PONE-D-24-20203weak acid and pepsin reflux  induced laryngopharyngeal mucosal barrier injury:a study  based on rabbit modelPLOS ONE

Dear Dr. Hou,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Mahmoud Kandeel

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Authors,

I have carefully reviewed your manuscript titled "Response of the Laryngopharynx to Acidic Reflux and Pepsin in Rabbit Models" and find it to be a promising and insightful study presenting novel findings on the effects of pepsin on laryngopharyngeal reflux. However, I believe the manuscript would benefit significantly from the following considerations:

1- Enhancement of English Punctuation and Style:

It would be advantageous to improve the punctuation and overall writing style to enhance readability and ensure the manuscript meets the highest standards of academic writing.

Grammar and Style:

A thorough proofreading to address minor grammatical errors and improve the overall readability of the manuscript.

2- E-Cadherin Expression:

- The expression of E-cadherin alone may not be a definitive indicator of cancer progression. Downregulation of this marker could also result from the wound healing process, considering the tissue damage duration.

The images provided for grading and scoring E-cadherin expression are of low resolution and should be improved. Furthermore, the images depicting high expression levels show a concerning degree of background staining.

- The significance of E-cadherin expression depends on both the intensity and localization of the staining within the tissue, particularly at cell-cell contacts. The image showing the lowest expression still indicates presence at cell-cell contacts, suggesting functional E-cadherin. Therefore, the assertion that this expression is downregulated and indicative of cancer progression is not entirely substantiated by the current images. I recommend including more images and additional markers to provide a clearer and more comprehensive analysis.

3- Consider evaluating additional markers related to cancer development or gene mutations, as they could provide more conclusive evidence.

4- Inflammatory Markers:

The inclusion of inflammatory markers and corresponding tissue images would serve as strong evidence of an inflammatory response. Also, addition of images of the tissue showing inflammation, tissue damage or any other findings would be beneficial.

5- Effect of Catheter and Standardization:

The potential impact of the catheter on the results should be addressed, and it is crucial to standardize the methodology to ensure that procedural variations do not influence the outcomes. Otherwise, providing explanation of the measures taken to reduce variability in results would provide more clarity.

6- Treatment Dosage:

The manuscript mentions that the tissue was sprayed with the test solution, but it lacks details regarding the exact volume used and whether the dosage was standardized across subjects. Providing this information is essential to avoid variability in treatment dosage.

7- Expand on Pepsin's Role:

Elaborate on the potential mechanisms of pepsin-induced damage in non-acidic conditions and its clinical implications.

8- Improve Figure Legends:

Ensure that all figure legends are detailed and fully explain the data presented, enhancing the reader's understanding.

While your research is promising and offers valuable insights, addressing these points will significantly enhance the manuscript's clarity, robustness, and overall impact. I encourage you to incorporate these suggestions to provide a more comprehensive and rigorous presentation of your findings.

Best regards,

Reviewer #2: I would like to thank the authors for their effort in this study. There are many serious concerns regarding this manuscript as highlighted below:

Title

I do not see what is special about this topic, “Weak acid and pepsin reflux induced laryngopharyngeal mucosal barrier injury: a study based on rabbit model Study LPRD on rabbit model.”

1. Weak acid is generally believed to be gastric acid. Why are the authors avoiding writing the proper term? They should be specific! The weak acid could be anything.

2. It is established knowledge that LPRD causes reflux. What is so special about this study? The significance of the study is not properly documented.

3. The mention of “Study LPRD on rabbit model” is unnecessary.

Abstract

The method is not detailed! Sprayed with different concentrations of acid— which acid? Hydrochloric or sulfuric?

The tissues were observed with Hematoxylin and eosin. For what? What was the observer looking for? This is not informative at all!

The conclusion part is not understood and rather confuses the readers, especially the statement “This study found that acid, weak acid, and pepsin…”

Introduction

Why is mentioning weak acid instead of gastric acid important in this context?

The two statements here, “Compared with the mucosa of the esophagus, the mucosa of the throat lacks a resistance mechanism to gastric acid and is more susceptible to reflux injury. Acid and pepsin disrupt barrier function and epithelial permeability by perturbing junctional complexes,” lack references.

The statement “Gill et al. [6] studied 18 patients diagnosed with LPRD and found that the expression of E-cadherin in the laryngeal mucosal epithelium was significantly reduced, and pepsin appeared” is not understood with the ending words “pepsin appeared.”

The following sentence should have been broken into two for clarity.

The statement “Notably, as a result of genetic diversity, individual expression of calcium mucin protection mechanisms must be differences” is poorly written and not scientifically constructed.

The sentence “Therefore, the existence of throat mucosa damage is defined, and the diagnosis of LPRD is unreliable” is not clear. Who defined it, or what does the author mean here?

