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研究生：	王惠玄 Wang, Hui-Hsuan
論文名稱：	Pentraxins 3 在肺動脈高壓中的角色 The role of Pentraxins 3 in Pulmonary Arterial Hypertension
指導教授：	劉秉彥 Liu, Ping-Yen
學位類別：	碩士 Master
系所名稱：	醫學院 - 生物化學暨分子生物學研究所 Department of Biochemistry and Molecular Biology
論文出版年：	2021
畢業學年度：	109
語文別：	英文
論文頁數：	62
中文關鍵詞：	肺動脈高壓、PTX3 、PTX3 抗體、發炎、纖維化、右心室肥大、血管重塑
外文關鍵詞：	PAH, PTX3, PTX3 antibody, inflammation, fibrosis, RV hypertrophy, vascular remodeling
相關次數：	點閱：67 下載：0
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Abstract  I
中文摘要 II
致謝 III
Table of contents IV
Abbreviations VII
Chapter 1. Introduction 1
1.1 Pulmonary arterial hypertension (PAH) 1
1.2 Inflammation in PAH 2
1.3 Treatment of PAH 2
1.4 Pentraxins and pentraxin 3 (PTX3) 3
1.5 The correlation of PAH with PTX3 4
1.6 Monocrotaline (MCT)-induced PAH model 4
1.7 Research motivation 5
1.8 Hypothesis 5
1.9 Specific aims 5
Chapter 2. Materials and Methods 6
2.1 MCT induced PAH animal model and treatment 6
2.2 Echo and hemodynamic 6
2.3 Tissue harvest  7
2.4 Protein extraction and quantitative analyze 7
2.5 Western blotting 8
2.6 RNA extraction and reverse transcription 9
2.7 Real-time quantitative PCR 9
2.8 Hematoxylin and Eosin staining 9
2.9 Masson’s trichrome staining 10
2.10 Quantified vascular collagen and thickness 10
2.11 Immunohistochemistry (IHC) staining 11
2.12 Double immunofluorescence (IF) staining 11
2.13 Statistical analysis 12
Chapter 3. Results 13
3.1 Establishing MCT-induced PAH model in rats 13
3.2 The association between PTX3 and rats with PAH 14
3.3 The effect of PTX3 Ab in PAH rat model 15
3.3.1 The expression of PTX3 after PTX3 Ab treatment  15
3.3.2 The influence of biological parameters after PTX3Ab treatment in PAH 16
3.3.3 The change of vascular in lungs 17
3.4 Anti-PTX3 Ab attenuated inflammation in rats with PAH 18
3.5 Anti-PTX3 Ab improved fibrosis in rats with PAH 19
3.6 The producers of PTX3  21
Chapter 4. Discussion  22
4.1 Sildenafil decreases PTX3 expression in PAH 22
4.2 The other reasons of PTX3 may influence the survival rate in the MCT-induced
PAH animal model 22
4.3 Mechanisms of PTX3 in PAH based on in vitro study 23
4.4 The potential pathway for PTX3 in PAH  23
4.5 The feasibility and the alternative program of PTX3 Ab 24
Future perspective 25
Knock out PTX3 is necessary 25
Chapter 5. Conclusions 26
References 27
List of figures and tables 36
Figure. 1. Establishing MCT-induced PAH rat model in different time points 36
Figure. 2. PTX3 expression increases in the vehicle group 36
Figure. 3. PTX3 expression after treatment in rats with PAH 38
Figure. 4. PTX3 Ab decreases RV hypertrophy and heart enlargement 41
Figure. 5. PTX3 Ab improves RV function by echocardiographic evaluation 42
Figure. 6. PA wall thickness was improved in PTX3 Ab group 43
Figure. 7. The difference between PTX3 Ab and sildenafil treatment 46
Figure. 8. PTX3 Ab decreases inflammation in lung of rats with PAH 47
Figure. 9. PTX3 Ab decreases inflammation in RV of rats with PAH 48
Figure. 10. PTX3 Ab decreases collagen deposition around PAs of rats with PAH 49
Figure. 11. PTX3 Ab decreases the relative gene of fibrosis in lung 51
Figure. 12. PTX3 Ab decreases fibrosis in RV in rats with PAH 52
Figure. 13. PAAFs was one of major producers to PTX3 in rats with PAH 53
Figure. 14. Macrophages/monocytes did not the major producer to PTX3 in rats
with PAH 54
Figure. 15. The schematic diagram about the role of PTX3 in the MCT-induced
PAH rat model 55
Supplementary figure. 1. PTX3 expression of the lung in an MCT-induced PAH
animal model 56
Table 1. Primer sequence for qPCR 57
Table 2. The physiological and hemodynamic parameters in rats with PAH 58
Table 3. The target gene in lung and RV tissue of rats with PAH 59
Table 4. The echocardiographic evaluation in rats with PAH 60
Table 5. The change of vascular in rats with PAH 61
                                    

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2. Austin ED and Loyd JE. The genetics of pulmonary arterial hypertension. Circ Res. 2014;115:189-202.
3. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM and Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34-41.
4. Fowler RM, Gain KR and Gabbay E. Exercise intolerance in pulmonary arterial hypertension. Pulm Med. 2012;2012.
5. Bossone E, D'Andrea A, D'Alto M, Citro R, Argiento P, Ferrara F, Cittadini A, Rubenfire M and Naeije R. Echocardiography in pulmonary arterial hypertension: from diagnosis to prognosis. J Am Soc Echocardiogr. 2013;26:1-14.
6. Deboeck G, Niset G, Vachiery JL, Moraine JJ and Naeije R. Physiological response to the six-minute walk test in pulmonary arterial hypertension. Eur Respir J. 2005;26:667- 672.
7. Naeije R and Manes A. The right ventricle in pulmonary arterial hypertension. Eur Respir Rev. 2014;23:476-487.
8. Casserly B and Klinger JR. Brain natriuretic peptide in pulmonary arterial hypertension: biomarker and potential therapeutic agent. Drug Des Devel Ther. 2009;3:269-287.
9. Gan CT, McCann GP, Marcus JT, van Wolferen SA, Twisk JW, Boonstra A, Postmus PE and Vonk-Noordegraaf A. NT-proBNP reflects right ventricular structure and function in pulmonary hypertension. Eur Respir J. 2006;28:1190-1194.
10. Lammers AE, Adatia I, Cerro MJ, Diaz G, Freudenthal AH, Freudenthal F, Harikrishnan S, Ivy D, Lopes AA, Raj JU, Sandoval J, Stenmark K and Haworth SG. Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011. Pulm Circ. 2011;1:280-285.
11. McLaughlin VV, Shillington A and Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477-1482.
12. McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G and American College of Chest P. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:78S-92S.
13. Shimoda LA and Laurie SS. Vascular remodeling in pulmonary hypertension. J Mol Med (Berl). 2013;91:297-309.
14. Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, Newman J, Oudiz RJ, Provencher S, Torbicki A, Voelkel NF and Hassoun PM. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol. 2013;62:D22-33.
15. McLaughlin VV, Shah SJ, Souza R and Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol. 2015;65:1976-1997.
16. Huertas A, Perros F, Tu L, Cohen-Kaminsky S, Montani D, Dorfmuller P, Guignabert C and Humbert M. Immune dysregulation and endothelial dysfunction in pulmonary arterial hypertension: a complex interplay. Circulation. 2014;129:1332-1340.
17. Humbert M, Guignabert C, Bonnet S, Dorfmuller P, Klinger JR, Nicolls MR, Olschewski AJ, Pullamsetti SS, Schermuly RT, Stenmark KR and Rabinovitch M. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J. 2019;53.
18. Rabinovitch M, Guignabert C, Humbert M and Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115:165-175.
19. Sakao S, Tatsumi K and Voelkel NF. Endothelial cells and pulmonary arterial hypertension: apoptosis, proliferation, interaction and transdifferentiation. Respir Res. 2009;10.
20. Luo Y, Teng X, Zhang L, Chen J, Liu Z, Chen X, Zhao S, Yang S, Feng J and Yan X. CD146-HIF-1alpha hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension. Nat Commun. 2019;10.
