Radiation-induced lung injury. Literature review Текст научной статьи по специальности «Клиническая медицина»

Received: 2 November 2016 / Accepted: 22 November 2016 / Published online: 30 December 2016 UDC 616-091/—092.19+616.24+614.876

RADIATION-INDUCED LUNG INJURY. LITERATURE REVIEW

Darkhan E. Uzbekov1, http://orcid.org/0000—0003—4399—460X Masaharu Hoshi2, http://orcid.org/0000—0001—6978—0883 Nailya Zh. Chaizhunusova3, http://orcid.org/0000—0002—6660—7118 Dariya M. Shabdarbaevai, http://orcid.org/0000—0001—9463—1935 Nurlan B. Sayakenovi, http://orcid.org/0000—0002—5082—7554

Semey State Medical University, 1 Department of Pathological anatomy and Forensic medicine, 3 Department of Nutrition and Hygienic disciplines, Semey, Kazakhstan; 2 Hiroshima University, Research Institute for Radiation Biology and Medicine, Hiroshima, Japan

Abstract

Introduction. Despite the numerous data about results of morphological studies of lungs at the cellular and tissue levels in different radiation situations, and also regarding connection assessment of increasing bronchopulmonary diseases with the values of external and internal doses exposure during acute and long-term periods, hitherto not fully explored the association revealed pulmonary disorders with exposure to y- and neutron radiation effects, it is not fully proven the value of radiation dose and duration of radiation influence on the nature of detectable pathology, there are no systemic data about morphogenesis of their damaging effect on the lungs.

The review purpose was to analysis of the literature regarding the nature of morphofunctional disorders in the lungs during exposed to radiation of different levels and types.

Materials and methods. To achieve this purpose we have searched and analysis of scientific publications. All received working to the review formation has been indexed in the databases PubMed, Medline, E—library, Cyberleninka using «Google Scholar» scientific search engine. The following search filters have been delivered before the start of the search: experimental studies carried out on mice and rats, for the past 10 years, published in English, Japanese and Russian languages, as well as full versions of papers with legibly formulated and statistically proven conclusions. Exclusion criteria included a review of publications became summary reports, newspaper articles and personal notifications.

Results. Analysis of published data showed that radiation—induced lung injury defined by the defeat by bronchial lesion, causing the development of atelectasis with subsequent connective tissue organization, serous—fibrinous alveolitis with epithelial desquamation, vascular damage and endothelial proliferation, increased vascular permeability with excretion of plasmatic proteins. It should be noted that the secondary immunodeficiency condition, developing under the influence of radiation factor are realization of pathogenetic mechanisms that contributes to formation of inflammatory and fibrotic processes in the lungs, inducing development of acute inflammatory infiltrative pneumonitis and chronic fibrosing pneumonitis.

Conclusion. The findings data support a role of ionizing radiation in the formation of morphological signs of the radiation—induced pneumonitis and pulmonary fibrosis which are form of lung damage depending on both the dose and type of radiation. According to result of majority of leading research in the field of radiology regarding the assessment of neutron radiation effect on the lungs, there is no consensus. Thus, radiobiologists and morphologists have opportunity to continue studies concerning neutron radiation effects, moreover to evaluate and compare the degree of pulmonary structural changes, which will develop diagnostic criteria for the study of persons' lungs exposed to different types of ionizing radiation.

Keywords: ionizing radiation, pulmonary pathology, morphofunctional changes, pro-inflammatory mediators, lung fibrosis.

Резюме

РАДИАЦИОННО-ИНДУЦИРОВАННЫЕ ПОВРЕЖДЕНИЯ ЛЕГКИХ. ОБЗОР ЛИТЕРАТУРЫ

Дархан Е. Узбеков1, http://orcid.org/0000-0003-4399-460X Масахару Хоши2, http://orcid.org/0000-0001-6978-0883 Найля Ж. Чайжунусова3, http://orcid.org/0000-0002-6660-7118 Дария М. Шабдарбаева1, http://orcid.org/0000-0001-9463-1935 Нурлан Б. Саякенов1, http://orcid.org/0000-0002-5082-7554

Государственный медицинский университет города Семей, 1 Кафедра патологической анатомии и судебной медицины, 3 Кафедра питания и гигиенических дисциплин, г. Семей, Казахстан;

2 Университет Хиросима, Научно-исследовательский институт радиационной биологии и медицины, г. Хиросима, Япония.

