Inflammation-Related Molecules at the Maternal–Fetal Interface during Pregnancy and in Pathologically Altered Endometrium
, Amira Podolak 3,*, Grzegorz Jakiel 1,4, Izabela Woclawek-Potocka 5, Jakub Lukaszuk 1 and Krzysztof Lukaszuk 1,3
Round 1
Reviewer 1 Report
In this review, the authors summarized the implicated inflammatory molecules and the underlying inflammatory processes during embryo implantation and pregnancy establishment, with emphasis on the roles of abnormal inflammatory responses in pregnancy disorders. Some of the comments need to be addressed.
1. The review is primary focused on the endometrial inflammatory aspects during embryo implantation and pregnancy establishment, however, the title is inconsistent with the keynote, it is better to revise the title.
2. In Introduction part, the authors introduced the three different pro- or anti-inflammatory phases during 1st, 2nd, and 3rd trimesters. However, the balance is different between the 1st and 3rd trimesters regarding to NF kappa B, the Figure 1 needs to be revised.
3. In table 1, there are many other cytokines that play important roles in embryo implantation and pregnancy establishment, eg, LIF is the key cytokine that controls the embryo implantation. In addition, the maternal immune response cells are also listed in the subtitle of table 1, however, they were ignored in this review.
4. Uterine microbiome has been extensively studies in recent years, which is closely related to endometrial inflammation, CE, embryo implantation, and infertility. The authors should discuss it in this review.
Author Response
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Reviewer 2 Report
Some suggestions are given as bellow:
1. The acute inflammatory and chronic inflammation were selected as the subtopics in the manuscript, however, the dominance of them in the normal or abnormal implantation process is not clearly introduced. The molecules involved in acute inflammatory and chronic inflammation can be overlapped as well. The structure and logic, subheadings of the manuscript are suggested to be adjusted. The Inflammatory molecules can be discussed along with normal pregnancy process and abnormal disorders.
2. Please clarify the driving force of inflammation change during pregnancy related to figure 1.
3. The immune environment is a very important topic for inflammation. The authors talked a little bit about CE. What’s it like during pregnancy and in other disorders, especially the population change of immune cell subtypes?
4. Please also discuss more about the therapeutic potential or current application status of those molecules involved in uterus disorders.
5. Row 51, missing punctuation.
6. Inconsistent spelling of NF-kB in row 130-131.
7. In figure 4, check spelling for IL-1β, BAX, use superscript for the “+” and “-” in “CD56 + CD16–”.
Author Response
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Reviewer 3 Report
The Authors detailedly describe the mechanisms (inflammatory/anti-inflammatory) leading to the blastocyst's implantation in uterus and some chronic inflammatory conditions that may prevent implantation or make it fails.
The review is quite well written, but there are some major concerns:
- page 2, line 45 "three distinct stages of the immune response (immune phases) [1], (Fig.1)"; please explain in the text, listing the phases or clearly state you are referring to the Figure. In the latter, please expand the figure legend. This passage is deeply unclear. Moreover, it is not understandable why the Authors divide the process in the three phases but will focus (or it seems to) only on the first phase (implantation and 1st trimester). The explicit target of the review at this point of the paper seems to be somehow confusing. The Authors maybe should re-think the paragraph, i.e. introducing the differences in acute inflammation in the normal process of implantation versus the acute and chronic inflammation in pathological processes (acute endometritis and chronic endometritis) according to the implantation process; introduce the argument of infertility (which is not related only to chronic inflammation, of course).
- page 6, line 211 The Authors should explain how this paragraph is related to the review title/argument. In the Abstract, the Authors state that they "would also like to present disorders involving excessive inflammatory response....". Chronic inflammation, however, is not necessarily quantitatively but it is surely qualitatively different from acute inflammation. This is probably the major flaw of the paper, because it is not clear the overall design of the review and its main focus. The Author should be more clear about it, defining what they are considering: e.g. normal implantation versus failing implantation related to acute/chronic inflammation?
- the bibliography is often outdated (and sometimes seems not to be pertinent): too many cited papers are older than 10 years.
Minor concerns
- page 2, lines 42-43: check for punctuation: "Invading trophoblast differentiates. Syncytiotrophoblast (outer layer) is in contact with the maternal blood. Cytotrophoblast...[..]" would sound better as "Invading trophoblast differentiates: syncytiotrophoblast (the outer layer) is in direct contact with the maternal blood; cytotrophoblast (the inner layer)...".
- page 2, line 44: space missing "membrane.During"
- page 2, lines 46-48 rewrite the sentence, check for english
- page 2, line 50: the comment is useless and out of target
- page 2, line 60: Maybe "Acute inflammatory phase" would sound more appropriate. Still, is not completely clear if it is referred to the "pro-inflammatory phase" of the 1st trimester (see fig. 1).
- page , line 89 IkB and LPS are never mentioned before, should be written per extenso
Author Response
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Reviewer 4 Report
The article is well written and in high importance, because infertility is increasing worldwide.
The authors should add some other facts in review, for example impact of smoking during implantation , and impact of previous use of oral contraceptives for subsequent implantation process.
Some biochemical processes involving CD14 molecules, and antiproteases system (alpha-1 antitrypsin) should be discussed in relation to impact for implantation.
Also the authors should include the articles about methylation process for pregnancy enabling (Serapinas D., Boreikaite E., Bartkeviciute A., Bandzeviciene R., Silkunas M., Bartkeviciene D. The importance of folate, vitamins B6 and B12 for the lowering of homocysteine concentrations for patients with recurrent pregnancy loss and MTHFR mutations. Reprod. Toxicol. 2017;72:159–163.)
Author Response
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Round 2
Reviewer 1 Report
All of my comments are well addressed.
Author Response
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Reviewer 3 Report
The Authors appropriately revised the manuscript, which is clearer now.
However, both the title and the paragraphs' s subdivision is still confusing and somehow misleading: is the paper about embryo implantation, infertility or inflammatory processes (both acute and chronic) occurring in the endometrium?
Please, try to homogenate the chapters' title in order to simplify and clarify the overall design of the study. In the introduction, try to provide a sort of list of the arguments object of the review.
Please check again English grammar, i.e. line 43 Fetaly derived placenta and maternally derived uterin epithelium (decidua) form the maternal-fetal interface. Correct: fetal-derived and maternal-derived uterine...
Author Response
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