Hypothermic liquid artificial lung ventilation in toxic pulmonary edema: selection of an experimental model based on literature data

Acute inhalation injuries caused by pulmonary toxicants, particularly chlorine, remain highly relevant for occupational health, clinical toxicology, and intensive care due to the risk of rapid development of acute respiratory distress syndrome (ARDS) and toxic pulmonary edema (TPE). Despite advances in pharmacological and respiratory support, treatment outcomes in severe toxic lung injury remain unsatisfactory, which sustains interest in novel therapeutic approaches, including total liquid ventilation. The study aims to analyze the literature data in order to select the experimental model most suitable for preclinical assessment of the possibilities of using full fluid ventilation of the lungs in TPE. The authors conducted a search and analysis of Russian and foreign publications devoted to models of ARDS of toxic origin and TPE. Special attention was paid to the comparative assessment of chlorine inhalation and intratracheal hydrochloric acid instillation models with respect to pathophysiological relevance, reproducibility, technical feasibility, and suitability for testing respiratory support technologies. Both models allow for the reproduction of the key manifestations of severe acute lung injury; however, the HCl instillation model is characterized by greater standardization, technical simplicity, and economic accessibility. Based on the analysis of the literature, HCl instillation can be considered the most practical surrogate model for preclinical evaluation of modern respiratory support strategies, including full liquid ventilation of the lungs, while maintaining the limitations associated with the incomplete reproduction of all features of chlorine inhalation injury.

Contributions:
Bonitenko E.Yu. — concept and design of research, writing and editing of text;
Isabekov N.R. — collection and processing of information;
Tonshin A.A. — collection and processing of information, writing text;
Kovtun A.L. — information processing, editing;
Bala A.M. — information processing, editing.

Funding. The work was carried out within the project of the Advanced research foundation of code "Ranova".

Conflict of interest. The authors declare no conflict of interest.

Received: 07.07.2026 / Accepted: 25.08.2026 / Published: 11.09.2026

1. Akimov A.G., Khalimov Yu.Sh., Shilov V.V. Acute occupational poisoning with chlorine and ammonia: clinical features, diagnosis, and treatment. Ehkologiya cheloveka. 2012; 6: 25–36. https://elibrary.ru/ozlwmz (in Russian).

2. Stolecka K. Analysis of the accidental release of chlorine. System Safety: Human – Technical Facility – Environment. 2019; 1(1): 149–155. https://doi.org/10.2478/czoto-2019-0019

3. Elsayed Y., Al-Ameri A-Q., Ahmed T.E-S., Idreese M., Kanan S. An immediate onsite chlorine leakage disaster management plan. Journal of Chemical Health & Safety. 2019; 26(4-5): 9–13. https://doi.org/10.1016/j.jchas.2018.12.005

4. Saroha A.K. Safe handling of chlorine. Journal of Chemical Health & Safety. 2006; 13(2): 5–11. https://doi.org/10.1016/j.chs.2005.02.005

5. Wiergowski M., Sołtyszewski I., Anand J.S. et al. Difficulties in interpretation when assessing prolonged and subacute exposure to the toxic effects of chlorine. Journal of Forensic and Legal Medicine. 2018; 58: 82–86. https://doi.org/10.1016/j.jflm.2018.05.003

6. Zhou T., Song W.-F., Shang Y. et al. Halogen inhalation‑induced lung injury and acute respiratory distress syndrome. Chin. Med. J. (Engl). 2018; 131(10): 1214–1219. https://doi.org/10.4103/0366-6999.231515

7. Clinical Guidelines in Medical Toxicology. Edited by E.A. Luzhnikov. Moscow: GEOTAR-Media; 2012. 610–630. (in Russian).

8. Medical Toxicology: National Guidelines. In 2 vols. Vol. 2: Special Topics. 2nd ed., revised and expanded. Edited by Yu.S. Goldfarb, M.M. Potskhveriya. Moscow: GEOTAR-Media; 2026: 780–820. https://elibrary.ru/nhksjz (in Russian).

9. Avdeev S.N., Vlasenko A.V., Eremenko A.A., Kirov M.Yu., Lebedinskiy K.M., Leiderman I.N., et al. Acute respiratory distress syndrome (in adult patients). Clinical guidelines (2025 revision). Vestnik intensivnoy terapii im. A.I. Saltanova. 2025; 4: 7–68. https://doi.org/10.21320/1818-474X-2025-4-7-68 https://elibrary.ru/sagidc (in Russian).

10. Bonitenko E.Yu., Isabekov N.R., Tonshin A.A., et al. Use of liquid ventilation for the treatment of toxic pulmonary edema. Medline.ru. 2026; 27: 230–257. https://elibrary.ru/cngfhp (in Russian).

