Suppression of Aseptic Inflammation Reduces the Severity of Remodeling of the Pulmonary Artery Branches and Improves Progressing of Experimental Chronic Thromboembolic Pulmonary Hypertension

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism, characterized by increased pressure in the pulmonary artery and impaired lysis of thromboemboli. Previously, the presence of aseptic inflammation in CTEPH was identified in the wall of the pulmonary artery branches and perivascularly. However, the role of this inflammation in the CTEPH formation is unknown. The aim of the work was to study the effect of aseptic inflammation on the CTEPH formation and progression. The experiments were performed on 54 male rats. The CTEPH model was reproduced by repeated intravenous administration of partially biodegradable microspheres (MS). Immediately after the last administration of MS, all animals were divided into groups: control CTEPH (c.CTEPH) – saline solution was administered intramuscularly (i/m) for 6 weeks; low dose of prednisolone (LD) – prednisolone was administered i/m at a dose of 1.5 mg/kg; high dose (HD) – prednisolone was administered i/m at a dose of 6 mg/kg; healthy animals. After 6 weeks, the following was performed: treadmill test, TTE, cardiac catheterization with manometry, and histological examination of the lungs. In a separate series of experiments, the severity of inflammatory infiltration of the vascular wall and perivascular zone was assessed by immunohistochemical studies (IHC). In the LD group, there was the decreasing of hypertrophy index (HI) and the percentage of collagen fibers in the vascular wall compared to c.CTEPH. There was a significantly greater reduction in HI compared to HD. In the HD group, there was positive effect on the percentage of collagen fibers in the vascular wall, this parameter did not significantly differ from healthy animals. According to IHC data, prednisolone in low dose effectively suppressed inflammatory infiltration of the vascular wall and perivascular space. The results of the study revealed the ability of prednisolone, by suppressing aseptic inflammation, to reduce the severity of remodeling of the pulmonary artery branches.

Full Text

Restricted Access

About the authors

А. А. Karpov

Almazov National Medical Research Centre; Saint-Petersburg State Chemical and Pharmaceutical University; Saint-Petersburg Electrotechnical University "LETI"

Email: uplavice@gmail.com
Russian Federation, Saint-Petersburg; Saint-Petersburg; Saint-Petersburg

А. А. Krylov

Almazov National Medical Research Centre; Herzen State Pedagogical University of Russia

Email: uplavice@gmail.com
Russian Federation, Saint-Petersburg; Saint-Petersburg

L. A. Shilenko

Almazov National Medical Research Centre

Email: uplavice@gmail.com
Russian Federation, Saint-Petersburg

А. М. Mihailova

Almazov National Medical Research Centre

Email: uplavice@gmail.com
Russian Federation, Saint-Petersburg

D. D. Vaulina

Almazov National Medical Research Centre

Author for correspondence.
Email: uplavice@gmail.com
Russian Federation, Saint-Petersburg

