I A Greer; J E Norman Journal: Hum Reprod Date: 1999-01 Impact factor: 6.918
Authors: R Romero; S T Parvizi; E Oyarzun; M Mazor; Y K Wu; C Avila; A P Athanassiadis; M D Mitchell Journal: J Reprod Med Date: 1990-03 Impact factor: 0.142
Authors: R Romero; M Mazor; F Brandt; W Sepulveda; C Avila; D B Cotton; C A Dinarello Journal: Am J Reprod Immunol Date: 1992 Apr-May Impact factor: 3.886
Authors: Roberto Romero; Percy Pacora; Juan Pedro Kusanovic; Eunjung Jung; Bogdan Panaitescu; Eli Maymon; Offer Erez; Susan Berman; David R Bryant; Nardhy Gomez-Lopez; Kevin R Theis; Gaurav Bhatti; Chong Jai Kim; Bo Hyun Yoon; Sonia S Hassan; Chaur-Dong Hsu; Lami Yeo; Ramiro Diaz-Primera; Julio Marin-Concha; Kia Lannaman; Ali Alhousseini; Hunter Gomez-Roberts; Aneesha Varrey; Angel Garcia-Sanchez; Maria Teresa Gervasi Journal: J Perinat Med Date: 2021-01-26 Impact factor: 2.716