The next statement, “Therefore, we may need to look for objective diagnostic indicators that can reflect mucosal injury,” is poorly written. Also, the knowledge gap here is different from what was stated in the abstract: “In this study, rabbit models were used to simulate the response of the laryngopharynx under the synergistic effects of various acidic reflux environments and pepsin to reveal the response mechanism of weak acid reflux…”

Therefore, the authors sound inconsistent with their objectives!

Methodology

The methodology was poorly described. For instance, the statement “The animals were randomly assigned into six groups (five animals per group). During the 8-week study, the rabbits in each group were treated with pH 3, 5, 7, and normal saline solution as the matrix, adding or not adding pepsin at 1 mL/kg for 3 min of slow spraying, twice per day, through the special catheter” is unclear.

Which group received what? This was poorly described. No one understands what was done to the animals and how each group was treated.

Also, the phrase in this statement “each group were treated with pH 3, 5, 7” is ambiguous and confusing.

In the statement “After intramuscular anesthesia, the animals received laryngoscopy. Because there was no previous assessment of normal values for rabbits, we referenced the method reported by Zhang et al. and Lou et al.[8,9] using a standard RFS system described by Belafsky et al.[10] to analyze images,” what does this mean? The author did not provide a detailed explanation of what those references mean. Are they not referring to rabbits? Are they pointing to abnormal values?

Also, the authors just jumped to “What is instantaneous impedance?” They failed to provide some important background information in the introductory section. They just jumped to the methodology without detailed information. Overall, the authors sound non-communicating and unscientific in their writing form.

The statement “After 8 weeks, the animals were sacrificed by air embolism…” Why air embolism? What does this suggest? There was no detailed explanation of how this impacts the results.

Also, what does lanthanum nitrate do? What is DIS? What do the immunostainers reveal, and what are those immunomarkers under the section “2.3 HISTOPATHOLOGY”? The information provided is below expectations without any details.

And so on….

Overall, the manuscript lacks clarity, proper documentation, and scientific rigor in its writing. The authors need to provide detailed explanations, proper references, and clear descriptions of their methodology and findings to make the study comprehensible and valuable.

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Arwa Flemban

Reviewer #2: Yes: Kamoru Adedokun

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Attachments

Attachment

Submitted filename: REVIEWERS RESPONSE.pdf

PONE-D-24-20203R1Weak acid and pepsin reflux induce laryngopharyngeal mucosal barrier injury: a rabbit-model-based studyPLOS ONE

Dear Dr. Chen,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Oct 25 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Miquel Vall-llosera Camps

Senior Staff Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: (No Response)

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Author,

I am writing to provide feedback on your manuscript, "[Manuscript Title]". I have carefully reviewed the original manuscript and the amendments you have provided.

I am pleased to note that many of the original comments have been addressed satisfactorily in the revised manuscript. The improvements you have made have significantly enhanced the clarity and overall quality of the work.

However, I would like to express some lingering concerns regarding the images of the E-cadherin staining. Based on my experience, E-cadherin, as an active molecule, is typically localized at the cell-cell adhesion points. While the images provided demonstrate two distinct intensity levels of the marker, neither image clearly shows staining at the cell membrane. The staining appears more like background noise.

I would recommend repeating the E-cadherin staining experiment with a different antibody or considering an alternative marker to assess EMT status or cellular epithelial integrity. Here are some suggestions for potential markers:

Occludin: A tight junction protein that is often downregulated during EMT.

ZO-1: Another tight junction protein that can be used to assess epithelial integrity.

Vimentin: An intermediate filament protein that is upregulated during EMT.

I believe that addressing these concerns will further strengthen the manuscript and provide a more compelling representation of your findings.

Thank you for your time and consideration.

Sincerely,

Reviewer #2: Thank you for explaining the concept. However, I find it concerning that your response to critiques, as well as those from other investigators I have come across in similar roles, often shows more clarity and strength than the original document. I notice that your revised explanation demonstrates greater energy and efficiency.

Could you incorporate this idea into your response to Reviewer 2, particularly regarding what your study contributes to existing knowledge on weak acids and why the treatment is important? You briefly touched on this in your response, but I believe this key information should have been highlighted in the abstract or introduction to provide a stronger foundation for the study.

It's essential for investigators to present their best insights upfront to engage and motivate readers.

Secondly, I would encourage you to pay close attention to capitalization in your title. It’s important to handle these details yourself, rather than relying on the journal office to perfect what should be done correctly from the start, especially after acceptance.

Good luck!

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Arwa Flemban

Reviewer #2: Yes: Kamoru A. Adedokun

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Weak acid and pepsin reflux induce laryngopharyngeal mucosal barrier injury: a rabbit-model-based study

PONE-D-24-20203R2

Dear Dr. Chen,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Miquel Vall-llosera Camps

Senior Staff Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: I have no other comments. I think the reviewers have satisfied with the critiques. Best of luck.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Kamoru Adedokun

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