Введение. Несмотря на существующие многочисленные данные по результатам морфологических исследований легких на клеточном и тканевом уровнях в различных радиационных ситуациях, по оценке связи увеличения бронхолегочных заболеваний с величинами доз внешнего и внутреннего облучения в остром и отдалённом периодах, до настоящего времени не до конца изучена связь выявленных легочных нарушений с воздействием y- и нейтронного излучения, не полностью доказано значение дозовых нагрузок и длительности радиационного влияния на характер выявляемой патологии, отсутствуют системные данные о морфогенезе их повреждающего действия на легкие.

Целью обзора явился анализ литературы о характере морфофункциональных расстройств в легких при разных уровнях и типах радиационного воздействия.

Материалы и методы исследования. Для достижения поставленной цели нами проведен поиск и анализ научных публикаций. Все принятые к формированию обзора работы были индексированы в базах данных PubMed, Medline, E—library, Cyberleninka при помощи научной поисковой системы «Google Scholar». Перед началом поиска были выставлены следующие поисковые фильтры: экспериментальные исследования, выполненные на мышах и крысах, в течение последних 10 лет, опубликованные на английском, японском и русском языках, а также полные версии статей с чётко сформулированными и статистически доказанными выводами. Критериями исключения публикаций в обзор стали резюме докладов, газетные публикации и личные сообщения.

Результаты. Анализ литературных данных показал, что радиационно—индуцированные повреждения легких определяются поражением бронхов, вызывающем развитие ателектазов с последующей соединительнотканной организацией, серозно—фибринозным альвеолитом с десквамацией эпителия, поражением сосудов, с пролиферацией эндотелия, повышенной проницаемостью сосудов с выхождением белков плазмы. Следует отметить, что вторичные иммунодефицитные состояния, развивающиеся под действием радиационного фактора являются патогенетическими механизмами, реализация которых способствует формированию воспалительных и фибротических процессов в легких, обуславливающих развитие острого воспалительно—инфильтративного пневмонита и хронического фиброзирующего пневмонита.

Выводы. Полученные данные подтверждают роль ионизирующего излучения в формировании морфологических признаков, характерных для радиационно—индуцированного пневмонита и фиброза легких, являющихся формой повреждения легких, зависящая не только от дозы, но и от вида излучения. По результатам большинства ведущих исследований в области радиологии по вопросу оценки действия нейтронного излучения на легкие нет единого мнения. Таким образом, для радиобиологов и морфологов представляется несомненной актуальность

продолжения исследований, посвященных изучению воздействия нейтронного излучения, оценить и сравнить степень структурных изменений в легких, что позволит разработать диагностические критерии при исследовании легких лиц, подвергавшихся воздействию различных видов ионизирующего излучения.

Ключевые слова: ионизирующее излучение, легочная патология, морфофункциональные изменения, провоспалительные медиаторы, фиброз легких.

Туйшдеме

РАДИАЦИЯ ЭСЕР1НЕН ТУЫНДАГАН ©КПЕ ЗАКЫМДАНУЛАРЫ. ЭДЕБИЕТТЕРГЕ ШОЛУ

Дархан Е. Узбеков1, http://orcid.org/0000-0003-4399-460X Масахару Хоши2, http://orcid.org/0000-0001-6978-0883 Найля Ж. Чайжунусоваз, http://orcid.org/0000-0002-6660-7118 Дария М. Шабдарбаева1, http://orcid.org/0000-0001-9463-1935 Нурлан Б. Саякенов1, http://orcid.org/0000-0002-5082-7554

Семей каласыньщ мемлекеттiк медицина университет^ i Патологиялык анатомия жэне сот медицина кафедрасы, з Тагамтану жэне гигиеналык пэндер кафедрасы, Семей к., Казакстан;

2 Хиросима университетi, Радиациялык биология жэне медицина гылыми -зерттеу институты, Хиросима, Жапония

К1р1спе. Кептеген радиациялык жагдайлар кезiнде туындайтын екпенН жасуша мен тiн децгейшдеп морфологиялык зерттеулердН сан алуан нэтижелерi бар екенiне жэне бронх— екпелт аурулар саны жогарылауыныц жедел мен кейшп кезеидердеп iшкi мен сырткы сэулелеу дозаларыныи мелшерiмен байланысын багалаудагы мэлiметтiц бар болуына карамастан, к^рге дейiн екnелiк бузылыстардыи y— мен нейтрон сэулелерi эсерiмен байланысы аягына шейiн зерттелмеген, ацгарылган дерттН сипатына радиациялык ыкпалдыи узактыгы мен дозалык жYктеменiц мэнi де толыктай дэлелденбеген, сонымен катар олардыи екпеге закымдаушы эсершН морфогенезi жайлы жYЙелiк акпараттыи жоктыгы да кYмэн тудырмайды.

