Liposomal form of dexamethasone in the correction of experimental acute lung injury

Objective. To investigate the possibility of pharmacological correction of acute lung injury of aspiration genesis with a liposomal form of dexamethasone in experiment.

Materials and methods. For the experiment, simple liposomes were prepared from phosphatidylcholine and cholesterol with an average size of 320±50 nm and a dexamethasone concentration of 2.98±0.02 mg/ml. The study used outbred white rats, divided into four groups of 16 animals. 1^st group Control (without experimental therapy), 2^nd group - Experiment 1, where a solution of dexamethasone was injected intravenously at a dose of 6 mg/kg, 3^rd group - Experiment 2, where an intravenous combination of dexamethasone solution (6 mg/kg) and hypertonic (7.5%) NaCl solution was administered once, and group 4 - Experiment 3, where liposomes with dexamethasone (6 mg/kg) were injected intravenously once in hypertensive (7.5%) NaCl solution. The main functional parameters of the animals (heart rate, blood pressure, saturation of hemoglobin with oxygen, partial pressure of blood oxygen and respiration rate) were subject to analysis. Functional parameters were analyzed before modeling acute lung injury and after 5 min, 1, 4, 24 hours, and 6 days. At the end of the experiment (day 6) the degree of pulmonary edema and histological signs of acute lung injury were assessed. Morphology was assessed quantitatively in each group.

Results. The study found that liposomal dexamethasone in hypertonic NaCl solution, when administered intravenously, was more effective than aqueous dexamethasone solution in correcting functional impairment in acute lung injury. The combination of hypertonic sodium chloride solution with dexamethasone more markedly increases blood pressure and reduces the degree of pulmonary oedema. In acidine pepsin aspiration, liposomal dexamethasone in hypertonic NaCl solution most effectively increased animal survival.

Conclusion. Compared with dexamethasone in hypertonic NaCl solution, liposomal dexamethasone is more effective in increasing animal survival and protecting lung tissue from aspiration damage by acidine pepsin.

1. Grippi M.A. Pulmonary pathophysiology. Moscow: Binom, St. Petersburg: Nevskiy dialekt, 2001. 318 p. (in Russ.)

2. Gushchin Ya.I., Muzhikyan A.A. Effect of different methods of euthanasia on lung histology of small laboratory animals. International bulletin of Veterinary Medicine. 2014;(4):96-104 (in Russ.)

3. Kassil’ V.L., Sapicheva Yu.Yu. Acute respiratory distress syndrome and hypoxemia. 2nd ed. Moscow: MEDpress-inform, 2016. 144 p. (in Russ.)

4. Kulikov O.A. Production and analysis of the nanosomal drug form of dexamethasone in a hyperosmolar aqueous medium. Problems of Biological, Medical and Pharmaceutical Chemistry. 2017;20(6):24-27 (in Russ.)

5. Moroz V.V., Golubev A.M., Marchenkov Yu.V., Gorodovikova Yu.A., Zorina Yu.G., Lysenko D.V., Sundukov D.V., Shaman P. Morphological signs of acute lung injury of varying etiology (experimental study). General Reanimatology. 2010;6(3):2-34 (in Russ.). DOI: 10.15360/1813-9779-2010-3-29

6. Brenner J.S., Kiseleva R.Y., Glassman P.M., Parhiz H., Greineder C.F., Hood E.D., Shuvaev V.V., Muzykantov V.R. The new frontiers of the targeted interventions in the pulmonary vasculature: precision and safety (2017 Grover Conference Series). Pulm Circ. 2018;8(1):2045893217752329. DOI: 10.1177/2045893217752329

7. Chen X.Y., Wang S.M., Li N., Hu Y., Zhang Y., Xu J.F., Li X., Ren J. et al. Creation of lung-targeted dexamethasone immunoliposome and its therapeutic effect on bleomycin-induced lung injury in rats. PLoS One. 2013;8(3):e58275. DOI: 10.1371/journal.pone.0058275

8. Galvão A.M., Galvão J.S., Pereira M.A., Cadena P.G., Magalhães N.S., Fink J.B., de Andrade A.D., Castro C.M. et al. Cationic liposomes containing antioxidants reduces pulmonary injury in experimental model of sepsis: Liposomes antioxidants reduces pulmonary damage. Respir Physiol Neurobiol. 2016;(231):55-62. DOI: 10.1016/j.resp.2016.06.001

9. Holms C.A., Otsuki D.A., Kahvegian M., Massoco C.O., Fantoni D.T., Gutierrez P.S., Auler Junior J.O. Effect of hypertonic saline treatment on the inflammatory response after hydrochloric acid-induced lung injury in pigs. Clinics (Sao Paulo). 2015;70(8):577-583. DOI: 10.6061/clinics/2015(08)08

10. Roch A., Hraiech S., Dizier S., Papazian L. Pharmacological interventions in acute respiratory distress syndrome. Ann Intensive Care. 2013;3(1):20. DOI: 10.1186/2110-5820-3-20

11. Shen W., Gan J., Xu S., Jiang G., Wu H. Penehyclidine hydrochloride attenuates LPS-induced acute lung injury involvement of NF-kappaB pathway. Pharmacol Res. 2009;60(4):296-302. DOI: 10.1016/j.phrs.2009.04.007

12. Wei Y., Liang J., Zheng X., Pi C., Liu H., Yang H., Zou Y., Ye Y. et al. Lung-targeting drug delivery system of baicalin-loaded nanoliposomes: development, biodistribution in rabbits, and pharmacodynamics in nude mice bearing orthotopic human lung cancer. Int J Nanomedicine. 2016;(12):251-261. DOI: 10.2147/IJN.S119895

13. Yoo J.W., Ju S., Lee S.J., Cho M.C., Cho Y.J., Jeong Y.Y., Lee J.D., Kim H.C. Characteristics and Outcomes of Patients with Pulmonary Acute Respiratory Distress Syndrome Infected with Influenza versus Other Respiratory Viruses. Tuberc Respir Dis (Seoul). 2019;82(4):328-334. DOI: 10.4046/trd.2019.0017