Lymphatics: Future Perspectives Unrealized Potential

Round 1

Reviewer 1 Report

There is a potential link between saturated fatty acids (SFA) and CRP levels

Elevated CRP has been associated with vitamin D deficiency

Leptin increases CRP production in the liver and blood vessels. High leptin levels are linked with obesity, overeating, and inflammation-related diseases

Author Response

Other links increasing C Reactive Protein include saturated fatty acids, bone metabolism including vitamin D deficiency and parathyroid excess.  Obesity through leptin mediated pathways and other immune diseases also contributes to elevations of C Reactive Protein and is associated with depression.  

The above statement was added. with references below

There is a potential link between saturated fatty acids (SFA) and CRP levels 

Santos S, Oliveira A, Casal S, Lopes C. Saturated fatty acids intake in relation to C-reactive protein, adiponectin, and leptin: a population-based study. Nutrition. 2013 Jun;29(6):892-7. doi: 10.1016/j.nut.2013.01.009. Epub 2013 Apr 14. PMID: 23594583. 

Elevated CRP has been associated with vitamin D deficiency 

Pasupuleti P, Suchitra MM, Bitla AR, Sachan A. Attenuation of Oxidative Stress, Interleukin-6, High-Sensitivity C-Reactive Protein, Plasminogen Activator Inhibitor-1, and Fibrinogen with Oral Vitamin D Supplementation in Patients with T2DM having Vitamin D Deficiency. J Lab Physicians. 2021 Dec 31;14(2):190-196. doi: 10.1055/s-0041-1742285. PMID: 35982882; PMCID: PMC9381323. 

Leptin increases CRP production in the liver and blood vessels. High leptin levels are linked with obesity, overeating, and inflammation-related diseases 

Hribal ML, Fiorentino TV, Sesti G. Role of C reactive protein (CRP) in leptin resistance. Curr Pharm Des. 2014;20(4):609-15. doi: 10.2174/13816128113199990016. PMID: 23688010; PMCID: PMC4155811. 

Reviewer 2 Report

The authors described "Lymphatics: Future Perspectives Unrealized Potential". I totally agree with you. Lymphatics, an ignored vascular system, is a prime target for new interventions with unrealized potential. There already has been a lot of lymphedema researches and therapies to maintain lymphatics. This topic should be informative and a pivotal role in the future of medicine.  I have some questions and suggestions to improve this manuscript.

1. In Line 112, "It should be noted that age is the greatest risk factor for heart failure and is associated with negative lymphangiontrope.The medications used to treat heart failure have positive lymphangiontrope. Heart failure medications are used to improve cardiac hemodynamics and blood vessel properties. These same medications have a dual role in improving lymphangiontrope. Cardiogenic edema and lymphedema should be different. What is the rationale for this?

2. In line 295, DNA related to lymphatics (e.g. lymphangiogenesis) has already investigated. Please add the references. 

3. More references should be added. Especially in immunology related to lymphatics. What is the relationship to T lymphocytes? What is the relationship to macrophages?

4. Please add the section of lymphedema. Lymphedema has been particularly well studied recently. Especially in emerging cell therapy and pharmacotherapy.

The authors described "Lymphatics: Future Perspectives Unrealized Potential". I totally agree with you. Lymphatics, an ignored vascular system, is a prime target for new interventions with unrealized potential. There already has been a lot of lymphedema researches and therapies to maintain lymphatics. This topic should be informative and a pivotal role in the future of medicine.  I have some questions and suggestions to improve this manuscript.

1. In Line 112, "It should be noted that age is the greatest risk factor for heart failure and is associated with negative lymphangiontrope.The medications used to treat heart failure have positive lymphangiontrope. Heart failure medications are used to improve cardiac hemodynamics and blood vessel properties. These same medications have a dual role in improving lymphangiontrope. Cardiogenic edema and lymphedema should be different. What is the rationale for this?

2. In line 295, DNA related to lymphatics (e.g. lymphangiogenesis) has already investigated. Please add the references. 

3. More references should be added. Especially in immunology related to lymphatics. What is the relationship to T lymphocytes? What is the relationship to macrophages?

4. Please add the section of lymphedema. Lymphedema has been particularly well studied recently. Especially in emerging cell therapy and pharmacotherapy.

Author Response

I appreciate the suggestions and additional text and references were added summarized below

The authors described "Lymphatics: Future Perspectives Unrealized Potential". I totally agree with you. Lymphatics, an ignored vascular system, is a prime target for new interventions with unrealized potential. There already has been a lot of lymphedema researches and therapies to maintain lymphatics. This topic should be informative and a pivotal role in the future of medicine.  I have some questions and suggestions to improve this manuscript. 

1. In Line 112, "It should be noted that age is the greatest risk factor for heart failure and is associated with negative lymphangiontrope.The medications used to treat heart failure have positive lymphangiontrope. Heart failure medications are used to improve cardiac hemodynamics and blood vessel properties. These same medications have a dual role in improving lymphangiontrope. Cardiogenic edema and lymphedema should be different. What is the rationale for this?
2. Lymphedema is primarily a failure of the lymphatic system, usually a structural or obstructive lesion.  In cardiogenic edema the lymphatic system is overwhelmed and fails to compensate for the closed circulatory system.  Both conditions can be enhanced by improving the function of structurally sound lymphangions.
3. In line 295, DNA related to lymphatics (e.g. lymphangiogenesis) has already investigated. Please add the references. The genetic information associated with lymphedema is under investigation and nicely outlined by Rockson.  Interspeicies genetic similarities has not been investigated and may be helpful understanding the genesis and potential repair mechanisms.

Rockson SG. Advances in Lymphedema. Circ Res. 2021 Jun 11;128(12):2003-2016. doi: 10.1161/CIRCRESAHA.121.318307. Epub 2021 Jun 10. PMID: 34110905.lym 

3. More references should be added. Especially in immunology related to lymphatics. What is the relationship to T lymphocytes? What is the relationship to macrophages?

Immunology is part of the lymphatic system with Th1 and Th2 balance of the innate and the immune system.  The lymphatic system delivers all these cells to targets of infection and repair. This system needs to be mapped with biomarkers that can identify repair mechanisms and excess activity. 

Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003 Aug;8(3):223-46. PMID: 12946237. 

Hunter MC, Teijeira A, Halin C. T Cell Trafficking through Lymphatic Vessels. Front Immunol. 2016 Dec 21;7:613. doi: 10.3389/fimmu.2016.00613. PMID: 28066423; PMCID: PMC5174098. 

Hampton HR, Chtanova T. Lymphatic Migration of Immune Cells. Front Immunol. 2019 May 28;10:1168. doi: 10.3389/fimmu.2019.01168. PMID: 31191539; PMCID: PMC6546724. 

Devaraj S, Jialal I. C-reactive protein polarizes human macrophages to an M1 phenotype and inhibits transformation to the M2 phenotype. Arterioscler Thromb Vasc Biol. 2011 Jun;31(6):1397-402. doi: 10.1161/ATVBAHA.111.225508. Epub 2011 Mar 17. PMID: 21415385; PMCID: PMC3099471. 

4. lease add the section of lymphedema. Lymphedema has been particularly well studied recently. Especially in emerging cell therapy and pharmacotherapy.

Ogino R, Yokooji T, Hayashida M, Suda S, Yamakawa S, Hayashida K. Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema. Int J Mol Sci. 2022 Jul 9;23(14):7614. doi: 10.3390/ijms23147614. PMID: 35886961; PMCID: PMC9322118. 

Round 2

Reviewer 2 Report

The authors revised the manuscript precisely. Thank you for this opportunity.