Эдеби шолудьщ максаты - радиацияныи тYрлi деигей мен типтершН эсерi кезшде екnедегi морфофункционалды бузылыстардыи сипаты туралы гылыми эдебиеттердi талдау.

Материалдар мен эд1стер. Алга койылган максатты жYзеге асыру Yшiн гылыми жарияланымдар табылып, талкыга салынган. Эдеби шолуды юке косуга усынылган барлык жумыстар «Google Scholar» гылыми iздеу жYЙесi аркылы PubMed, Medline, E—library, Cyberleninka базаларында индекстелген. Таидау алдында келесi шарттар ескерiлген: агылшын, жапон жэне орыс тiлдерiнде жарияланган соцгы 10 жыл iшiндегi тышкандар мен егеукуйрыктарга жасалган эксnерименттiк зерттеулер, сонымен катар айкын мэлiмделген жэне статистика тургысынан дэлелденген корытындылары бар макалалардыи толык акпараты колданылган. Эдеби шолу кезiнде баяндамалар тужырымдары, газет макалалары мен жеке ю акпараттары кажет емес жарияланымдар ретшде колданылмаган.

Нэтижелер. Эдеби мэлiметтердi талдау радиация эсерiнен туындаган екпе закымдануларыныи ателектаздар мен дэнекер тшдм организациясы дамуын тудыратын бронх бYлiнiстерiн, эпителий десквамациясымен керiнетiн серозды—фибринозды альвеолитпен, эндотелий пролиферациясымен жэне плазма нэруыздары шыгуына алып келетiн кантамыр кабыргасы еткiзгiштiгi жогарылауымен аныкталатын кантамыр бузылыстарымен сипатталатынын керсеттi. Жедел кабынулык—инфильтрациялык пневмонитт жэне созылмалы фиброздаушы nневмониттi тудыратын екпедеп кабынулык пен фиброздык YPДiстердiи

калыптасуын жYзеге асыратын патогенездт механизмдер ретiнде радиациялык; фактор эсершен дамитын екiншiлiк иммундык; тапшылыкты жагдайлардыц болып табылатынын айта кеткен жен.

Корытынды. Алынган нэтижелер иондаушы сэулелердН екпе закымдануларыныц бiр тYрi болып табылатын радиациялык-индукцияланган пневмонит пен екпе фиброзына тэн морфологиялык; белгтердН дамуындагы релiн дэлелдейдi. Бул белгiлер сэуленН дозасы мен тYрiне байланысты туындайды. Радиология саласындагы кептеген зерттеулердН нэтижелерше сай нейтронды сэулелердН екпеге эсерш багалаудагы орта; кезкарастардыц калыптаспаганы аныкталды. Демек, радиобиологтар мен морфологтарга нейтронды сэулелердН эсершен туындайтын екпедегi курылымдык; езгерiстер децгейш багалау мен салыстыру ыкпалын карастыруга арналган зерттеулердi жалгастырудыц езектiлiгi еш кYмэн тудырмайды. Бул эр тYрлi иондаушы сэулелер эсерше ушырагандардыц екпесiн зерттеу кезiндегi диагностикалык; нышандарды курастыру мYмкiндiгiн тугызады.

Негiзгi свздер: иондаушы сэулелер, екпе патологиясы, морфофункционалды бузылыстар, н;абыну медиаторлары, екпе фиброзы.

Библиографическая ссылка:

Узбеков Д.Е., Хоши М., Чайжунусова Н.Ж., Шабдарбаева Д.М., Саякенoв Н.Б. Радиационно-индуцированные повреждения легких. Обзор литературы / / Наука и Здравоохранение. 2016. № 6. С. 160178.

^Ье^ D.E., Hоshi M., Chaizhunusova N.Zh., Shаbdаrbаеvа D.M., Sayakenov N.B. Radiation-induced lung injury. Literature review. Nauka i Zdravookhranenie [Science & Healthcare]. 2016, 6, pp. 160-178.

