EFFECT OF INHALED PLASMINOGEN ADMINISTRATION ON ACUTE PULMONARY INFLAMMATION IN RATS: INHIBITION OF THE HYPOXIC-ANGIOGENIC CASCADE AND FIBROGENESIS
D.S. Zyablitsev1, A.O. Tikhomyrov2, V.V. Mykhailovska1
- Bogomolets National Medical University, Kyiv
- Palladin Institute of Biochemistry, NAS of Ukraine
DOI: https://doi.org/10.15407/fz72.04.003
Abstract
Acute pulmonary inflammation (API) and acute respiratory
distress syndrome (ARDS) are accompanied by severe hy-
poxemia, coagulopathy, and a high risk of post-inflammatory
pulmonary fibrosis. A central role in the cellular response to
hypoxia is played by hypoxia-inducible factor-1α (HIF-1α),
which activates the transcription of vascular endothelial growth
factor (VEGF), thereby promoting pathological angiogenesis,
increased vascular permeability, and fibrogenesis. Inhaled
administration of plasminogen may represent a promising
approach to local fibrinolytic therapy in ARDS. The aim of
this study was to evaluate the effect of inhaled plasminogen
administration on pulmonary HIF-1α and VEGF content in a
rat model of API. The study was performed on 45 male Wistar
Д.С. Зябліцев, А.О. Тихомиров, В.В. Михайловська
12
rats in which API was induced by systemic and endotracheal
administration of lipopolysaccharide combined with mechani-
cal aspiration using a nylon thread. On day 21, pronounced
fibrosis was observed, accompanied by microvascular throm-
bosis, vascular hyalinosis, and deposition of coarse, disordered
collagen fibers. The content of HIF-1α and dimeric VEGF in
lung tissue greatly exceeded the corresponding values in intact
animals. Inhaled administration of plasminogen resulted in a
reduction of HIF-1α and VEGF levels. Morphologically, this
was accompanied by a desrease in fibrosis, formation of thin
and organized collagen structures, and hyperplasia of type II al-
veolocytes and goblet cells. Thus, inhaled plasminogen admin-
istration provides an effective pharmacological interruption of
the pathological hypoxic-angiogenic cycle through inhibition
of HIF-1α-mediated VEGF transcription. Morphologically, this
effect is manifested by a shift of the reparative process from
pathological fibrosis toward physiological regeneration. These
findings substantiate the potential of inhaled plasminogen as
a pathogenetically targeted agent for the prevention of post-
inflammatory pneumosclerosis.
Keywords:
hypoxia-inducible factor 1α; vascular endothelial growth factor; plasminogen; inhalation administration; acute lung inflammation; pulmonary fibrosis; Wistar rats
References
1. Livingstone S, Lemberg C, Kozlowski P, Singh G, Sahi H, Serrano K. Acute respiratory distress syndrome: current understanding and future directions in treatment. Crit Care Med. 2021;49(7):1143-55. doi: 10.1097/ CCM.0000000000004918.
2. Suresh MV, Balijepalli S, Solanki S, Aktay S, Choudhary K, Shah YM, Raghavendran K. Hypoxia-inducible factor 1α and its role in lung injury: Adaptive or maladaptive. Inflammation. 2023;46(2):491-508. doi: 10.1007/s10753- 022-01769-z.
3. Zhang Y, Yu W, Ma Z, Kang L, Yao Q, Sun Z, Ma X. Role of IL33/HIF1α/VEGF in intermittent hypoxia-induced lung injury. Immunobiology. 2025;230(6):153132. doi:10.1016/j.imbio.2025.153132.
4. Camprubí-Rimblas M, Tantinyà N, Guillamat-Prats R, Artigas A. Anticoagulant and fibrinolytic therapy in acute respiratory distress syndrome. Ann Transl Med. 2018;6(19):388. doi: 10.21037/atm.2018.09.22.
5. Vizzoni L, Migone C, Nesti SE, Bona ND, Franzini M, Brogi S, Calderone V, Fabiano A, Zambito Y, Mori F, Ferro B, Piras AM. Plasminogen-cyclodextrin aerosol for ARDS: activity retention in simulated oxygen therapy and inflammation-triggered clot lysis. Int J Pharm. 2025;686:126359. doi: 10.1016/j.ijpharm.2025.126359.
6. Ziablitsev DS. Morphogenesis of pulmonary damage in lipopolysaccharide-induced acute aspiration bronchopneumonia. Morphologia. 2021;15(4):48-55. [Ukrainian]. doi: 10.26641/1997-9665.2021.4.48-55.
