Prospects for the use of flavonoid substances in pulmonary fibrosis (review of experimental studies) Текст научной статьи по специальности «Клиническая медицина»

South Russian Journal of Cancer. 2024. Vol. 5, No. 4. P. 46-57 4.0

https://doi.org/10.37748/2686-9039-2024-5-4-6

https://elibrary.ru/hfikew

South Russian

Journal of Cancer REVIEW

Южно-Российский

онкологический журнал

Vol. 5

No. 4, 2024 Prospects for the use of flavonoid substances in pulmonary fibrosis

(review of experimental studies)

E. A. Gubareva, A. L. Semenov

N. N. Petrov National Medicine Research Center of Oncology, St. Petersburg, Russian Federation

 [email protected]

ABSTRACT

Pulmonary fibrosis develops both spontaneously and as a result of lung damage by radiotherapy and chemotherapy, infectious

diseases, and inhalation of harmful substances and particulate matter. In this case, normal tissue repair is disturbed: instead

of regeneration of normal lung cells, the damaged tissue is replaced by fibrotic one consisting of dense collagen fibers. This

leads to loss of lung tissue elasticity and impairment of its function, which significantly reduces the quality of patients’ lives.

The search for drugs for interstitial fibrotic lung diseases remains an urgent task, since the existing antifibrotic drugs only

slow down disease progression and have side effects that significantly reduce the patients’ quality of life. It is believed that

natural polyphenolic substances, in particular flavonoids, can be used for the treatment of pulmonary fibrosis. Flavonoids

present in various fruits, vegetables, tea and wine show a wide range of biological activities. They have antioxidant, anti-in-

flammatory and immunomodulatory properties, making them promising for the treatment of various diseases, including

pulmonary fibrosis. Some studies have shown that flavonoids can inhibit myofibroblast activation and collagen production,

which is directly related to the fibrotic process. Flavonoids are safe and can influence the hallmarks of fibrosis: oxidative stress,

inflammation, cell proliferation and differentiation. To date, a large amount of experimental data confirming the antifibrotic

effect of flavonoids has been accumulated. In recent years, clinical studies have been conducted to investigate the efficacy

and safety of flavonoids in patients with pulmonary fibrosis. For example, quercetin and curcumin are being explored and

have shown encouraging results in reducing markers of inflammation and fibrosis in the lung. However, the main obstacle

to the widespread introduction of flavonoid substances into clinical practice remains their low oral bioavailability and rapid

metabolism. The experimental data on the effect of flavonoids on the development of pulmonary fibrosis is analyzed in this

review. The perspectives for improving their bioavailability using modern delivery systems (nanoparticles, liposomes, etc.),

as well as dosage forms for topical application, are discussed in this paperwork.

Keywords: pulmonary fibrosis, flavonoids, experimental models

For citation: Gubareva E. A., Semenov A. L. Prospects for the use of flavonoid substances in pulmonary fibrosis (review of experimental studies). South

Russian Journal of Cancer. 2024; 5(4): 46-57. https://doi.org/10.37748/2686-9039-2024-5-4-6, https://elibrary.ru/hfikew

For correspondence: Ekaterina A. Gubareva – Cand. Sci. (Biol.), senior researcher, N. N. Petrov National Medicine Research Center for Oncology,

St. Petersburg, Russian Federation

Address: 68 Leningradskaya str., Pesochny settlement, Saint Petersburg 197758, Russian Federation

E-mail: [email protected]

ORCID: https://orcid.org/ 0000-0002-9212-6086

SPIN: 5556-8242, AuthorID: 895429

ResearcherID: AAD-2072-2020

Scopus Author ID: 56909987000

Funding: the project was supported by RSF grant No. 22-25-20177 and RSF (St. Petersburg Science Foundation) grant No. 50/2022

Conflict of interest: the authors declare that there are no obvious and potential conflicts of interest associated with the publication of this article

The article was submitted 07.11.2023; approved after reviewing 20.07.2024; accepted for publication 28.10.2024