Узбеков Д.Е., Хоши М., Чайжунусова Н.Ж., Шабдарбаева Д.М., Саякенсв Н.Б. Радиация эсерЫен туындаган екпе за;ымданулары. Эдебиеттерге шолу / / Гылым жэне Денсаулы; са;тау. 2016. № 6. Б. 160-178.

Introduction

It is known that in 2012, a technical meeting and symposium were held to discuss the problem of residual radiation exposures to the A-bomb survivors of Hiroshima and Nagasaki [50]. It was allowed for participants to evaluate the use of data from many different research programs in clarifying the potential residual radiation doses to survivors of Japanese cities bombing. Factors for the evaluation of exposure to y- and neutron radiation at both cities are discussed in the external and internal doses from residual radiation exposure. Questions were asked about the conclusion that manganese-56 (56Mn) is the most important radionuclide, and offering were made to consider not only half-lives but the number and energies of y-rays emanated by each radionuclide and time-dependent survivor actions. Radiobiologists concluded that the methodological guides on external and internal dose estimation developed for the public living near Semipalatinsk Nuclear Test Site can be applied with modifications to the conditions of residual radiation exposure to Japanese A-bomb survivors. A view, based on an analysis using a

multi-step pathologic process model, suggests that residual radiation doses in Hiroshima were approached to 2 Gy to match the modeled incidence. This analysis suggests a residual y-dose that could dominate over the initial radiation dose for most survivors [49]. Therefore, the radiation dose of critical organs affected by the A-bombing should be particularly taken into account [39]. Scientists have long been proven that exposure to ionizing radiation can cause long-term effects, such as chronic inflammation and diffuse fibrosis of the affected organ and tissue [14, 98]. Nevertheless, despite decades of research the pathophysiological mechanisms of fatal radiation-induced lung injury in organ level warranted further investigations [51]. Moreover, the presence of numerous data on the results of morphological study of the lung at the cellular and tissue levels in different radiation situations, according to the connection of increasing bronchopulmonary diseases with the values of external and internal doses exposure during acute and long-term periods. Did not fully demonstrated the link identified pulmonary disorders with exposure to y- and neutron

radiation, it is not fully proved the value of radiation dose and duration of radiation effect on the nature of detectable pathology, there are no system data on the morphogenesis of their damaging effect on the lungs.

The research purpose: identification of differences between the nature of the structural changes in the lungs at different levels and types of radiation exposure.

Materials and methods

To achieve this purpose we have searched and analysis of scientific publications. All received working to the review formation has been indexed in the databases PubMed, Medline, E-library, Cyberleninka using «Google Scholar» scientific search engine. The following search filters has been presented before the start of the search: experimental studies carried out on mice and rats, for the past 10 years (from 2006 to 2016), published in English, Japanese and Russian languages, as well as full versions of papers with legibly formulated and statistically proven conclusions. The key points of search requests were submitted to the following elements: «ionizing radiation», «pulmonary pathology», «morphofunctional changes», «pro-inflammatory mediators», «pulmonary fibrosis».

Exclusion criteria included a review of publications became summary reports, newspaper articles and personal notifications. There were found 1210 literary sources of which were for analysis selected 100 papers. After fulfillment the stage of automatically search we had conducted the search of publications by «simple method», which made it possible further to identify the scientific sources included in this review.

Results and discussion

It was proved that lung exhibits the abrupt dose-related response to ionizing radiation [99]. At estimate the internal doses in rat organs exposed to neutron-activated 56Mn using nuclear reactor (Experimental facility «Baikal-1», Kurchatov, Kazakhstan) with neutron flux 4*1014 n/cm2 [7], the highest doses were recorded in the lung. Consequently, the cumulative absorbed dose of internal radiation exposure for the first version (without forced ventilation) was equal to 0.1 Gy, and for the second variant of radiation (with forced ventilation box with animals) cumulative absorbed dose of internal radiation

was 0.03 Gy for the lung, respectively [8]. Therefore, currently, particular interest is a comparative characteristic of morphofunctional changes in the persons' lung exposed to 60Co and 56Mn, allowing to identify the informative criteria for assessing the effect of the radiation factor on the respiratory organs, depending on the acumulative dose [89].