D. Yu. Ivkin

Saint-Petersburg State Chemical and Pharmaceutical University

Email: uplavice@gmail.com
Russian Federation, Saint-Petersburg

N. P. Isakova

Herzen State Pedagogical University of Russia

Email: uplavice@gmail.com
Russian Federation, Saint-Petersburg

A. V. Vorotilov

Almazov National Medical Research Centre

Email: uplavice@gmail.com
Russian Federation, Saint-Petersburg

N. Y. Semenova

Almazov National Medical Research Centre

Email: uplavice@gmail.com
Russian Federation, Saint-Petersburg

V. A. Zinserling

Almazov National Medical Research Centre

Email: uplavice@gmail.com
Russian Federation, Saint-Petersburg

М. М. Galagudza

Almazov National Medical Research Centre

Email: uplavice@gmail.com
Russian Federation, Saint-Petersburg

References

  1. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R (2019) Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 53(1): 1801913. https://doi.org/10.1183/13993003.01913–2018
  2. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S; ESC/ERS Scientific Document Group (2022) 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 43(38): 3618–3731. https://doi.org/10.1093/eurheartj/ehac237
  3. Yang J, Madani MM, Mahmud E, Kim NH (2023) Evaluation and Management of Chronic Thromboembolic Pulmonary Hypertension. Chest 164(2): 490–502. https://doi.org/10.1016/j.chest.2023.03.029
  4. Rådegran G, Kjellström B, Ekmehag B, Larsen F, Rundqvist B, Blomquist SB, Gustafsson C, Hesselstrand R, Karlsson M, Kornhall B, Nisell M, Persson L, Ryftenius H, Selin M, Ullman B, Wall K, Wikström G, Willehadson M, Jansson K, Söderberg S, on behalf of SveFPH and SPAHR (2016) Characteristics and survival of adult Swedish PAH and CTEPH patients 2000–2014. Scand Cardiovasc J 50(4): 243–250. https://doi.org/10.1080/14017431.2016.1185532
  5. Quadery SR, Swift AJ, Billings CG, Thompson AAR, Elliot CA, Hurdman J, Charalampopoulos A, Sabroe I, Armstrong IJ, Hamilton N, Sephton P, Garrad S, Pepke-Zaba J, Jenkins DP, Screaton N, Rothman AM, Lawrie A, Cleveland T, Thomas S, Rajaram S, Hill C, Davies C, Johns CS, Wild JM, Condliffe R, Kiely DG (2018) The impact of patient choice on survival in chronic thromboembolic pulmonary hypertension. Eur Respir J 52(3): 1800589. https://doi.org/10.1183/13993003.00589–2018
  6. Lang IM, Dorfmüller P, Vonk Noordegraaf A (2016) The Pathobiology of Chronic Thromboembolic Pulmonary Hypertension. Ann Am Thorac Soc 13 Suppl 3: S215–S221. https://doi.org/10.1513/AnnalsATS.201509–620AS
  7. Delcroix M, Vonk Noordegraaf A, Fadel E, Lang I, Simonneau G, Naeije R (2013) Vascular and right ventricular remodelling in chronic thromboembolic pulmonary hypertension. Eur Respir J 41(1): 224–232. https://doi.org/10.1183/09031936.00047712
  8. Andersen S, Reese-Petersen AL, Braams N, Andersen MJ, Mellemkjær S, Andersen A, Bogaard HJ, Genovese F, Nielsen-Kudsk JE (2023) Biomarkers of collagen turnover and wound healing in chronic thromboembolic pulmonary hypertension patients before and after pulmonary endarterectomy. Int J Cardiol 384: 82–88. https://doi.org/10.1016/j.ijcard.2023.05.016
  9. Matthews DT, Hemnes AR (2016) Current concepts in the pathogenesis of chronic thromboembolic pulmonary hypertension. Pulm Circ 6(2): 145–154. https://doi.org/10.1086/686011
  10. Quarck R, Wynants M, Verbeken E, Meyns B, Delcroix M (2015) Contribution of inflammation and impaired angiogenesis to the pathobiology of chronic thromboembolic pulmonary hypertension. Eur Respir J 46(2): 431–443. https://doi.org/10.1183/09031936.00009914
  11. Zhang M, Zhang Y, Pang W, Zhai Z, Wang C (2019) Circulating biomarkers in chronic thromboembolic pulmonary hypertension. Pulm Circ 9(2): 2045894019844480. https://doi.org/10.1177/2045894019844480
  12. Koudstaal T, van Uden D, van Hulst JAC, Heukels P, Bergen IM, Geenen LW, Baggen VJM, van den Bosch AE, van den Toorn LM, Chandoesing PP, Kool M, Boersma E, Hendriks RW, Boomars KA (2021) Plasma markers in pulmonary hypertension subgroups correlate with patient survival. Respir Res 22(1): 137. https://doi.org/10.1186/s12931–021–01716-w
  13. Magoń W, Stępniewski J, Waligóra M, Jonas K, Przybylski R, Podolec P, Kopeć G (2022) Changes in Inflammatory Markers in Patients with Chronic Thromboembolic Pulmonary Hypertension Treated with Balloon Pulmonary Angioplasty. Cells 11(9): 1491. https://doi.org/10.3390/cells11091491
  14. Zabini D, Heinemann A, Foris V, Nagaraj C, Nierlich P, Bálint Z, Kwapiszewska G, Lang IM, Klepetko W, Olschewski H, Olschewski A (2014) Comprehensive analysis of inflammatory markers in chronic thromboembolic pulmonary hypertension patients. Eur Respir J 44(4): 951–962. https://doi.org/10.1183/09031936.00145013
  15. Reesink HJ, Meijer RC, Lutter R, Boomsma F, Jansen HM, Kloek JJ, Bresser P (2006) Hemodynamic and clinical correlates of endothelin-1 in chronic thromboembolic pulmonary hypertension. Circ J 70(8): 1058–1063. https://doi.org/10.1253/circj.70.1058
  16. Smolders VFED, Lodder K, Rodríguez C, Tura-Ceide O, Barberà JA, Jukema JW, Quax PHA, Goumans MJ, Kurakula K (2021) The Inflammatory Profile of CTEPH-Derived Endothelial Cells Is a Possible Driver of Disease Progression. Cells 10(4): 737. https://doi.org/10.3390/cells10040737
  17. Ferré A, Thille AW, Mekontso-Dessap A, Similowski T, Legriel S, Aegerter P, Demoule A; Réseau Européen de Recherche en Ventilation Artificielle (REVA) research network (2023) Impact of corticosteroids on the duration of ventilatory support during severe acute exacerbations of chronic obstructive pulmonary disease in patients in the intensive care unit: a study protocol for a multicentre, randomized, placebo-controlled, double-blind trial. Trials 24(1): 231. https://doi.org/10.1186/s13063–023–07229–9
  18. Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7(2): 27–31. https://doi.org/10.4103/0976–0105.177703
  19. Karpov AA, Anikin NA, Mihailova AM, Smirnov SS, Vaulina DD, Shilenko LA, Ivkin DY, Bagrov AY, Moiseeva OM, Galagudza MM (2021) Model of Chronic Thromboembolic Pulmonary Hypertension in Rats Caused by Repeated Intravenous Administration of Partially Biodegradable Sodium Alginate Microspheres. Int J Mol Sci 22(3): 1149. https://doi.org/10.3390/ijms22031149
  20. Mukhopadhyay S, Johnson TA, Duru N, Buzza MS, Pawar NR, Sarkar R, Antalis TM (2019) Fibrinolysis and Inflammation in Venous Thrombus Resolution. Front Immunol 10: 1348. https://doi.org/10.3389/fimmu.2019.01348
  21. Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Preston IR, Souza R, Waxman A, Escribano Subias P, Feldman J, Meyer G, Montani D, Olsson KM, Manimaran S, Barnes J, Linde PG, de Oliveira Pena J, Badesch DB; PULSAR Trial Investigators (2021) Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 384(13): 1204–1215. https://doi.org/10.1056/NEJMoa2024277
  22. Barnes PJ, Adcock IM, Ito K (2005) Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J 25(3): 552–563. https://doi.org/10.1183/09031936.05.00117504
  23. Chapados I, Lee TF, Chik CL, Cheung PY (2011) Hydrocortisone administration increases pulmonary artery pressure in asphyxiated newborn piglets reoxygenated with 100% oxygen. Eur J Pharmacol 652(1–3): 111–116. https://doi.org/10.1016/j.ejphar.2010.10.089
  24. Gluskowski J, Hawrylkiewicz I, Zych D, Zieliński J (1990) Effects of corticosteroid treatment on pulmonary haemodynamics in patients with sarcoidosis. Eur Respir J 3(4): 403–407.
  25. Kerr KM, Auger WR, Marsh JJ, Devendra G, Spragg RG, Kim NH, Channick RN, Jamieson SW, Madani MM, Manecke GR, Roth DM, Shragg GP, Fedullo PF (2012) Efficacy of methylprednisolone in preventing lung injury following pulmonary thromboendarterectomy. Chest 141(1): 27–35. https://doi.org/10.1378/chest.10–2639

