**5. Conclusion**

**4.2. Proteins involved in immune response**

14 Electrophoresis - Life Sciences Practical Applications

fluid from patients with spontaneous PTL [39].

subsequently can result in spontaneous PTL.

**4.3. Proteins with fetal and placenta development**

identified from the fetal side of placenta tissues (**Figure 1C**).

tor" epitopes and plays a role in cytoskeletal reorganization [44].

Immunomodulatory proteins were also identified in placenta tissues from pregnant women with sPTL-IM. These include S100-A9, IGKC (fetal side of placenta tissues), and ANXA1 (maternal side of placenta tissues) (**Figure 1C**). Inflammation has been attributed to the occurrence of PTL in human [38]. This is possible because the presence of inflammatory cytokines cause cervical ripening and the maturation of the chorioamnion, leading to labor [38]. In addition, Pereira et al. also observed the presence of calgranulins and annexins in cervical-vaginal

S100-A9 (also known as calgranulin B) is a calcium-binding protein that regulates inflammatory and immune responses which function extracellularly as an antimicrobial agent [40, 41]. Various studies have reported significantly elevated levels of calgranulins A and B in amniotic fluid from intra-amniotic-infected women [41], as well as in vaginal fluid from 86% of patients who were presented with PTL without obvious evidence of genital tract infection or inflammation [42]. Women in labor secondary to intra-amniotic inflammation have also been found to have increased *S100-A8* and *S100-A9* in amniotic fluid and maternal blood [41, 43]. Moreover, calgranulin B can interact directly with β2 integrins in forming "activated recep-

IGKC functions as an antigen-binding, immune regulation, and disposal of immune complexes [45]. Several lines of evidence suggested that during late pregnancy, recruitment of circulating maternal innate and adaptive leukocytes into the cervix and/or myometrium, and then to the decidua inter-

ANXA1 is a calcium-dependent phospholipid-binding protein that is involved in cell proliferation, differentiation, mediating inflammation, apoptosis, and maintenance of pregnancy [42, 47, 48]. It has been reported that *ANXA1* deficiency leads to changes in the inflammatory response and the anti-inflammatory effects of glucocorticoids [48]. Moreover, anti-inflammatory effects by the potent inhibition of neutrophil trafficking were observed from mice that were administered with ANXA1 [49]. A decrease of ANXA1 expression can result in the liberation of phospholipase A2 activity, making more arachidonic acid (precursor of prostaglandins) available for prostaglandin generation [50], which is crucial in uterine contraction and cervical ripening. Therefore, it remains possible that the premature activation of this inflammatory pathway can lead to a breakdown of feto-maternal tolerance and play a role in the induction of labor, which

Identified proteins that are associated to this function were Prdx 3 and FTL where both were

Prdx 3 is a mitochondria antioxidant enzyme that was known to involve in apoptosis and response to oxidative stress [51]. Previous studies have shown that a lower expression of Prdx 3 in human placenta tissues triggered oxidative stress and caused dysfunction of mitochondria in trophoblast cells [52]. From our results, the downregulation of this protein in placentas of sPTL-IM patients suggested the stimulation of fatty acid cascade, such as arachidonic acid and cell cycle arrest by oxidative stress [53, 54]. Both processes are potentially synergistic

mechanisms that contribute to preterm contractions, cervical dilatation, and PTL.

face via chemotactic cascades induces a pro-inflammatory state which leads to labor [46].

The underlying mechanisms leading to sPTL-IM are not fully understood. This leads to limited prediction and prevention of sPTL-IM due to its complex pathophysiological process. Placenta was an excellent biological tissue that might facilitate the discovery of potential biomarkers as well as to assess dysfunction in the framework of sPTL-IM. Moreover, sPTL-IM may alter selected placenta functions that lead to PTL. For this, proteomic approaches have enabled the discovery of potential biomarkers in the placenta and unveiled the pathophysiological pathways associated to sPTL-IM. The identified proteins involved in four distinct functional classes include inflammation, oxidative stress, anticoagulation, and extracellular matrix remodeling leading to preterm parturition. These results can help in the future selection of more meaningful potential biomarkers for the early detection of sPTL-IM that might appear in easily accessible body fluid. Lastly, it is postulated that signals for the initiation of sPTL-IM are more likely to arise from the fetus and to a lesser extent from the mother due to more proteins differentially expressed in the fetal side of the placenta of sPTL-IM.

**References**

[1] Das A, Subrat P, Ahanthem SS, Sourabh GD, Bhanu Pratap SG. Preterm birth: Analysis of risk factors and neonatal outcome. Gynecology & Obstetrics Case Report. 2015;**1**:1-5

Spontaneous Unexplained Preterm Labor with Intact Membrane: Finding Protein Biomarkers…

http://dx.doi.org/10.5772/intechopen.74925

17

[2] Kugelman A, Colin AA. Late preterm infants: Near term but still in a critical develop-

[3] Ahuja R, Sood A, Pal A, Mittal R. Role of micronized progesterone in prevention of preterm labour in women with previous history of one or more preterm births: A research study at a tertiary care hospital. International Journal of Reproduction, Contraception,

[4] Georgiou HM, Di Quinzio MK, Permezel M, Brennecke SP. Predicting preterm labour:

[5] Liong S, Di Quinzio MK, Fleming G, Permezel M, Rice GE, Georgiou HM. Prediction of spontaneous preterm labour in at-risk pregnant women. Reproduction. 2013;**146**:335-345

[6] Conde-Agudelo A, Papageorghiou AT, Kennedy SH, Villar J. Novel biomarkers for the prediction of the spontaneous preterm birth phenotype: A systematic review and metaanalysis. BJOG: An International Journal of Obstetrics & Gynaecology. 2011;**118**:1042-1054

[7] Shah J, Baxi B. Identification of biomarkers for prediction of preterm delivery. Journal of

[8] Fox SI. Reproduction. In: Human Physiology. 9th ed. New York: McGraw-Hill Higher

[9] Takemura M, Kimura T, Nomura S, Makino Y, Inoue T, Kikuchi T, Kubota Y, Tokugawa Y, Nobunaga T, Kamiura S. Expression and localization of human oxytocin receptor mRNA and its protein in chorion and decidua during parturition. Journal of Clinical

[10] Mine K, Katayama A, Matsumura T, Nishino T, Kuwabara Y, Ishikawa G, Murata T, Sawa R, Otsubo Y, Shin S, Takeshita T. Proteome analysis of human placentae: Pre-

[11] Liu B, Xu Y, Voss C, Qiu FH, Zhao MZ, Liu YD, Nie J, Wang ZL. Altered protein expression in gestational diabetes mellitus placentas provides insight into insulin resistance

[12] Menon R, Taylor RN, Fortunato SJ. Chorioamnionitis—A complex pathophysiologic

[13] Tan NJ, Daim LD, Jamil AA, Mohtarrudin N, Thilakavathy K. An effective placental cotyledons proteins extraction method for 2D gel electrophoresis. Electrophoresis.

eclampsia versus normal pregnancy. Placenta. 2007;**28**:676-687

and coagulation/fibrinolysis pathways. PLoS One. 2012;**7**:e44701

Current status and future prospects. Disease Markers. 2015;**2015**:1-9

mental time period. Pediatrics. 2013;**132**:741-751

Obstetrics and Gynecology. 2017;**4**:1176-1180

Medical Society. 2016;**30**:3

Education; 2006. pp. 700-730

Investigation. 1994 Jun;**93**(6):2319

syndrome. Placenta. 2010;**31**:113-120

2017;**38**:633-644