Radiation-induced lung injury (RILI) produces an eligible pre-metastatic microenvironment for cancer cells [34]. According to many scientists, one of the common neoplastic diseases ascribable to ionizing radiation in A-bomb survivors and nuclear reactor workers are lung cancers [1, 2, 74], which accounts for almost a quarter of radiotherapy-induced secondary malignant tumors [5, 6, 56]. Some researchers argue that radiation-induced pulmonary injury of varying severity still significantly affects the quality of patients life, and may even lead to death [81, 92]. According to the results of foreign authors, about 10-15% of non-small cell lung cancer patients develop severe lung toxicity after chest irradiation, and a significant percentage of patients die due to irreversible pulmonary inflammation [13, 27, 78, 79].

It is known that development of lung damage after radiotherapy is a continuous process that can be attributed to radiation damage in parenchymal cells, specifically the inflammatory, fibroblastic, and epithelial cells, that appear to play the most critical roles in radiation-induced pulmonary pathogenesis [85]. However, available data on histological alterations after radiotherapy human lung is limited, since patients are unlikely to give consent for diagnostic thoracotomy and autopsy. The existing histological data have mostly come from animal models [96]. For this reason, animal models that reproduce radiation injuries in humans are mandatory. Rodents are the animal models of selection, because they are well characterized, easy to work with, and have genetically altered strains accessible for advanced research [28, 95]. It was experimentally confirmed that the lungs are damaged when exposed to a single lethal dose of Y-radiation. Several radiation dose- and time-dependent tissue outcome develop following acute highdose radiation exposure. One of the recognized delayed effects of such exposures is pulmonary injury, characterized by respiratory failure as a

result of pneumonitis that may subsequently develop into lung fibrosis. Since this pulmonary subsyndrome associated with high morbidity and mortality [29]. It should be noted that clinically, radiation induced lung toxicity also manifested by cough, fever, shortness of breath and other signs of respiratory failure [15, 21].

One of acute or subacute form of the lung damage related to radiation dose is radiation pneumonitis (RP) [45]. RP always associated with fibrosis and never relapses, while organizing pneumonia (OP) usually resolves without fibrosis but commonly relapse [24, 66]. OP is identified inside and outside of the tangential irradiated field and occurs independent of the radiation dose. Also, OP lesions are characterized by lung infiltrates out side the radiation field and frequently migrate. This type of pneumonia is a form of lung toxicity that arises due to some interaction between radiotherapy and the immune system, which may also explain the occurrence of OP lesions outside the irradiated field. It is an important question why OP occurs after radiotherapy for breast cancer more frequently than after radiotherapy for other malignancies. Lungs are often exposed to radiation for the treatment for malignant tumor. Late damage to the lung, which usually manifests as fibrosis, is a radiation dose—dependent occurrence in patients undergoing radiotherapy for lung cancer. The incidence of OP after radiotherapy in patients with breast cancer significantly higher than another one. In contrast, RP occurs much more commonly after radiotherapy in patients with lung cancer [67].

As is known that underlying molecular and cellular mechanisms of RP are very complex [10, 59, 75, 77]. Although the molecular mechanism for RP is complex and obscure, involvement of cytokines, chemokines, and cell adhesion molecules has been implicated [15, 21]. Many investigators have shown that in the pathogenesis of RP or alveolitis essential roles play interleukins (IL) [42, 82, 93] produced through epithelial cells [46]. Clinical as well as experimental findings have suggested the participation of IL—6 as a pro—inflammatory cytokine in RP [18]. RILI includes various types of radiation damage of target cells and the release of multiple inflammatory mediators [30, 44]. A number of authors have described the mechanisms of

interaction of the pulmonary and cardiac pathology that associated with development of RILI [31, 90]. It was noted that in rats exposed to letal dose of Y—radiation is observed loss of pulmonary vessels, right ventricular hypertrophy, increased pulmonary vascular resistance, an increase in the dry weight of the lungs and reduce the overall activity of pulmonary angiotensin— converting enzyme (ACE), and extensibility of the pulmonary artery. In contrast, subletal dose alone resulted in a moderate increase in weight of the right ventricle and the decrease in the activity of ACE in lungs [32]. This data confirm the clinically significant lesions that appear in time and on the dose—exposure after a relatively low radiation doses [60]. Irradiation with 10 Gy resulted in increased breathing rate, a reduction in oxygen saturation, an increase in bronchoalveolar lavage fluid protein and attenuation of vascular reactivity between 2—3 months after irradiation. These changes were not observed with the lower dose of 5 Gy. Histological examination revealed perivascular edema at 4—8 weeks after exposure to both doses, and mild fibrosis beyond some month after fatal dose of Y—radiation [62, 100]. Some authors believe that pulmonary vascular resistance associated with hypoxia of the lung tissue and decreased cardiac output [73, 87]. Thus, lethal RP may happen if a large volume of normal lung tissue is irradiated, even at dose lower than 5 Gy [43].