© Gubareva E. A., Semenov A. L., 2024

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Южно-Российский онкологический журнал. 2024. Т. 5, № 4. С. 46-57

https://doi.org/10.37748/2686-9039-2024-5-4-6

https://elibrary.ru/hfikew

3.1.6. Онкология, лучевая терапия

ОБЗОР

Перспективы применения веществ флавоноидного ряда при фиброзе легкого

(обзор экспериментальных исследований)

Е. А. Губарева, А. Л. Семенов

ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Петрова» Министерства здравоохранения Российской

Федерации, г. Санкт-Петербург, Российская Федерация

 [email protected]

РЕЗЮМЕ

Фиброз легкого развивается как спонтанно, так и вследствие воздействия повреждающих факторов, включая лучевую

и химиотерапию, инфекционные заболевания, вдыхание вредных веществ и твердых частиц. При этом происходит

нарушение нормальной репарации тканей: вместо регенерации нормальных клеток легкого происходит замещение

поврежденной ткани фиброзной, состоящей из плотных коллагеновых волокон. Этот процесс ведет к утрате эла-

стичности легочной ткани и нарушению ее функции, что существенно снижает качество жизни пациентов. Поиск

средств для лечения интерстициальных фиброзирующих заболеваний легкого остается актуальной задачей, т. к.

существующие антифибротические препараты лишь замедляют их прогрессирование и обладают побочными эф-

фектами, существенно снижающими качество жизни пациентов. Считается, что природные вещества полифенольной

природы, в частности, флавоноиды, могут применяться для лечения фиброза легкого. Флавоноиды, присутствующие

в различных фруктах, овощах, чае и вине, демонстрируют широкий спектр биологических активностей. Они обладают

антиоксидантными, противовоспалительными и иммуномодулирующими свой ствами, что делает их перспективными

для лечения различных заболеваний, включая фиброз легкого. Некоторые исследования показали, что флавоноиды

могут ингибировать активацию миофибробластов и продукцию коллагена, что непосредственно связано с процессом

фиброзирования. Флавоноиды нетоксичны и способны регулировать процессы, связанные с развитием фиброза:

окислительный стресс, воспаление, пролиферацию и дифференцировку клеток. На сегодняшний день накоплено

большое количество экспериментальных данных, подтверждающих антифибротическое действие флавоноидов.

В последние годы проводятся клинические исследования, направленные на изучение эффективности и безопасности

флавоноидов у пациентов с фиброзом легкого. Например, исследуются кверцетин и куркумин, которые показали

обнадеживающие результаты в снижении маркеров воспаления и фиброза в легких. Однако основным препятствием

для широкого внедрения флавоноидных веществ в клиническую практику остается их низкая биодоступность при

пероральном применении и быстрый метаболизм. В данной работе проанализированы данные литературы о вли-

янии флавоноидов на развитие фиброза легкого в экспериментах и в клинических исследованиях, обсуждаются

перспективы улучшения их биодоступности с помощью современных систем доставки (наночастицы, липосомы

и др.), или использования лекарственных форм для местного применения.

Ключевые слова: фиброз легкого, флавоноиды, экспериментальные модели

Для цитирования: Губарева Е. А., Семенов А. Л. Перспективы применения веществ флавоноидного ряда при фиброзе легкого (обзор

экспериментальных исследований). Южно-Российский онкологический журнал. 2024; 5(4): 46-57. https://doi.org/10.37748/2686-9039-2024-5-4-6,

https://elibrary.ru/hfikew

Для корреспонденции: Губарева Екатерина Александровна – к.б.н., старший научный сотрудник, ФГБУ «Национальный медицинский

исследовательский центр онкологии имени Н. Н. Петрова» Министерства здравоохранения Российской Федерации, г. Санкт-Петербург,

Российская Федерация

Адрес: 197758, Российская Федерация, г. Санкт-Петербург, п. Песочный, ул. Ленинградская, д. 68