7. Castellino FJ, Ploplis VA. Structure and function of the plasminogen/plasmin system. Thromb Haemost. 2005;93(4):647-54. doi: 10.1160/TH04-12-0842.
8. Tykhomyrov AA, Yusova EI, Diordieva SI, Korsa VV, Grinenko TV. Production and characteristics of antibodies against K1-3 fragment of human plasminogen. Biotechnol Acta. 2013;6(1):87-97. doi: 10.15407/biotech6.01.086.
9. Ziablitsev DS, Kostenko VO, Mykhaylovska VV, Likhodievsky VV, Kurchenko AI. Effect of experimental therapy on pulmonary content of hypoxia-inducible factor-1α and vascular growth factor in acute lung inflammation in rats. Fiziol Zh. 2026;72(1):3-15. [Ukrainian]. doi: 10.15407/ fz72.01.003.
10. Ziablitsev DS, Mykhailovska VV, Kurchenko AI. Dynamics of the content of hypoxia-inducible factor-α (HIF-1α) and vascular growth factor (VEGF) in the pulmonary tissue during the development of hemorrhagic pneumonia with fibrosis. Med Sci Ukraine. 2025;3(21):94-105. [Ukrainian]. doi:10.32345/2664-4738.3.2025.10.
11. Özsoy Ş, Karakuş Yılmaz B, Sultan Oran D. Acute respiratory injury model in rats. J Istanbul Vet Sci. 2023;7(3): 172-7. doi: 10.30704/http-www-jivs-net.1350614.
12. Vizzoni L, Migone C, Grassiri B, Zambito Y, Ferro B, Roncucci P, Mori F, Salvatore A, Ascione E, Crea R, Esin S, Batoni G, Piras AM. Biopharmaceutical assessment of mesh aerosolised plasminogen, a step towards ARDS treatment. Pharmaceutics. 2023;15(6):1618. doi: 10.3390/ pharmaceutics15061618.
13. Chowdary P, Agarwal B, Peralta MR, Bhagani S, Lee S, Goldring J, et al. Nebulized recombinant tissue plasminogen activator (rt-PA) for acute COVID-19-induced respiratory failure: an exploratory proof-of-concept trial. J Clin Med. 2023;12(18):5848. doi: 10.3390/jcm12185848.
14. Huppert LA, Matthay MA, Ware LB. Pathogenesis of acute respiratory distress syndrome. Semin Respir Crit Care Med. 2019;40(1):31-9. doi: 10.1055/s-0039-1683996.
15. Li X, Zhang Q, Nasser MI, Xu L, Zhang X, Zhu P, He Q, Zhao M. Oxygen homeostasis and cardiovascular disease: A role for HIF? Biomed Pharmacother. 2020;128:110338. doi: 10.1016/j.biopha.2020.110338.
16. Whyte CS, Morrow GB, Mitchell JL, Chowdary P, Mutch NJ. Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. J Thromb Haemost. 2020;18(7):1548-
55. doi: 10.1111/jth.14872.
17. Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: good and evil. Genes Cancer. 2011;2(12):1117-33. doi: 10.1177/1947601911423654.
18. Barratt SL, Flower VA, Pauling JD, Millar AB. VEGF (vascular endothelial growth factor) and fibrotic lung disease. Int J Mol Sci. 2018;19(5):1269. doi: 10.3390/ ijms19051269.
19. Idell S, Rahman NM. Intrapleural fibrinolytic therapy for pleural infection: current evidence and future directions. Ann Am Thorac Soc. 2021;18(5):771-8. doi: 10.1513/ AnnalsATS.202008-1010FR.
20. Deryugina EI, Quigley JP. Cell surface remodeling by plasmin: a new function for an old enzyme. J Biomed Biotechnol. 2012;2012:564259. doi: 10.1155/2012/564259.
21. Guillamat-Prats R, Camprubí-Rimblas M, Puig F, Herrero R, Tantinyà N, Serrano-Mollar A, Artigas A. Alveolar type II cells restore the alveolar epithelial barrier in acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2021;321(5):L912-26. doi: 10.1152/ajplung.00063.2021.
22. Suresh MV, Aggarwal V, Raghavendran K. The intersection of pulmonary vascular disease and hypoxia-inducible factors. Card Electrophysiol Clin. 2025;17(3):429-38. doi: 10.1016/j.ccep.2024.12.014.
|
