Characteristics of inflammatory response and repair after experimental blast lung injury in rats

Jürg Hamacher; Yalda Hadizamani; Hanno Huwer; Ueli Moehrlen; Lia Bally; Uz Stammberger; Albrecht Wendel; Rudolf Lucas

doi:10.1371/journal.pone.0281446

Peer Review History

Original SubmissionApril 4, 2022
4 Jul 2022 Decision Letter - Nicolas Tsapis, Editor PONE-D-22-09944Characteristics of inflammatory response and repair after experimental blast lung injury in ratsPLOS ONE Dear Dr. Hadizamani, 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 Aug 09 2022 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. 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Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. [Note: HTML markup is below. Please do not edit.] 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: Yes Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A Reviewer #2: No ****** 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 ****** 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 ****** 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: The article by Hamacher et al. concerns the characterization of inflammatory response an repair after experimental blast injury. They showed that following blast injury an alteration of cytokines and activity cells is observed. They showed a neutrophil infiltration into the alveolar space, signature of inflammation. The study is well conduct but I would like to mention that I am not specialized in blast injury. I have some comments. Figure 2 is is not mentioned in the text as figure 3 (results paragraph e3.2, Figure 3C is mentioned instead of figure 2). What is the number of animals per group? 1? n is the number of experiments ? one experiment is one animal /group ? Regarding the statistics, I am quite surprised because the results are expressed as an mean +/- SEM. SEM is important. It would be interesting to represent the results as a scatter plot to show the individual response of all animals. For figure 11, the points are connected, which is not acceptable because the animals are not the same for each time. This figure must be modified and represented like the others. I suggest to include the MPO result with neutrophils paragraph. For the MMP part (results) it could be shorter by extracting a part already integrated in the discussion. The discussion is rather long and not concise enough. It's confusing. Why not discuss the elements as a whole. For example, the discussion on TNF is in three paragraphs or even 4 and quite long and a bit redundant. PMN, MMP, CINC could be discussed together in sub-paragraphs. Reviewer #2: This manuscript dealing with post blast lung inflammatory response presents results of interest for the scientific community. However, numerous issues prevent this manuscript being published as is. Global remarks: 1- the manuscript has to be professionaly language edited 2- the figure's numbers are incorrect 3- citations are sometimes not cited correctly Specific remarks: 4- the statistics are using parametric tests with very small n in each groups. Non parametric tests need to be used. Also, when using small groups, data must be presented as Median [IQR] instead of mean (SEM or SD) 5- the authors does not discuss the similarities/differences with a classical blunt trauma model. An interesting question should be: How the blast related lung injuries are different from blunt chest trauma related lung injuries? 6- thus, the definition of the incoming blast overpressure wave is of importance. The OP wave provided by the shock tube is very short (0.6 ms) where standout open field OP waves are close to 2-4 ms. It is understandable that even if very short, this OP wave is responsible for lung injuries, but this singularity is not discussed in the paper. how short OP wave related lung injury is different from normal length OP wave related lung injury? 7- the wet to dry ratio study is of interest but it does not take the intra-alveolar hemorrhage into account. Also, methods don't describe if W/D ratio lungs were previously injected for BAL... The methods need to be clearer. 8- concerning the methods, why is the anesthetic strategy biphasic (firs halothan then pentothal) ? Also the pro-inflammatory effect of buprenorphine is not discussed. ****** 6. 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Revision 1
15 Sep 2022 Author Response 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: The article by Hamacher et al. concerns the characterization of inflammatory response an repair after experimental blast injury.They showed that following blast injury an alteration of cytokines and activity cells is observed. They showed a neutrophil infiltration into the alveolar space, signature of inflammation. The study is well conduct but I would like to mention that I am not specialized in blast injury. I have some comments. 1. Figure 2 is not mentioned in the text as figure 3 (results paragraph e3.2, Figure 3C is mentioned instead of figure 2). The reviewer is right, now we have corrected figures’ numbers. 2. What is the number of animals per group? 1? n is the number of experiments ? one experiment is one animal /group ? In every paragraph the numbers of animals per experiment has been indicated. 3. Regarding the statistics, I am quite surprised because the results are expressed as an mean +/- SEM. SEM is important. It would be interesting to represent the results as a scatter plot to show the individual response of all animals. Unfortunately we have not the original data any more in our hands and are therefore not able to re-plot the graphs in scatter plots. We asked the university of Konstanz to have access to the original data, but have not yet got this access as all those laboratory books including all data from assays are given in those books. Unfortunately so far we have not had this access. 4. For figure 10, the points are connected, which is not acceptable because the animals are not the same for each time. This figure must be modified and represented like the others. Reviewer is totally right. We have modified this figure. 