E-mail: [email protected]

ORCID: https://orcid.org/0000-0002-9212-6086

SPIN: 5556-8242, AuthorID: 895429

ResearcherID: AAD-2072-2020

Scopus Author ID: 56909987000

Финансирование: финансирование работа была поддержана грантом РНФ № 22-25-20177 и грантом РНФ (Санкт-Петербургский научный фонд)

№ 50/2022

Конфликт интересов: все авторы заявляют об отсутствии явных и потенциальных конфликтов интересов, связанных с публикацией настоящей статьи

Статья поступила в редакцию 07.11.2023; одобрена после рецензирования 20.07.2024; принята к публикации 28.10.2024

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Gubareva E. A., Semenov A. L. Prospects for the use of flavonoid substances in pulmonary fibrosis (review of experimental studies)

INTRODUCTION interstitial pneumonia, chronic pneumonitis on the

background of hypersensitivity), because of viral and

The spectrum of interstitial fibrotic lung diseas- bacterial infections. These diseases are designat-

es is quite wide, but all of them lead to a gradual ed as chronic interstitial fibrotic lung diseases with

decrease in respiratory function, a significant de- a progressive course [11]. IPF, interstitial pneumonia,

crease in the quality of patients’ life and prema- is isolated as a separate disease without clarified

ture death [1]. Life expectancy after diagnosis in etiological factors [1]. Risk factors for the develop-

idiopathic pulmonary fibrosis (IPF) is on average ment of IPF include smoking, inhalation of particu-

3–5 years [2], and the average five-year survival rate late substances, viral infections, gastroesophageal

for this disease is 45.6 % [3]. Existing treatment reflux syndrome, genetic predisposition, the use of

methods and registered antifibrotic drugs some- certain medications, ionizing radiation [2, 12].

what slow down the progression of the disease and In this paperwork, we will use the term "pulmonary

reduce the mortality rate, but have contraindications fibrosis" in relation to all progressive fibrotic intersti-

and side effects, so their long-term use is not al- tial lung diseases, with clarifications if necessary.

ways possible [4, 5]. Since the disease can occur The incidence of diseases in which PF occurs

for several years, finding drugs that can slow down is relatively low. According to a 2021 study, the in-

or stop the progression of pulmonary fibrosis (PF) cidence of IPF (per 100,000 population per year)

and are safe with long-term use, is an urgent task. ranged from 3.5 to 13 in the Asia- Pacific region, from

In recent years, much attention has been paid in this 0.9 to 4.9 in Europe and from 7.5 to 9.3 in North

regard to natural substances of polyphenolic nature, America [11]. In Russia, during 2018, an average of

in particular, flavonoids. 7 new cases of IPF per 100,000 people per year were

These substances are found in various parts of registered in women and 11 in men [2].

plants and are an important component of tradition- The incidence of other fibrosing interstitial lung

al medicine and functional nutrition [6]. Flavonoids diseases in the United States is about 52 patients

are nontoxic and are able to regulate the processes per 100,000 people per year, of which 33 cases are

involved in the development of fibrosis: oxidative with a progressive phenotype [14]. It is assumed that

stress, inflammation, cell proliferation and differen- after the SARS-CoV19 epidemic, these figures may

tiation (in particular, epithelial- mesenchymal tran- increase: after the coronavirus infection is cured,

sition), intercellular interactions [7, 8]. To the date, some patients experience a decrease in respirato-

a substantial experimental evidence base has been ry function and changes in the X-ray picture of the

accumulated justifying the use of flavonoids as anti- lungs, similar to that of PF [15].

fibrotic agents. In addition, several pilot clinical trials Normally, epithelial damage is repaired by type

have been conducted on patients with IPF [9, 10]. II alveolocytes, capable of proliferating and dif-

However, their low bioavailability prevents the wide- ferentiating into type I alveolocytes, which line

spread introduction of flavonoid substances into clin- most of the surface of the alveoli and carry out

ical practice. In this regard, the prospects of using gas exchange. At the same time, in the places of

dosage forms for topical use are being considered. damage, epithelial cells secrete profibrotic factors