11. Isabekov N.R., Tonshin A.A., Bonitenko E.Yu. Justification of the possibility of using liquid artificial lung ventilation for the treatment of acute respiratory distress syndrome of toxic genesis. Russian Journal of Occupational Health and Industrial Ecology [Med. truda i prom. ekol.]. 2024; 64(8): 506–517. https://doi.org/10.31089/1026-9428-2024-64-8-506-517 https://elibrary.ru/dvgnwe (in Russian).

12. Isabekov N.R., Tonshin A.A., Krikunov O.V., Bonitenko E.Yu. The use of gas-liquid artificial lung ventilation in acute inhalation chlorine poisoning (experimental study). Russian Journal of Occupational Health and Industrial Ecology [Med. truda i prom. ekol.]. 2025; 65(1): 4–17. https://doi.org/10.31089/1026-9428-2025-65-1-4-17 https://elibrary.ru/jqcdps (in Russian).

13. Bonitenko E.U., Kashuro V.A., Basharin V.A. Modeling issues in experimental toxicology and medicine. Zero-order biomodels. Russian Journal of Occupational Health and Industrial Ecology [Med. truda i prom. ekol.]. 2022; 62(11): 718–732. https://doi.org/10.31089/1026-9428-2022-62-11-718-732 https://elibrary.ru/alhmie (in Russian).

14. Bastarache J.A., Blackwell T.S. Development of animal models for the acute respiratory distress syndrome. Dis. Model Mech. 2009; 2(5-6): 218–223. https://doi.org/10.1242/dmm.001677

15. Matute-Bello G., Frevert C.W., Martin T.R. Animal models of acute lung injury. Am. J. Physiol. Cell. Mol. Physiol. 2008; 295(3): L379–L399. https://doi.org/10.1152/ajplung.00010.2008 https://elibrary.ru/qtwnlc

16. White C.W., Martin J.G. Chlorine gas inhalation: human clinical evidence of toxicity and experience in animal models. Proceedings of the American Thoracic Society. 2010; 7(4): 257–263. https://doi.org/10.1513/pats.201001-008sm

17. Pelosi P., D'Onofrio D., Chiumello D. et al. Pulmonary and extrapulmonary acute respiratory distress syndrome are different. European Respiratory Journal. 2003; 22(42): 48s–56s. https://doi.org/10.1183/09031936.03.00420803

18. Ballard-Croft C., Wang D., Sumpter L.R. et al. Large-animal models of acute respiratory distress syndrome. The Annals of Thoracic Surgery. 2012; 93(4): 1331–1339. https://doi.org/10.1016/j.athoracsur.2011.06.107

19. Kamuf J., Garcia-Bardon A., Ziebart F et al. Oleic acid-injection in pigs as a model for acute respiratory distress syndrome. Journal of Visualized Experiments. 2018; 140. https://doi.org/10.3791/57783

20. Bastarache J.A., Blackwell T.S. Development of animal models for the acute respiratory distress syndrome. Disease Models & Mechanisms. 2009; 2(5-6): 218–223. https://doi.org/10.1242/dmm.001677

21. Engel M., Nowarck R.V.E., Jonker E.M. et al. A comparison of four different models of acute respiratory distress syndrome in sheep. Respiratory Research. 2020; 21(1): 209. https://doi.org/10.1186/s12931-020-01475-0 https://elibrary.ru/odoulp

22. Rosenthal C.D.O., Caronia C., Quinn C.R.N. et al. A comparison among animal models of acute lung injury. Crit. Care Med. 1998; 26(5): 912–916. https://doi.org/10.1097/00003246-199805000-00027

23. Castillo R.L., Carrasco Loza R., Romero-Dapueto C. Pathophysiological approaches of acute respiratory distress syndrome: Novel bases for study of lung injury. Open Respir. Med. J. 2015; 9: 83–91. https://doi.org/10.2174/1874306401509010083 https://clck.ru/3VcYux

24. Matute-Bello G., Downey G., Moore B.B. et al. An official American thoracic society workshop report: features and measurements of experimental acute lung injury in animals. Am. J. Respir. Cell. Mol. Biol. 2011; 44: 725–38. https://doi.org/10.1165/rcmb.2009-0210ST

25. Geilen J., Kainz M., Zapletal B. Unilateral acute lung injury in pig: a promising animal model. J. Transl. Med. 2022; 20(1): 548. https://doi.org/10.1186/s12967-022-03753-5 https://elibrary.ru/warlko

26. Reiss L.K., Uhlig U., Uhlig S. Models and mechanisms of acute lung injury caused by direct insults. Eur. J. Cell. Biol. 2012; 91: 590–601. https://doi.org/10.1016/j.ejcb.2011.11.004

