Review Reports - Fluticasone Propionate/Anti-IgE Combination Preserves Bone Mechanical and Mineral Integrity Better than Monotherapies or Anti-TNF-α in Mice with Ovalbumin-Induced Allergic Airway Inflammation

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Review for ijms-4314566

In this research article entitled “Superior Preservation of Bone Mechanical and Mineral Integrity by Combined Fluticasone Propionate and Anti-Immunoglobulin E over Monotherapies and Anti-Tumor Necrosis Factor-α in a Chronic Allergic Asthma Model: A Comparative Study”, the authors (Gürgül et al.) compared the beneficial effects of anti-TNF, FP, and anti-IgE monotherapies, and the FP+anti-IgE combination. The efficacy was evaluated in a mitigating Chronic allergic asthma (ChAA)-induced deteriorations in both bone mechanical and mineral integrity following treatment of BALB/c mice with ovalbumin (OVA).

Hereafter some comments to improve the current version of the manuscript.

First of all, the title is relevant but it is quiet long (30 words). It would be better to make it shorter.
The major lack of the study is mainly related to the fact that OVA-induced animal model of asthma does not mimic all phenotypes of human asthma. Hence, the findings cannot be extrapolated to the human disease, rather than to the Ig-E associated allergenic category.
The scientific approach is consistent, appropriate and technically sound.
The readers, particularly those interested in asthma and/or skeletal disorders, would like to see the effects not only on the bone mechanical properties, geometry, and mineral composition but also on the histological and specifically the histomorphometric properties of the bone.
I suggest to change “or” in line 461 by “and/or” as both inhibition of osteoblastic activity and stimulation of osteoclastic activity have been reported in previous studies.
These non-supported sentences “Asthma is a complex…pathophysiological mechanisms.”, “Historically, asthma was…systemic disorder.” and “In allergic asthma…allergen complex.” can be supported by the following recent and relevant citations; doi: 10.1007/s13205-022-03249-5.
The conclusions are consistent with the evidence and arguments that the authors presented.
English language is acceptable just a minor editing and checking is needed.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

With initial interest, I read the manuscript entitled ”Superior Preservation of Bone Mechanical and Mineral Integrity by Combined Fluticasone Propionate and Anti-Immunoglobulin E over Monotherapies and Anti-Tumor Necrosis Facor-α in a Chronic Allergic Asthma Model: A Comparative Study” (Manuscript ID: ijms-4314566).

My original enthusiasm, got substantially toned down after I read the manuscript in more detail. While I am unavble to comment much on the bones, as it is int my area of expertise, I can throughly comment on asthma or, actually, allergic airway inflammation (AAI; see further). And asthma/AAI is the huge problem of this paper.

Major comments:

”Chronic allergic asthma (ChAA)?”. Something like this does not exist. Asthma is per se chronic. By the way, acute events are called in asthma ”exacerbations”.
Besides, what the authors did, was a murine model of AAI (let us say ”chronic” AAI, if required) mimicking human asthma and so it should be presented/reported/written throughout the manuscript.
The Authors provide some reference to the model, but I would like to hear from them what type of asthma was supposed to be mimicked here, type 2, non-type 2, or mixed (PMID: 30267575)?
It is impossible to figure it out from the data, as the authors present absolutely no data from the model! One would expect BAL eosinophilia in type 2 model, neutrophilia in non-type 2 model, etc.
What is even the bigger problem resulting from lack of any data from the model is that the authors are completely unlabelled to state that the model worked … To demonstrate the the model worked, absolute BAL cell counts (at least total cells, eosinophils, neutrophil and, if possible, macrophages and lymphocytes) should be presented for all groups. Otherwise, the rest of the data makes not sense, and the authors could have tested the treatments in any mice.
Besides, the reader has a right to see how the substance worked on AAI. We’re they effective? Which were more and which less effective?
How the dosages of the therapeutic substances were decided? Preliminary experiments? Literature? How can one be sure that very low doses of one substance are not compared to very high doses of the other? Maybe it is all “comparing apples to oranges", thus fully inconclusive? Do the dosages correspond to those used in human, at lest in case of approved drugs? In continuation, how it was decided what is high and “what” is “low” omalizumab dose?

Other comments:

What were the exact names of post-hoc tests following ANOVA or Kruskal-Wallis test, apart from Tamhane's T2? Bonferroni correction is not a test itself (but a correction for MT).
Lines 458-459: “In allergic asthma, mast cells are activated through cross-linking of high-affinity IgE receptor (FcεRI) with the IgE/allergen complex.”. It is not true! MCs are activated by cross-linking of IgE-FcεRI complexes by allergen molecules (PMID: 22909159)!
All abbreviations used in figures or tables must be explained in respective legends.