The purpose of the study was to analyze the liter- that cause the activation of resident fibroblasts

ature data on the effect of flavonoid substances on and their differentiation into myofibroblasts [16].

the development of lung fibrosis in experiments with Myofibroblasts are also formed from circulating

laboratory animals and in clinical studies, to identify bone marrow precursors, epithelial and endothe-

prospects for increasing their bioavailability using lial cells [17]. The main function of these cells is

modern delivery systems. the synthesis of the intercellular matrix, which is

necessary for tissue repair at the site of injury, af-

Pulmonary fibrosis: risk factors, occurrence, ter which they normally undergo apoptosis, and

main mechanisms of pathogenesis the excess extracellular matrix is cleaved [18]. The

PF can occur as a manifestation of certain sys- literature describes several mechanisms that can

temic diseases (systemic sclerosis, rheumatoid ar- interfere with the normal resolution of the repara-

thritis, etc.), interstitial lung diseases (nonspecific tive process.

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Губарева Е. А., Семенов А. Л. Перспективы применения веществ флавоноидного ряда при фиброзе легкого (обзор экспериментальных исследований)

Many authors consider excessive activation of the increased mortality and hospitalization rates [4].

immune system and chronic inflammation to be the Two drugs have been registered for the treatment

main factors in the development of PF [2, 19]. It has of IPF – nintedanib, an oral inhibitor of intracellu-

been shown that various cells of the immune system, lar tyrosine kinases, and pirfenidone, a pyridone

e. g. neutrophils, macrophages, lymphocytes, contrib- compound with anti-inflammatory, antifibrotic and

ute to the development of PF due to the activation antioxidant properties [4]. Both drugs reduce the

of oxidative stress and the production of profibrotic risk of mortality by almost 2 times, and quintedanib

growth factors, cytokines and chemokines [2, 20]. It also significantly reduces the risk of acute compli-

is assumed that activation of the immune response cations compared with patients who do not take

makes a significant contribution to the development drugs [29]. Nintedanib and pirfenidone have been

of PF associated with COVID-19 [15]. recognized as effective for other fibrotizing lung

The mechanism of PF development is also de- diseases [1, 11]. Nevertheless, the long-term use of

scribed, in which the main role is given to the chronic these drugs often becomes impossible due to the

epithelial damage, leading to an increase in the level refusal of treatment due to the lack of effect and/

of reactive oxygen species, apoptosis, activation of or side effects [4, 5, 28].

cellular aging, depletion of the stem cell pool and the To date, antibodies to the connective tissue

so-called "phenotypic reprogramming" of the type growth factor (CTGF), pentraxin-2, an endothelin

II alveolocytes [16, 21], i. e. aberrant activation of receptor antagonist, new small molecules (inhibi-

normal repair pathways and the release of mediators tors of autotaxin phosphodiesterase, integrins, etc.),

activating fibroblasts [22, 23]. and others are being studied as potential antifibrotic

Another mechanism of tissue fibrotization is be- drugs (check reviews [4, 30] for details).

ing considered due to positive feedback from the The prospects for the use of substances of natural

extracellular matrix [24]. It has been shown that origin, in particular, flavonoids, are discussed, since

with excessive deposition of the matrix, its densi- such compounds have anti-inflammatory, antiprolif-

fication occurs, which leads to tissue hypoxia and erative and immunomodulatory effects, as well as

epithelial damage; the compacted matrix creates low toxicity and can be used long-term. In addition,

a profibrotic environment and promotes cellular flavonoids (and polyphenols in general) reduce the

aging [25, 26]. Thus, a so-called "fibrogenic niche" toxicity of cytostatics, for example, cyclophospha-

is created, and the fibrotic process is self-sus- mide, which is used in patients with PF as an immu-

taining [24]. Shochet et al. [27] showed that while nosuppressant.

