Ductal Hyperkeratinization and Acinar Renewal Abnormality: New Concepts on Pathogenesis of Meibomian Gland Dysfunction

Round 1

Reviewer 1 Report

The review from Du et al. titled ‘Ductal Hyperkeratinization and Acinar Abnormal Renewal: 2 Progression of Pathogenesis in Meibomian Gland Dysfunction’. The review is comprehensive and overall, well written. Here are some of my comments.

1.       In line 58 ‘Morphologically, meibocytes undergo 4 different stages’. The authors should specify if these are stages of maturation or differentiation.

2.       Please revise this sentence in line 59 for clarity: ,Cell components and lipids are released to the ductal system after lipid synthesis, accumulation, and centripetal movement’

3.       Define Pyknosis in line 70

4.       Please revisit the sentence ‘To have a further study of MG stem 83 cells, it is important to have a better understanding of the localization of distinct ECM 84 components within the MGs. Not sure what the authors are trying to say in the sentence above.

5.       Sentence in line 89 is the same as in line 58, please revise

6.       No figure legend is provided for panel A in figure 1

7.       In line 137, the authors need to expand a write a few more sentences on high delivery and low delivery.

8.       8. Please rewrite the sentence in line 262 ‘In nowadays, more and more researchers pay their attention to protein production, deposition, and aggregation in the pathogenesis of MGD’

9.       The authors should check for grammar.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

This review paper describes the current approach to two mechanisms hypothesized to cause meibomian gland dysfunction, ductal hyperkeratinization and acinar abnormal renewal. The authors of the review have extensively studies these two mechanisms, and the review could have alternatively been named "Our studies on the pathogenesis of meibomian gland dysfunction". That said, the paper is overall well written and adequately summarizes the authors' research. 

Main comments

1 The authors present meibography photos without detailing how MGD is assessed. The paper would benefit from the addition of a paragraph describing how the function and morphology of the MGs is assessed with special focus on the validity of current methods. Some suggested studies include: 

Ngo Srinivasan Schulze (2014) Repeatability of Grading Meibomian Gland Dropout Using Two Infraref Systems 
Gulmez Gumus Unlu (2020) Reliable, noncontact tool for the evaluation of MG function
Ifrah R, Quevedo L, Gantz L. (2022) Repeatability and reproducibility of Cobra HD fundus camera meibography in young adults with and without symptoms of dry eye. 

2 Throughout the manuscript, the authors should be careful to discriminate between aqueous deficient dry eye and evaporative dry eye (MGD-DE) without simply stating DE.

3 In figure 4, the authors detail several external factors that contribute to MGD including age,sex, and hormontal disturbances . These are also referred to in figure caption. Age is discussed in several instances in the manuscript. However, the other external factors are not discussed and should be added to the manuscript.

4 No attention has been given by the authors to other factors contributing to human MGD-DE such as contact lenses, keratoconus, diabetes, and other systemic diseases. 

5 There are several repetitive sentences in the introduction and within the body

6 There are many abbreviations that are not first detailed.

7 The hedgehog pathway should be described

8 The authors describe evidence that supports the ductal-centric hypothesis, presumably because it is consistent with their findings. However, they do not detail any findings that support the conflicting meibocyte centric theory, that in one instance is not even described.

Minor Comments

Abstract

MGD is a functional and morphological disorder 

Introduction 

Line 29 meibomian glands (MGs) were

Line45- the meibocyte centric hypothesis should be detailed here as well

2 Physiology of MG- repeatative sentence mentioned previously " They are modified holocrine glands in the upper and lower eyelids which are the largest sebaceous glands in the human body. "

Line 58 spell out the number four

Line 63 The progenitor cells located

constantly produce

Line 66 what is it? transitional zones? unclear

2.1 MG Stem Cells

Line 71 cell not cells

Line 72 which relies on the MG stem cells

Line 75 are located 

Line 76: the authors previously said that there is no transition zone in humans and now statethat stem cells are located in that very transition zone. Please explain

Line 77 No initial (J) should be stated

Line 82 are located at the periphery of MG acini

Line 83 To further study MG stem cells it is important to gain better understanding of the localization of distinct ECM components within the MGs

Line 84 what is ECM?

Line 89 previously stated in lines 57-58 same exact sentence

Line 93-94 unclear. Do stem cells destroy meibocytes?

Line 105 Our group also recently reported

Line 105 marker instead of maker

Line 107 the Hedgehog pathway

Line 112 which regulates

Line 114are mediated

Line 116 Over the past few years

Line 129 HMGEC was previously detailed. What is IHMGEC?