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Design of the study.

Download (99KB)
Indexing metadata
3. Fig. 2. The scheme of losses of experimental animals in the main series. CTEPH – chronic thromboembolic pulmonary hypertension, MS – microspheres, RV – right ventricle, Saline – saline solution.

Download (237KB)
Indexing metadata
4. Fig. 3. Results of noninvasive tests. (a – b) – the results of an echocardiographic examination. (a) – systolic excursion of the tricuspid valve ring (TARSE). (b) is the maximum linear flow velocity (Vmax) in the pulmonary trunk (LS). (c) – the distance covered according to the treadmill test. Int is a group of healthy animals, c.CTEPH is a group of control chronic thromboembolic pulmonary hypertension, LD is a low dose of prednisone, HD is a high dose of prednisone.

Download (178KB)
Indexing metadata
5. Fig. 4. Systolic pressure in the right ventricle (RVSP) according to cardiac catheterization data. INT is a group of healthy animals, c.CTEPH is a group of control chronic thromboembolic pulmonary hypertension, LD is a low dose of prednisone, HD is a high dose of prednisone.

Download (105KB)
Indexing metadata
6. Fig. 5. The results of the histological examination. (a – b) – representative vascular micrographs: (a) – Picro – Mallory staining; (b) – selection of vessel boundaries using ImageJ (Wayne Rasband, USA); (c) – nominal percentage of vascular wall fibrosis on representative micrographs; (d) – percentage of collagen fibers in the structure vascular wall of the branches of the pulmonary artery in the studied groups; (e) – index of vascular wall hypertrophy. One division = 100 microns. INT is a group of healthy animals, c.CTEPH is a group of control chronic thromboembolic pulmonary hypertension, LD is a low dose of prednisone, HD is a high dose of prednisone.

Download (528KB)
Indexing metadata
7. Fig. 6. The results of an immunohistochemical study to assess inflammatory infiltration of the vascular wall and perifocal region. (a) – representative micrographs of immunohistochemical preparations in the groups of K.HTELG and GCS: upper row – staining for CD20 (B lymphocytes), lower row – staining for CD68 (monocytes / macrophages). Positive cells are marked with bright brown membrane staining. (b – e) is the average number of positive cells in the analyzed cells for each vessel. (b) – CD45 (general leukocyte antigen); (c) – CD68 (monocytes / macrophages), (d) – CD3 (T lymphocytes); (e) – CD20 (B lymphocytes). One division = 50 microns. Int is a group of healthy animals, c.CTEPH is a group of control chronic thromboembolic pulmonary hypertension, PSL is a group of low–dose prednisone.

Download (519KB)
Indexing metadata

Copyright (c) 2024 Russian Academy of Sciences