In a setting of chronic inflammation, the persistent lung tissue damage and cellular proliferation are associated with superfluous of reactive oxygen species (ROS) [11, 72]. It has been suggested that the generation of ROS instantly after irradiation, together with a cyclic up—regulation of cytokines and the recruitment of inflammatory cells are responsible for the injury observed in the lung [23, 25]. Thereby, accumulation of lipoperoxidation (LPO) products in the lung tissue homogenates caused by free radicals effects after Y—radiation exposure was noticed by several authors. Free radical— mediated LPO is harmful not only because damaged lipids disrupt the structure of pulmonary cell membrane, but also because the process produces potentially mutagenic and carcinogenic byproducts. One such product is the highly reactive carbonyl compound, malondialdehyde (MDA), which can react with deoxyadenosine and

deoxyguanosine in deoxyribonucleic acid (DNA) to form DNA adducts. LPO reactions can occur at the both the cellular membrane and mitochondria membranes, and either can subsequently trigger cell death through apoptosis [3, 4].

It was considered that tissue reactions in cases where the threshold dose has been exceeded may be of the inflammatory type resulting due to the cellular factors release, or can be reactions resulting from cell lesion [84]. The time at which an effect may be discovered depends on the temporal course of the injury and progresses with time after irradiation [36]. It is known that radiation activates immunity via initiation of T-cells recruitment [16, 54]. More relevant than the availability of lymphocytes in the irradiated lung is their profile of secreted mediators. In particular, the pro-inflammatory T-helper cells oppose the pro-fibrotic T-lymphocytes [37]. As evidenced by a number of authors, the T-helper response to thoracic irradiation of different lines of mice has not been reported, but mouse strains have been shown to differ in their cytokine response post radiation and in gene expression profiles suggestive of differing adaptive immune responses [38, 47, 52, 83]. Thoracic irradiation causes also activation of various immune cells into the lung, including monocytes, neutrophils and basophils, that are responsible for local and systemic expression of mediators after radiation exposure [22, 48, 57], which are important in the pathogenesis of lung injury [97]. It should be noted that inflammatory infiltrates appear as secondary effects in the setting of high-single or fractionated radiation doses [51]. Basically, irradiation induces tissue injury across sensitization of autoreactive lymphocytes, reacting with lung tissue [64]. Endogenous and migrating leukocytes together with lung epithelial and endothelial cells create a feedback loop where stimuli from damage responses can activate alveolar and interstitial macrophages [19]. Various inflammatory mediators released from injured alveolar and interstitial cells produce inflammation, which also increase of vascular permeability. Moreover, the alveolar space is filled with exudates because of direct radiation damage and inflammatory process [69].

It was experimentally confirmed that in the rats, morphologically, mild interstitial inflammatory

cell infiltration was observed at third day and intra-alveolar hyaline material was found at second week after Y-irradiation. Concerning focal irradiation, numerous foamy macrophages aggregated in a distal part of the irradiated area, while hemosiderin-laden macrophages were observed in the center of the irradiated zone. Two month after irradiation, the hyaline materials fragmented and disappeared to a definite extent, and fibrous exudates were present in the air spaces along with inflammatory cellular infiltration. The alveolar inflammation score at 2 weeks post-irradiation characterised by a small amounts of collagen which were detected in the intra-alveolar and interstitial areas. At 1 month after irradiation, extensive collagen was observed, correlating with late-stage fibrosis [41]. It is important to note that pathological final stage which characterised by excessive deposition of this fibrillar component in the pulmonary interstitium leads to disorder of normal gaseous exchange [65, 80]. Pathologists' results showed minimal edema and minimal to mild increase of cellularity in alveolar walls, interstitial inflammation, enlargement and atypical pneumocytes by 3 month post irradiation [58]. Histologically, lung tissue of irradiated rats include also highly thickened, corrugated and distorted arterial walls with different granulomatous masses, and also congested alveolar septae, highly elongated and branched bronchioles, their lumen contained debris of degenerated epithelial cells with ruptured epithelial lining of these bronchioles and dense fibrous layers nearby them [9]. After radiation effect the majority of pneumocytes are lost at which point alveolocytes begin to proliferate and produce important biopolimers to repair the surrounding injury changes [68].