21. Hoffmann J, Marsh LM, Pieper M, Stacher E, Ghanim B, Kovacs G, Konig P, Wilkens H, Haitchi HM, Hoefler G, Klepetko W, Olschewski H, Olschewski A and Kwapiszewska G. Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients. Am J Physiol Lung Cell Mol Physiol. 2015;308:L1002-13.
22. Pullamsetti SS, Savai R, Janssen W, Dahal BK, Seeger W, Grimminger F, Ghofrani HA, Weissmann N and Schermuly RT. Inflammation, immunological reaction and role of infection in pulmonary hypertension. Clin Microbiol Infect. 2011;17:7-14.
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2. Austin ED and Loyd JE. The genetics of pulmonary arterial hypertension. Circ Res. 2014;115:189-202.
3. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM and Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34-41.
4. Fowler RM, Gain KR and Gabbay E. Exercise intolerance in pulmonary arterial hypertension. Pulm Med. 2012;2012.
5. Bossone E, D'Andrea A, D'Alto M, Citro R, Argiento P, Ferrara F, Cittadini A, Rubenfire M and Naeije R. Echocardiography in pulmonary arterial hypertension: from diagnosis to prognosis. J Am Soc Echocardiogr. 2013;26:1-14.
6. Deboeck G, Niset G, Vachiery JL, Moraine JJ and Naeije R. Physiological response to the six-minute walk test in pulmonary arterial hypertension. Eur Respir J. 2005;26:667- 672.
7. Naeije R and Manes A. The right ventricle in pulmonary arterial hypertension. Eur Respir Rev. 2014;23:476-487.
8. Casserly B and Klinger JR. Brain natriuretic peptide in pulmonary arterial hypertension: biomarker and potential therapeutic agent. Drug Des Devel Ther. 2009;3:269-287.
9. Gan CT, McCann GP, Marcus JT, van Wolferen SA, Twisk JW, Boonstra A, Postmus PE and Vonk-Noordegraaf A. NT-proBNP reflects right ventricular structure and function in pulmonary hypertension. Eur Respir J. 2006;28:1190-1194.
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13. Shimoda LA and Laurie SS. Vascular remodeling in pulmonary hypertension. J Mol Med (Berl). 2013;91:297-309.
14. Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, Newman J, Oudiz RJ, Provencher S, Torbicki A, Voelkel NF and Hassoun PM. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol. 2013;62:D22-33.
15. McLaughlin VV, Shah SJ, Souza R and Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol. 2015;65:1976-1997.
16. Huertas A, Perros F, Tu L, Cohen-Kaminsky S, Montani D, Dorfmuller P, Guignabert C and Humbert M. Immune dysregulation and endothelial dysfunction in pulmonary arterial hypertension: a complex interplay. Circulation. 2014;129:1332-1340.
17. Humbert M, Guignabert C, Bonnet S, Dorfmuller P, Klinger JR, Nicolls MR, Olschewski AJ, Pullamsetti SS, Schermuly RT, Stenmark KR and Rabinovitch M. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J. 2019;53.
18. Rabinovitch M, Guignabert C, Humbert M and Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115:165-175.
19. Sakao S, Tatsumi K and Voelkel NF. Endothelial cells and pulmonary arterial hypertension: apoptosis, proliferation, interaction and transdifferentiation. Respir Res. 2009;10.
20. Luo Y, Teng X, Zhang L, Chen J, Liu Z, Chen X, Zhao S, Yang S, Feng J and Yan X. CD146-HIF-1alpha hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension. Nat Commun. 2019;10.
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22. Pullamsetti SS, Savai R, Janssen W, Dahal BK, Seeger W, Grimminger F, Ghofrani HA, Weissmann N and Schermuly RT. Inflammation, immunological reaction and role of infection in pulmonary hypertension. Clin Microbiol Infect. 2011;17:7-14.
23. Savai R, Pullamsetti SS, Kolbe J, Bieniek E, Voswinckel R, Fink L, Scheed A, Ritter C, Dahal BK, Vater A, Klussmann S, Ghofrani HA, Weissmann N, Klepetko W, Banat GA, Seeger W, Grimminger F and Schermuly RT. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:897-908.
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