Calcium–Permeable Channels and Endothelial Dysfunction in Acute Lung Injury
Round 1
Reviewer 1 Report
Dear Colleagues,
Thank you for your work, Bellow please find couple of comments for your review:
-
Significant part of this materials should be organized as tables and pictures.
-- characteristics of the main calcium channels involved in endothelial cell activation, activity of clinical stage inhibitors, etc can be provided as tables
-- the role of endothelial dysfunction in Acute Lung Injury pathogenesis, as well as involvement Ca2+ channels in Endothelial Dysfunction signaling pathways can be provided as pictures.
- The role of other Ca2+ channels (L- and N-types) in Endothelial Dysfunction and ALI should be described (or at least mentioned).
- List of clinical stage Ca2+ channels blockers should be provided (for example TRPV4 inhibitors GSK2798745 with published clinical data even not mentioned)
- Information related with clinical development of Ca2+ channels blockers should be provided together with disscussion reasons of its falure
Author Response
Dear Colleagues,
Thank you for your work, Bellow please find couple of comments for your review:
Point 1: Significant part of this materials should be organized as tables and pictures. characteristics of the main calcium channels involved in endothelial cell activation, activity of clinical stage inhibitors, etc can be provided as tables
Response 1：We thank reviewer suggestions. We summarized the important EC calcium channels, which may play key roles in dysfunction of EC in Table 1 and the molecular mechanisms in Figure 2. Channel blockers in clinical trail are not many, so we described it in text (line 284-293).
Point 2: the role of endothelial dysfunction in Acute Lung Injury pathogenesis, as well as involvement Ca2+ channels in Endothelial Dysfunction signaling pathways can be provided as pictures.
Response 2： We modified our figure 2 and the main calcium channel and channel related phycological pathways are illustrated in the new figure 2.
Point 3: The role of other Ca2+ channels (L- and N-types) in Endothelial Dysfunction and ALI should be described (or at least mentioned).
Response 3： Other voltage gated calcium channels including L-and N-types calcium channels now described in line 154-156.
Point 4: List of clinical stage Ca2+ channels blockers should be provided (for example TRPV4 inhibitors GSK2798745 with published clinical data even not mentioned). Information related with clinical development of Ca2+ channels blockers should be provided together with discussion reasons of its failure
Response 4： Thank review point this shortage of our MS. We included the information of channels’ blockers and discussed GSK2798754 in clinical trial in line 284-293.
Reviewer 2 Report
In this review article, Hao et al. discuss the role of Calcium channels in Endothelial dysfunction associated with Acute Lung injury. It covers most of the relevant aspects of endothelial dysfunction and functional significance of calcium channels in this process. Overall, it is a well drafted and timely review. However, following concerns should be addressed before review is accepted for the publications.
- In section 3, authors discuss about several stimuli that induce endothelial dysfunction but do not cover the literature on the role of thrombin in inducing endothelial dysfunction. It is important to deliberate on thrombin literature especially because thrombin mediates endothelial dysfunction by perturbing calcium signaling.
- Similarly in SOC channel section, authors missed on discussing in detail the role of STIM1 in regulating endothelial barrier function. In particular, Orai1 independent role of STIM1 in modulating endothelial permeability should be deliberated (Shinde et al., Science Signaling 2013).
- The manuscript requires through proofreading as there are several typos and grammatical errors.
Minor points:
- The manuscript is full of very long phrases that are difficult to follow. Therefore, authors should breakdown such phrases into smaller sentences. For example: line no. 232-234; 252-256 etc.
- In table 1, correct “Refence” channel to “Target” channel.
- Reference no. 53 and 55 are same. Please correct.
Author Response
Point 1: In this review article, Hao et al. discuss the role of Calcium channels in Endothelial dysfunction associated with Acute Lung injury. It covers most of the relevant aspects of endothelial dysfunction and functional significance of calcium channels in this process. Overall, it is a well drafted and timely review. However, following concerns should be addressed before review is accepted for the publications.
Response 1：We thank the positive evaluation of the reviewer and the comments and suggestions from the reviewer do help us to improve our manuscript.
Point 2: In section 3, authors discuss about several stimuli that induce endothelial dysfunction but do not cover the literature on the role of thrombin in inducing endothelial dysfunction. It is important to deliberate on thrombin literature especially because thrombin mediates endothelial dysfunction by perturbing calcium signaling.
Response 2： We agree with reviewer that endothelial dysfunction induced by thrombin is associated with calcium signaling and we added this important information in our MS（line77-81）.
Point 3: Similarly in SOC channel section, authors missed on discussing in detail the role of STIM1 in regulating endothelial barrier function. In particular, Orai1 independent role of STIM1 in modulating endothelial permeability should be deliberated (Shinde et al., Science Signaling 2013).
Response 3： The role of STIM1 and Orai 1, separately in endothelial permeability now has been discussed in line 199-203.
Point 4: The manuscript requires through proofreading as there are several typos and grammatical errors.
Response 4：Thank reviewer’s suggestion and we asked our college from Foreign Language Department to read and edit our MS.
Minor points:
Point 5: The manuscript is full of very long phrases that are difficult to follow. Therefore, authors should breakdown such phrases into smaller sentences. For example: line no. 232-234; 252-256 etc.
Response 5： We revised the manuscript and break the long phrases into shorter sentences.
Point 6: In table 1, correct “Refence” channel to “Target” channel.
Response 6：The ‘Refence’ has been changed into “Target”
Point 7: Reference no. 53 and 55 are same. Please correct.
Response 7：Thanks to point out it. We corrected it.
Round 2
Reviewer 1 Report
Complete List of clinical stage Ca2+ channels blockers should be provided. A complete list of inhibitors can be prepared based on reviews or data from clinicaltrials.gov. Information related with clinical development of Ca2+ channels blockers should be provided together with discussion reasons of its failure
Author Response
Response to Reviewer 1 Comments
Point 1：Complete List of clinical stage Ca2+ channels blockers should be provided. A complete list of inhibitors can be prepared based on reviews or data from clinicaltrials.gov.
Response 1：Indeed, we wish more calcium channels blockers can enter clinical trails for ALI or ARDS. We searched all compounds mentioned here in clinicaltrials.gov and found the information of GSK2798745, GMT4, flunarizine and mibefradil. Only GSK2798745 was evaluated in ALI or ARDS model. Therefore, we summarized the compounds tested in animal model and Phase I in table 1.
Point 2：Information related with clinical development of Ca2+ channels blockers should be provided together with discussion reasons of its failure
Response 1：Thanks for reviewer’s suggestion. We revised the text and discussed the shortage of GSK2798745 in clinical trial （line 313-318）.