Depending on both radiation dose and volume, lung injury is characterized by formation of pulmonary fibrosis [35, 94] that is integral to development and progression inflammatory airway diseases, including asthma, chronic bronchitis and bronchiectasis, where histological development of airway remodeling correlates with irreversible lesion of lung function. Diffuse parenchymal pulmonary diseases are a heterogeneous group of illnesses characterized by various degrees of lung inflammation and fibrosis [61]. Pathohistologists showed that

fibrogenesis phase was characterized by development of typical fibroblast foci in lungs irradiated animals. Furthermore, the later fibrogenesis phase was accompanied by a strong second onset of leukocyte infiltration that began some month after irradiation. At later time points the fibrotic foci evolved and combined into widespread fibrosis with remodelling of the lung architecture [53].

Kazakhstan morphologists featuring Japanese researchers revealed that in majority of experimental animals exposed to neutron— activated 56Mn on the 3rd and 14th days after irradiation observed thickening of intra—alveolar septa in virtue of leucocytes, erythrocytes, lymphocytes, histiocytes, alveolocytes, and on the 60th day was found fibrosis phenomenon, whereas like rats exposed to Y—radiation except signs of inflammation were noted foci of emphysematous expanded alveoli [89]. Pathologists reported that, especially, the combination of pulmonary fibrosis and emphysema, which are defined by the presence of emphysematous foci and overgrowth of connective tissue in the same patients lung, has a poor prognosis, similar to that of idiopathic pulmonary fibrosis [76]. Although according to some scientists, none of the currently accepted animal models of radiation—induced lung fibrosis accurately mimic human idiopathic pulmonary fibrosis [63, 71, 86].

Scientists have proved that susceptibility to fibrosis can be a strain—specific or organ—specific. A systematic review was conducted to obtain the results of the feasibility of using a particular mouse strain to simulate the human body specific fibrotic pathology. Such information is useful in determining which genetic signatures are associated with susceptibility to fibrosis and also important to identify individuals susceptible to the development of a fibrotic phenotype in the organ following injury [91]. Regulation mechanism of lung fibroblast proliferation remains not fully understood. To elucidate the key molecules in it, the authors established mortal and immortal nontransformed lung fibroblast cell line or strains with elongated life span by telomerase reverse transcriptase gene transfection. Comparing the expression profiles of them, genes were explored to be the candidates responsible for regulation of cellular proliferation of lung fibroblasts. This set of

fibrobrast strains of same origin with different proliferative capacities may become useful model cells for research on lung fibroblast growth regulation and the candidate genes explored that may provide biomarkers or therapeutic targets of pulmonary fibrosis [40]. Combining genomic approaches identified variation within specific genes which function in the tissue response to injury as associated with fibrosis following thoracic irradiation in mice [70]. Thus, whole-genome studies have provides a useful conception into that gene patterns may influence the development of fibrotic process to various injurious agents [12].

Equally important is the fact that, microvascular injury is a prominent feature of normal tissue radiation injury and plays a decisive role in both inflammatory and fibrotic radiation responses. Injury of the vascular endothelium is presumed to play a principal role in the response of most normal tissues to ionizing radiation and to the progressive character of chronic radiation fibrosis. This is particularly true for chronic radiation toxicity, in which microvascular injury seems to be a key to the unique self-perpetuating nature of radiation injury [17]. Others authors have demonstrated that the recovery after vascular injury and reendotelization enhanced by circulating endothelial progenitor cells [55]. Studies of microcirculation, inflammation and leukocyte-endothelium interactions at radiation influence could enhance understanding of the underlying pathophysiological mechanisms that result in histological changes [33].

Conclusion

Summing up, presented by us the information by virtue of foreign and domestic literature indicates assess the effect of different types of ionizing radiation on the lung. The findings data support a role of ionizing radiation in the formation of structural disorders of the radiation-induced pneumonitis and pulmonary fibrosis which are form of acute or chronic lung damage depending on both the dose and type of radiation [20, 26].