culturing normal fibroblasts on a "fibrotic" matrix In a pilot study carried out on patients with IPF,

obtained after culturing fibroblasts of patients with it was shown that after 14 days of EGCG

IPF (IPF), the expression of genes associated with (epigallocatechin gallate, the most common catechin

the HIF1 signaling pathway is activated, which con- found in tea), the content of two biomarkers pro-

tributes to the differentiation of myofibroblasts and duced by fibroblasts, cartilage oligomeric matrixpro-

the progression of fibrosis. tein (COMP) and periostin, was reduced in serum, as

well as collagen I in lung biopsies, SNAI1, phosphory-

Pulmonary fibrosis treatment lated SMAD3 [9]. The same team of authors showed

Medicinal and non-medicinal methods are used to that in ex vivo lung tissue obtained from patients

treat PF. The latest ones include lung transplantation undergoing lung transplantation, EGCG suppresses

and the use of palliative methods (oxygen therapy, the TGF-β1 signaling cascade and collagen accu-

physical exercises, etc.) [28]. mulation, as well as activates its MMP-dependent

Initially, anti-inflammatory drugs, corticosteroids decay [31].

and immunosuppressive drugs were used to treat In pilot trials on patients with IPF, it was shown

IPF, based on the hypothesis that chronic inflam- that physical performance improved in the group

mation is the main mechanism of development of of people taking a combination of dasatinib and

this disease. These drugs did not improve surviv- quercitin. In addition, a decrease in the level of

al and pulmonary function, and combined therapy some markers of cellular aging in the blood was

with prednisone, azathioprine and N-acetylcysteine noted [10].

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Gubareva E. A., Semenov A. L. Prospects for the use of flavonoid substances in pulmonary fibrosis (review of experimental studies)

The use of flavonoids in experiments on contribute to a decrease in the production of profi-

laboratory animals brotic cytokines in the lung: TGF-β [41–43] and proin-

To study PF using laboratory animals, a wide flammatory cytokines [35, 39, 42, 44]. The positive

range of models are used that reproduce the ef- effect of the studied substances on the activity of

fect of the main etiological factors of disease de- enzymes of the antioxidant defense system and a de-

velopment, i. e. genetic predisposition, drug use, crease in markers of oxidative stress were found [35,

radiation, inhalation of solid particles [19, 32]. If 36, 43, 44]. Despite the fact that the antifibrotic effect

experiments with genetically modified or immuno- of flavonoids has been studied in several experimen-

deficient mice help to better understand the molec- tal models, and the range of techniques used and the

ular genetic mechanisms of PF development, then estimated indicators differed, the results of these

cheaper and more convenient models of fibrosis studies show that flavonoids are able to affect the

induction using tissue- damaging light chemical main mechanisms/aspects of fibrogenesis in vivo.

agents, solid particles or irradiation are most of- The results of animal experiments are supported

ten chosen for screening potential antifibrotic by data obtained in experiments using flavonoids

drugs [32]. The most commonly used well–char- in vitro. Thus, baicalin has been shown to reduce the

acterized PF model using bleomycin, systemic ad- proliferation of rat pulmonary fibroblasts induced by

ministration of which leads to damage to the lung bleomycin [45].

endothelium, inflammation, apoptosis of epithelial Flavonoids also have a protective effect on mod-

cells and the launch of reparative processes, and els of chronic obstructive pulmonary disease in-

local – directly into the respiratory tract causes duced by cigarette smoke or its components. The

direct damage to the alveolar and bronchial epi- observed effects of flavonoids are consistent with

thelium, followed by pronounced inflammation and the results obtained in lung fibrosis models: these

tissue fibrosing [33]. substances reduce inflammation, activate antioxi-

The relevance of these models is being discussed, dant defense mechanisms, and prevent cellular aging

however, they reproduce the main aspects of fibrotiz- and cell death of the alveolar epithelium [46].

ing lung diseases in humans at the tissue (excessive Nevertheless, such experimental studies have

deposition of extracellular matrix, decrease in respi- been conducted for more than 10 years, and clinical

ratory volume), cellular (epithelial damage, fibroblast studies remain isolated.

proliferation, epithelial- mesenchymal transition) and Thus, there is a significant gap between the stages

molecular (oxidative stress, secretion of profibrotic of preclinical development and clinical trials for this

factors) levels. class of compounds.