5. I suggest to include the MPO result with neutrophils paragraph. Thank you for this comment. It has been done. For the MMP part (results) it could be shorter by extracting a part already integrated in the discussion. Thank you for this comment. Now, it has been done. 6. The discussion is rather long and not concise enough. It's confusing. Why not discuss the elements as a whole. For example, the discussion on TNF is in three paragraphs or even 4 and quite long and a bit redundant. PMN, MMP, CINC could be discussed together in sub-paragraphs. Reviewer #2: This manuscript dealing with post blast lung inflammatory response presents results of interest for the scientific community. However, numerous issues prevent this manuscript being published as is. Global remarks: 1- the manuscript has to be professionally language edited We acknowledge that Dr. Rudolf Lucas who works since > 15 y in the USA co-wrote and several times revised the text and that we therefore think that language is acceptable. 2- the figure's numbers are incorrect The reviewer is totally right. Now the figure’s numbersa have been corrected. 3- citations are sometimes not cited correctly Thank you for this comment. They have been corrected and corrected. Specific remarks: 4- the statistics are using parametric tests with very small n in each groups. Non parametric tests need to be used. Also, when using small groups, data must be presented as Median [IQR] instead of mean (SEM or SD) We always were attentive to check whether we had to do non-parametric testing. In all the dataset we are confident that we did not violate the rules for parametric tests. We otherwise would have given the data and results with median and ranges and would have indicated the non-parametric test methods. 5- the authors does not discuss the similarities/differences with a classical blunt trauma model. An interesting question should be: How the blast related lung injuries are different from blunt chest trauma related lung injuries? The reviewer is right that we did not discuss. We discussed it in the discussion section as: Blast thoracic injury seems to be the most dangerous type of non-penetrating thoracic injury that may more regularly lead to death due to acute lung injury than in other non-penetrating thoracic injuries (CDC Explosions and blast injuries. A primer for Clinicians). 6- thus, the definition of the incoming blast overpressure wave is of importance. The OP wave provided by the shock tube is very short (0.6 ms) where standout open field OP waves are close to 2-4 ms. It is understandable that even if very short, this OP wave is responsible for lung injuries, but this singularity is not discussed in the paper. how short OP wave related lung injury is different from normal length OP wave related lung injury? The question is for sure of physical and of pathophysiological importance. We had a clear and defined experimental setting, also certainly with minimal distance to the subject, and we have no clear clue to alternative and slower overpressure waves. Unfortunately, we can therefore not answer the question. 7- the wet to dry ratio study is of interest but it does not take the intra-alveolar hemorrhage into account. Also, methods don't describe if W/D ratio lungs were previously injected for BAL... The methods need to be clearer. The wet to dry ratio is a standardized procedure performed in acute lung injury research since decades. Every clinically relevant acute lung injury is accompanied with some degree of destruction of the alveolar-capillary barrier and therefore of alveolar haemorrhage. This is e.g. very well seen in the scientific work on clinical acute lung injury and ARDS work where bronchoalveolar lavages have been analysed. The only point is that there it is in many times not quantified, but it is present. Therefore in virtually all data on severe acute lung injury some alveolar haemorrhage is present. We therefore are confident that this does not inferiorize the dataset presented on an injury where about 10 % of rats died within a few minutes thereafter. We consider it as a normal phenomenon not disturbing the value of wet to dry ratio. 8- Concerning the methods, why is the anesthetic strategy biphasic (firs halothan then pentothal) ? Also the pro-inflammatory effect of buprenorphine is not discussed. The anaesthetic strategy was also given by the ethics committee, as in animal research the main focus is - e. g. besides reduction of animal numbers – to give the animals intravitally minimal harm. We therefore had to cover the whole intravital research for the rats with maximal analgesia, and therefore this anaesthetic strategy had to be chosen. Neither pain or dyspnea itself, nor an analgetic drug is probably completely free of biologic effects, and therefore any way with more or less pain and with any major analgetic drug may modify to a certain extent the read-outs as e.g. discussed by you. This dilemma of animal in vivo research is in many instances best solved with rather generous analgetics and anaesthetics, and with the use of sham controls, as it is done only with very few scientifically and ethically acceptably exceptions in the animal research and its moral obligation of humane care. The literature on buprenorphine is impressive and shows a number of anti-as a number of prl-inflammatory research papers. We integrated in the limitation section one sentence on the possible effect of buprenorphine concerning the influence on outcome. Attachments Attachment Submitted filename: Response to Reviewers_inflammatory response_004_220822_YH.doc https://doi.org/10.1371/journal.pone.0281446.r002
6 Dec 2022 Decision Letter - Nicolas Tsapis, Editor PONE-D-22-09944R1Characteristics of inflammatory response and repair after experimental blast lung injury in ratsPLOS ONE Dear Dr. Hadizamani, 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 Jan 20 2023 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, Nicolas Tsapis, Ph.D. Academic 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. [Note: HTML markup is below. Please do not edit.] 