27. Batchinsky A.I., Martini D.K., Jordan B., Disk E.J. Acute respiratory distress syndrome secondary to inhalation of chlorine gas in sheep. The Journal of Trauma: Injury, Infection, and Critical Care. 2006;60(5):944–957 https://doi.org/10.1097/01.ta.0000205862.57701.48

28. Tavares A.H., Colby J.K., Levy B.D., Abdulnour R-E.E. A model of self-limited acute lung injury by unilateral intra-bronchial acid instillation. J. Vis. Exp. 2019: 150. https://doi.org/10.3791/60024

29. Alluri R., Kutscher H.L., Mullan B.F. et al. Open tracheostomy gastric acid aspiration murine model of acute lung injury results in maximal acute nonlethal lung injury. J. Vis. Exp. 2017; (120): 54700. https://doi.org/10.3791/54700

30. Jonasson S., Koch B., Bucht A. Inhalation of chlorine causes long-standing lung inflammation and airway hyperresponsiveness in a murine model of chemical-induced lung injury. Toxicology. 2013; 303: 34–42. https://doi.org/10.1016/j.tox.2012.10.022

31. Gunnarsson M., Walther S.M., Seidal T., Bloom G.D., Lennquist S. Exposure to chlorine gas: effects on pulmonary function and morphology in anaesthetised and mechanically ventilated pigs. Journal of Applied Toxicology. 1998; 18(4): 249–255. https://clck.ru/3VcZ9u

32. Musah S., Schlueter C.F., Humphrey D.M. et al. Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation. Toxicology and Applied Pharmacology. 2017; 315: 1–11. https://doi.org/10.1016/j.taap.2016.11.017

33. Setzer F., Schmidt B., Hueter L. et al. Characterization of the seven-day course of pulmonary response following unilateral lung acid injury in rats. PLOS ONE. 2018; 13(6): e0198440. https://doi.org/10.1371/journal.pone.0198440

34. Pakulla M.A., Detlef D.S., Loer O.S.A. Hydrochloric acid-induced lung injury: effects of early partial liquid ventilation on survival rate, gas exchange, and pulmonary neutrophil accumulation. Intensive Care Medicine. 2004; 30(11): 2110–2119. https://doi.org/10.1007/s00134-004-2419-x

35. Zellner T., Eyer F. Choking agents and chlorine gas – History, pathophysiology, clinical effects and treatment. Toxicology Letters. 2020. 320: 73–79. https://doi.org/10.1016/j.toxlet.2019.12.005 https://elibrary.ru/ybtbqb

36. Wheeldon E.B., Walker M.E., Murphy D.J., Turner C.R. Intratracheal aerosolization of endotoxin in the rat: a model of the adult respiratory distress syndrome (ARDS). Laboratory Animals. 1992: 26(1): 29–37. https://doi.org/10.1258/002367792780809020

37. Marinova M. Solopov P., Dimitropoulou C. et al. Acute exposure of mice to hydrochloric acid leads to the development of chronic lung injury and pulmonary fibrosis. Inhalation Toxicology. 2019; 31(4): 147–160. https://doi.org/10.1080/08958378.2019.1624895

38. Samal A., Honovar J., White C.R., Patel R.P. Potential for chlorine gas-induced injury in the extrapulmonary vasculature. Proceedings of the American Thoracic Society. 2010; 7(4): 290–293. https://doi.org/10.1513/pats.201001-006sm

39. Košútová P., Nemcová N., Kolomazník M., et al. A novel rabbit model of severe ARDS: Synergistic effects of acid aspiration and harmful mechanical ventilation. Translational Research. 2025; 281: 43–54. https://doi.org/10.1016/j.trsl.2025.05.009 https://elibrary.ru/psyeba

40. White C.W., James G Martin J.G. Chlorine gas inhalation. Human clinical evidence of toxicity and experience in animal models. Proc. Am. Thorac. Soc. 2010; 7(4): 257–263. https://doi.org/10.1513/pats.201001-008SM

41. Rotar E.P., Haywood N.S., Mehaffey J.H. et al. Gastric aspiration and ventilator-induced model of acute respiratory distress syndrome in swine. J. Surg. Res. 2022; 280: 280–287. https://doi.org/10.1016/j.jss.2022.07.023 https://elibrary.ru/igabbh

42. Chen J., Mo Y., Schlueter C.F., Hoyle G.W. Inhibition of chlorine-induced pulmonary inflammation and edema by mometasone and budesonide. Toxicol. Appl. Pharmacol. 2013; 272(2): 408–413. https://doi.org/10.1016/j.taap.2013.06.009