Upregulation of elafin expression in the fallopian tube of ectopic tubal pregnancies compared to the normal tubes
Introduction
The female reproductive system must provide fertility, implantation, and normal pregnancy while maintaining the ability to respond to infections. Genital tract infection is associated with infertility, ectopic pregnancy, and early delivery (King et al., 2008). Ectopic pregnancy is one of the most important causes of maternal deaths and fallopian tubes are the location of 95% of ectopic pregnancies (Sotelo, 2019). Improved understanding of the innate immune mechanisms at the implantation site will affect the development of a public health strategy and reducing ectopic pregnancy (Dalgetty et al., 2008).
The innate immune response is an important part of the mucosal defense system. The mucosal immune system in the female reproductive tract has evolved to eliminate sexually transmitted diseases (STDs) and maintaining the ability of adaptation to specialized physiological situations such as menstruation, fertilization, implantation, pregnancy, and childbirth. Antimicrobial molecules are an integral part of the innate immune system, which is extensively involved in the reproductive potential of women (Williams et al., 2006; Givan et al., 1997).
Elastase-specific inhibitor, also known as elafin, is a natural antimicrobial molecule and an antileukoproteinase family member (Neto et al., 2014). It is known as a proteinase inhibitor 3 (PI3), skin-derived antileukoproteinase (SKALP) (Hiramatsu et al., 2019; Korkmaz et al., 2016) or Trappin-2 (pre‐elafin) (Neto et al., 2014). This protein is encoded in humans by the gene PI3 and is a part of the whey acidic protein (WAP) or WAP four-disulfide-core (WFDC) family (Korkmaz et al., 2016). Its expression has been reported in normal epithelial cells, including skin, lung, oral cavity and vagina epithelia (Neto et al., 2014; Moreau et al., 2008). Elafin is localized in vaginal secretions, amnion epithelium, decidua, chorion, and placental trophoblast during pregnancy and it is responsible for the regulation of proinflammatory paracrine interactions needed to maintain the pregnancy and to limit uterine infections. Other functions of elafin include the intrinsic pathways of protection in tubal mucous membranes against uterine infections and regulation of menstruation through antiproteolytic mechanisms and involving in the tissue repair (Neto et al., 2014; Horne et al., 2008).
The human endometrium is an important site for the cyclic pattern of cell destruction and regeneration during fertility-related events such as implantation and menstruation. These processes require the activity of some key molecules (eg, matrix metalloproteinase (MMPs)) in the fallopian tube. MMPs have an important role in the destruction of endometrial tissues during menstruation (King et al., 2003; Grudzinski et al., 2015).
Briefly, the activity of MMPs has been triggered by neutrophil elastase (NE) and subsequently disable natural inhibitors of MMPs in the tissue. Elafin is probably responsible to decrease effects of MMPs by inhibiting NE and proteinase 3 (P3) (Neto et al., 2011).
Therefore, elafin is involved in the controlling of tissue regeneration required for implantation and early pregnancy. Elafin is detected throughout the menstrual cycle and is mainly expressed by endometrial neutrophils. Neutrophils infiltrate into the endometrium during the menstrual cycle and are associated with tissue destruction and repair that occurs at this time (King et al., 2003; Grudzinski et al., 2015).
Therefore because of the limited number of studies on the role of elafin in ectopic pregnancy (Grudzinski et al., 2015), the present study aimed to determine the expression of elafin at both mRNA and protein levels in the mucosa of the normal fallopian tubes in comparison with the ectopic pregnancy using the immunohistochemistry (IHC) and quantitative reverse transcription PCR (qRT-PCR) methods.
Section snippets
Tissue collection
Ethical approval for this study was obtained from the ethics committee of Zahedan University of Medical Sciences (IR.ZAUMS.REC.1397.022). Written and informed consent was obtained from all individuals before sample collection. In this case-control study, uterine tube samples were obtained from patients with surgical removal of the tube in the department of obstetrics and gynecology at Ali ibn Abi Talib Hospital, Zahedan University of Medical Sciences (ZAUMS), Zahedan, Iran. All women were aged
Results
After filling out the information forms for each sample and data analysis, the average age of the subjects in the control group was 30.70 ± 3.895, with a range of 24–35 years and the median of 31 years. In the patient group, the mean age of people was 30.25 ± 3.143, with a range of 25–35 years and the median age of 30 years.
In patients, the mean of gestational age was 6.93 ± 1.293 weeks, range of 4–10 and Mean of 7 weeks. Study groups were matched for maternal age, ethnicity and gestational age.
Discussion
The present study showed that, based on immunohistochemical analysis, the expression of elafin in the fallopian tube increased significantly in the tubal pregnancy in comparison with the normal mucosa. We also observed that the mRNA level of elafin had increased in the mucous membrane of the fallopian tube in the ectopic pregnancy compared to the normal mucosa.
According to our results, the expression of elafin in the area of connective and epithelium tissue increased significantly in the
Conclusion
In conclusion, based on immunohistochemical analysis and mRNA determination, the expression of elafin in the fallopian tube increased in the ectopic tubal pregnancy in comparison with the normal mucosa. Understanding the causes of starting and treating ectopic pregnancy is necessary to develop preventive treatments. Elafin may be involved in the innate immune protection of the fallopian tube during ectopic pregnancy and may be important in pathological conditions such as infection and ectopic
Authors’ contributions
Z. Heidari and H. Mahmoudzadeh-Sagheb co-designed the study, supervised all the experiments and analyzed the results. M. Ghasemi, A. Asemi-Rad, B. Moudi, and Z. Asadikalameh participated in the study design and collecting and selection of samples. F. Zakizadeh and N. Sheibak participated in the literature review, data analysis, provided technical assistance and drafted the manuscript. All authors read, modified and approved the final version of the manuscript.
Funding/support
The present study was supported by the vice-chancellor of research and technology of Zahedan University of Medical Sciences(research project No: 8693).
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgments
The authors would like to thank all participants who willingly participated in this study. We appreciate all who helped us in this project.
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