Table 1 shows studies over the past 5 years that

studied the effect of individual flavonoid compounds Prospects for the use of flavonoids for the

on the development of experimental lung fibrosis in treatment of lung fibrosis

mice and rats. In almost all the analyzed studies, it The probable reason for the slow introduction of

was shown that the use of flavonoid-type substanc- flavonoid preparations into clinical practice, in addi-

es reduces the severity of PF at the morphological tion to the difficulties of standardization and com-

level; in two studies, no statistically significant de- mercial component, may be the limited bioavailability

crease in the histopathological index [34] and rel- of flavonoids.

ative lung mass [35] was revealed when quercetin Unlike other molecules included in the compo-

was used, however, the drug influenced other stud- sition of drugs, flavonoids in unchanged form do

ied indicators. not reach target organs when administered orally.

Compared with untreated animals, the use of When ingested in the form of aglycones, flavonoids

flavonoids in the lungs reduces the synthesis of undergo metabolic transformation in the intestine

extracellular matrix proteins such as collagen and (including with the participation of microorgan-

fibronectin [34, 36–38], the content of the myofibro- isms) and the liver; the initial forms are practically

blast marker α-S MA and markers of the epithelial- not detected in blood plasma [54]. The antioxidant

mesenchymal transition [37, 39, 40]. It was also re- activity of conjugated products entering the sys-

vealed in experiments that flavonoid preparations temic circulation after methylation, sulfation and

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Губарева Е. А., Семенов А. Л. Перспективы применения веществ флавоноидного ряда при фиброзе легкого (обзор экспериментальных исследований)

Table 1. Flavonoid-type substances with proven in vivo antifibrotic activity

Substance formula Substance Model Reference

C57BL/6 mice; IT bleomycin [34]

Quercetin Mice, SiO2 [47]

Wistar rats; IT bleomycin [35]

Dihydroquercetin C57BL/6 rats; IT SiO2 [48]

Cyanidine C57BL/6 mice; IT SiO2 [49]

Calicosin C57BL/6 mice, IT bleomycin [36]

Hesperidin Sprague-Dawley Rats; IP bleomycin [42]

Hesperidin Wistar rats; IT SiO2 [44]

Epicatechin NMRI mice; IT bleomycin [43]

C57BL/6 mice;

solid particles intranasally [50]

Epigallocatechin gallate

Wistar rats; IT SiO2 [51]

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Gubareva E. A., Semenov A. L. Prospects for the use of flavonoid substances in pulmonary fibrosis (review of experimental studies)

Table 1. Flavonoid-type substances with proven in vivo antifibrotic activity

Substance formula Substance Model Reference

Isoramnetin C57BL/6 mice; IP bleomycin [37]

Baikal Wistar rats; IT bleomycin [45]

Yuglanin C57BL/6 mice; IT bleomycin [40]

Galangin C57BL/6 mice; IT bleomycin [52]

Dihydromyricetin C57BL/6 mice; IT bleomycin [39]

Naringenin Balb/c mice; Mycoplasma infection [53]

Biochanin А Wistar rats; IT bleomycin [38]

Notes: IT stands for intratracheal, IP stands for intraperitoneal

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Губарева Е. А., Семенов А. Л. Перспективы применения веществ флавоноидного ряда при фиброзе легкого (обзор экспериментальных исследований)

glucuronidation is significantly reduced compared The bioavailability of naringenin complexes with

to that of the corresponding aglycones [7]; metab- hydroxypropyl-β-cyclodextrin was studied in vivo. It

olites are rapidly excreted from the body. It is more was found that the solubility of the flavonoid in the

likely that flavonoids, more precisely, the products complex increases, and with intratracheal applica-

of their metabolism, are able to activate the anti- tion, naringenin accumulates mainly in the lung [58].