Line 135 function and/or structure

Line 135 structure is better renamed morphology

Line 136 Leads

Line 137 is commonly

Line 138 includes

Line 139 As stated above, there are two main

Line 147 leads

Line 148 describe evidence for this theory

Line 154 results

Line 156 dry eye signs or symptoms?

Line 178 MGD-DE or any DE?

180 insufficient secretion

Line 181 rabbits, mice and humans

Line 182 Based on our earlier research,

Line 192 production of free fatty acids

Line 208 include

Line 209 result

Line 209 Based on our previous study,

Line 209 - same sentence must have appeared at least two times previously

Line 225 resulting

Line 227 of MGs? (instead of meibomian)

Line 238 the Hedgehod signaling

Line 239 When the Hedgehog

Line 244 In addition instead of Besides

Line 260- first sentence was stated previously

Line 260 previous studies instead of previous evidences

Line 262 instead of "In nowadays" "Presently, a growing number of researchers"

Line 269 require instead of need

Line 270 delete the word "us"

 

Figure 1 caption: different stages of what?

Figure 2 it is strange that meibography photographs are included without the text describing what the procedure is and how it relates to MGD

Figure 3 what type of DE? add the word "showing"

Table 1: the title on the left column says "signaling pathways" so just stating the name is sufficient, not need to write "signaling pathways" after each of the names on the left column of the table

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

The review is well-written and narrowly focused on 2 hypothesis which are in the title. 

There are a few word choice issues.

1. The title could be improved because "Progression of Pathogenesis" is more like a deterioration. They may mean new concepts in the pathogenesis of MGD. Also, acinar renewal abnormality instead of "Acinar abnormal Renewal"

2.In the abstract, alternation should be "alteration"

3. in Line 105, "marker" not maker

4. Line 108 acinar cells not cell

5. a summary table of the pathogenetic mechanisms described in the past could be an addition ( suggested but not absolutely necessary)

6. There is very little on new therapeutic alternatives. Are there new treatments in clinical trials?

7. The claim that the primary mechanism for MGD is keratinization of the MGducts and aberrant renewal of acinar cells is a broad statement. Does this include all the different types of MGDs? There are drug-induced, congenital, etc, types. 

8. Last sentence "progression of MGD"-- please clarify because again, it may connote deterioration.

Comments for author File: Comments.pdf

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Overall comments:

The authors have addressed my the majority of my concerns ad suggestions. I am curious as to why of the three studies that I recommended, only two were mentioned.

In the newly added sections, there are some grammatical errors to correct, and the authors added new abbreviations that are not defined.

Note that in different parts of the world, there are optometrists who treat MGD and this should be added in the conclusion.

Specific comments:

In section (3. Meibography and Function of MGs) I think types of meibographers commonly used for assessing MGs should be mentioned (and referenced). It is strange that only the Keratograph is mentioned, and in a figure caption. A review should state several devices otherwise it seems as if the authors are publicizing one specific company.

Page 4 Lines 160-161:With the advancement of technology, noncontact infrared photography has been used to assess MG morphology [47, 48].

Page 4 Line 168: drug use and corneal contact lens wear [55]. 
Contact lens wear is typically corneal, I think the word corneal can be deleted.

Page6 Line 228: IL-1β induced hyperkeratinization

Page 7 Line 254: SRC not defined

Page 7 Line 260: animal models

Page 7 Line 260: PM not defined

Page 7 Line 267: Bacterial lipase may modify the lipid content, by affecting the physical properties of the mucous layer and inducing MGD-DE [71].

Page 8 Line 275-276: Inhibition of the Hedgehog pathway decreased acinar cell proliferation , while increasing differentiation and lipid synthesis  [16].

Page 8 Line 280: and destructed the morphology of acinar and duct. 

Page 8 Line 282: delete the word "The" and begin the sentence with "Figure 4"

Page 8 Line 282: rephrase to "presents the pathological mechanism"

Page 8 Line 299: anti-inflammatory and antibiotic medications

Page 9 Line 308: replace "by latest evidence indicates" with "with the latest evidence indicating"

Page 9 Line 323: may enable treatment of MGD in patients with meibocyte atrophy

Page 9 Line 322-323: A better understanding on the pathological mechanisms helps ophthalmologists and optometrists in effective decision making.

 

 

Author Response

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Author Response File: Author Response.pdf