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: (No Response) ******** 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: Yes ****** 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 ****** 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: We thank the authors for their responses, however some points needs to be clarified in the manuscript. Point 1-3: ok Point 4 – Statistics. The authors state in their response and in the ARRIVE document that they did all the controls needed to use the parametric tests. This have to be also stated in the manuscript, section 2.6. Point 5: Comparison with blunt thoracic trauma. The authors add a comparison with blunt trauma concerning the general severity. The manuscript would benefit from an addition on the difference, even if poorly known, on the pathophysiological aspect of the lung contusion formation between the two different sorts of insult. Point 6: Discussion on OP characteristics In their response, the authors acknowledge they cannot answer the question whether short duration blast OP related injuries are or are not different from longer (and more representative) duration BOP related injuries. This has to be discussed in the manuscript as a limitation. Point 7: W/D ratio The information given in the response should benefit to the discussion in the manuscript. For sure, the rise in W/D ration at 15 min is solely due to intra-alveolar hemorrhage, the rise at 3h due to both hemorrhage and edema. Point 8: OK New point: Can the authors specify at what time control animals were sacrificed? ****** 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: Nicolas J. PRAT ******** [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. https://doi.org/10.1371/journal.pone.0281446.r003
Revision 2
13 Jan 2023 Author Response Response to Reviewers 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: We thank the authors for their responses, however some points needs to be clarified in the manuscript. Point 1-3: ok Point 4 – Statistics. The authors state in their response and in the ARRIVE document that they did all the controls needed to use the parametric tests. This have to be also stated in the manuscript, section 2.6. Thank you very much for this comment. In the section 2.6., and ARRIVE document we mentioned that "Notably, we have done all the controls needed to use the parametric tests." Point 5: Comparison with blunt thoracic trauma. The authors add a comparison with blunt trauma concerning the general severity. The manuscript would benefit from an addition on the difference, even if poorly known, on the pathophysiological aspect of the lung contusion formation between the two different sorts of insult. The shock wave produced by explosions and high-velocity projectiles may cause serious trauma to the pulmonary parenchyma. The onset of damage from a blast wave occurs when the blast wave hits the thoracic wall and compresses thorax and intrathoracic tissues and thus, in particular, the intrathoracic gas volume. The resulting forces exceed the tensile strength of the tissues and damage their structural texture. So the most common injury associated with a blast wave is a pulmonary contusion. On microscopic examinations the changes closely resemble contusions in non-penetrating blunt chest trauma. Lung injury by a blast wave occurs when an overpressure of about 40 PSI is reached. Blunt chest trauma leads to a comparable lung contusion, when traumata produce instantaneous changes in velocity when frontal crashes into a fixed object occur as well as near-side lateral impact during a vehicular crash (O'Connor et al., 2009). Pulmonary contusion from blunt non-penetrating chest trauma is often accentuated to one side and in areas where the thoracic cage is relatively elastic and compressible. Radiographic changes are localized accordingly. Explosion-related trauma, on the other hand, often produces a characteristic "butterfly" pattern in chest CT due to the broad front of the blast wave and reflections of the blast wave if explosions occur in an enclosed space. We have added in the introduction this interesting point for the reader, and we thank the reviewer for this input. We discussed this subject in less detail, so that we did not too much extend the text. Point 6: Discussion on OP characteristics In their response, the authors acknowledge they cannot answer the question whether short duration blast OP related injuries are or are not different from longer (and more representative) duration BOP related injuries. This has to be discussed in the manuscript as a limitation. Thank you very much for noting this issue. We formulated this fact in the limitation section as follows: Furthermore, it is unclear whether shorter and possibly more representative duration blast over pressure related injuries are distinct from longer and more frequent duration blast over pressure related injuries. Point 7: W/D ratio The information given in the response should benefit to the discussion in the manuscript.For sure, the rise in W/D ration at 15 min is solely due to intra-alveolar hemorrhage, the rise at 3h due to both hemorrhage and edema. I appreciate your comment in this case. In the related section now we have noted that: Indeed the rise in wet/dry ratio at 15 minutes is solely due to intra-alveolar haemorrhage, while the rise of this ratio at 3 hours could be due to both haemorrhage and oedema. Point 8: OK New point: Can the authors specify at what time control animals were sacrificed? 10 minutes, which is the identical time point as the sacrifice of the first group concerning time points. Reference O'Connor, J. V., Kufera, J. A., Kerns, T. J., Stein, D. M., Ho, S., Dischinger, P. C., & Scalea, T. M. (2009). Crash and occupant predictors of pulmonary contusion. J Trauma, 66(4), 1091-1095. https://doi.org/10.1097/TA.0b013e318164d097 Attachments Attachment Submitted filename: Response to Reviewers_003_230113_YH.doc https://doi.org/10.1371/journal.pone.0281446.r004
24 Jan 2023 Decision Letter - Nicolas Tsapis, Editor Characteristics of inflammatory response and repair after experimental blast lung injury in rats PONE-D-22-09944R2 Dear Dr. Hadizamani, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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, Nicolas Tsapis, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): The authors have addressed all the criticism raised by the reviewers, have answered appropriately and have modified the article appropriately. In my opinion the article can be accepted. Reviewers' comments: https://doi.org/10.1371/journal.pone.0281446.r005
Formally Accepted
8 Mar 2023 Acceptance Letter - Nicolas Tsapis, Editor PONE-D-22-09944R2 Characteristics of inflammatory response and repair after experimental blast lung injury in rats Dear Dr. Hadizamani: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Nicolas Tsapis Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0281446.r006

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