oxidant defense system through the KEAP1-NRF2 It has also been shown that the bioavailability of

pathway, which regulates the adaptive response to naringenin in solid lipid particles is 2.5 times higher

cellular stress [8]. than in free form when administered intratrache-

Obviously, in order to increase the activity of fla- al [59]. The effectiveness of naringenin-l oaded phyto-

vonoids, it is necessary to provide ways and forms ses based on the surfactant component dipalmitoyl

of administration that will avoid or minimize meta- phosphatidylcholine was demonstrated in a model

bolic transformation in the intestine and liver. For the of acute lung injury in rats [60].

treatment of PF, these may be options for inhalation Thus, the use of flavonoids in the composition of

use or taking flavonoids in complexes with carriers. nanoparticles, liposomes and other carriers, includ-

Such delivery systems include phytosomes (com- ing in the form of inhaled dosage forms, makes it

plexes of plant substances with phospholipids), lipid possible to improve their bioavailability, as well as

nanoparticles, polymer nanoparticles, and inorganic ensure the delivery of starting substances to the

nanoparticles [7]. lung, rather than products of their metabolism.

In particular, after administration of quercetin

to mice as part of cationic lipid carriers, its higher CONCLUSION

content was observed in the lung, liver and kidneys

compared with the control group that received free Treatment of PF remains an urgent problem,

quercetin [55]. It was shown that apigenin more ef- because existing drugs only slow down the pro-

fectively inhibited the development of bleomycin- gression of this deadly disease, and their long-term

induced lung fibrosis in rats when it was adminis- use is often associated with serious side effects.

tered to animals as part of polymer nanoparticles, In recent years, natural substances, in particular,

compared with the substance in free form [56] flavonoids, have been studied as an alternative or

The use of dosage forms for inhalation has a num- accompanying therapy. Numerous animal and in

ber of advantages, such as the delivery of active sub- vitro studies prove that flavonoids have antifibrotic

stances directly to the lung, a relatively low content properties. At the same time, due to the peculiari-

of substances in the systemic circulation, and ease ties of the metabolism of these substances in the

of use [57]. In rats with induced PF, inhalation of pir- mammalian body, with oral administration of flavo-

fenidone or quintedanib gave the same therapeutic noids, they enter the lung only in small amounts in

effect as oral administration, while the dose with the form of secondary metabolites. The solution

topical application and, accordingly, the manifesta- to this problem may be the development of deliv-

tions of side effects were significantly lower Rasooli ery systems such as liposomes, as well as dosage

et al. 2018; Surber et al. 2020, cit. according to [57]). forms for topical use.

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Губарева Е. А., Семенов А. Л. Перспективы применения веществ флавоноидного ряда при фиброзе легкого (обзор экспериментальных исследований)

Information about authors:

Ekaterina A. Gubareva  – Cand. Sci. (Biol.), senior researcher, N. N. Petrov National Medicine Research Center of Oncology, St. Petersburg,

Russian Federation

ORCID: https://orcid.org/0000-0002-9212-6086, SPIN: 5556-8242, AuthorID: 895429, ResearcherID: AAD-2072-2020, Scopus Author ID: 56909987000

Alexander L. Semenov – Cand. Sci. (Med.), MD, senior researcher, N. N. Petrov National Medicine Research Center of Oncology, St. Petersburg,

Russian Federation

ORCID: https://orcid.org/0000-0002-5190-0629, SPIN: 4301-8679, AuthorID: 900704, ResearcherID: S-1484-2016, Scopus Author ID: 16307589600

Contribution of the authors:

Gubareva E. A. – article concept, writing source text, collecting material, article design;

Semenov A. L. – text revision, scientific and technical editing.

57