Thus, at present according to result of majority of leading research in the field of radiobiology and radiation medicine regarding evaluation the effects of different types of ionizing radiation on the bronchopulmonary system, there is no consensus. In this regard, for scientists of

Kazakhstan and Japan are undoubted relevance of continuing research concerning radiation effects on the lungs, to evaluate and compare the degree of pathological processes in them under the influence of y- and neutron radiation, which will develop diagnostic criteria of morphofunctional changes in the lungs exposed individuals [88].

Interest conflict

All authors declare that they have no conflict of interest.

Authors contributions:

Uzbekov D. - literature collection, writing the paper;

Hoshi M. - scientific guidance in writing the paper;

Chaizhunusova N. - scientific guidance on the literature collection;

Shabdarbaeva D. - literature collection, scientific guidance in writing the paper;

Sayakenov N. - literature collection.

Литература:

1. Апсаликов К.Н., Гусев Б.И., Мулдагалиев Т.Ж., Кенжина Л.Б., Белихина Т.И. Объeктивизaция MapKepoB paqMaqMoHHoro noвpeждeния в rpynnax paдиaциoннoгo pиcкa, пpeдcтaвлeнных экcпoниpoвaнным paдиaциeй нaceлeниeм ВКО и их пoтoмкaми // HayKa и Здpaвooхpaнeниe. 2011. № 4. С. 20-22.

2. Апсаликов Р.К. OqeH^ мeдицинcких noTepb cpeди лиц, пpoживaющих Ha тeppитopиях, пpилeгaющих к ceмипaлaтинcкoму ядepнoму пoлигoну в oтдaлeннoм пepиoдe // Hay^ и Здpaвooхpaнeниe. 2013. № 5. С. 49-52.

3. Жетписбаев Б.А., Мадиева М.Р., Сайдахметова А.С., Танатова З.А., Оразбаева А.К. и др. Hapyшeниe мeтaбoлизмa в лeгких и миoкapдe пpи paдиaциoннoм пopaжeнии opгaнизмa в экcпepимeнтe // Hayкa и Здpaвooхpaнeниe. 2009. Т. 2, № 4. С. 153154.

4. Жетписбаев Б.А., Мадиева М.Р., Сайдахметова А.С., Танатова З.А., Оразбаева А.К. и др. Сocтoяниe nepewcHoro oкиcлeния лиnидoв в лeгких и миoкapдe nocлe фpaкциoниpoвaннoгo гaммa-oблyчeния // Hay^ и Здpaвooхpaнeниe. 2009. Т. 2, № 4. С. 127-128.

5. Жетписбаев Б.А., Серимханова Б.Т., Аргынбекова А.С., Мусайнова А.К., Оразбаева А.К. и др. Мeдицинcкиe nocлeдcтвия влияния

мaлoй дoзы paдиoaктивнoгo зaгpязнeния oкpyжaющeй cpeды // Hayкa и Здpaвooхpaнeниe. 2010. Т.1, № 1. С. 7-11.

6. Манамбаева З.А., Апсаликов Б.А., Жабагин К.Т., Оспанов Е.А., Камзин К.Ж. Рeзyльтaты лyчeвoй тepanии paкa лeгких и npимeнeния npeдyктaлa // Hayкa и Здpaвooхpaнeниe. 2012. № 5. С. 124-125.

7. Рахыпбеков Т.К., Хоши М., Степаненко В.Ф., Жумадилов К.Ш., Чайжунусова Н.Ж. и др. Рaдиaциoннo-биoлoгичecкий экcnepимeнт Ha кoмnлeкce иccлeдoвaтeльcких peaктopoв «Бaйкaл-1» // Чeлoвeк. Энepгия. Атом. 2015. № 2 (24). С. 43-45.

8. Степаненко В.Ф., Рахыпбеков Т.К., Каприн А.Д., Иванов С.А., Отани К. и др. Облyчeниe экcnepимeнтaльных живoтных aктивиpoвaннoй нeйтpoнaми paдиoaктивнoй пылью: paзpaбoткa и peaлизaция мeтoдa -nepвыe peзyльтaты мeждyнapoднoгo мнoгoцeнтpoвoгo иccлeдoвaния // Рaдиaция и pиcк. 2016. Т. 25, № 4. С. 112-125.

9. Abuo El Naga I., Abd Rabou M. The possible protective role of bone marrow transplantation on irradiated mothers and their fetuses // Stem Cell. 2012. Vol. 3, N 3. P. 8-30.

10. Baker R., Han G., Sarangkasiri S., DeMarco M., Turke C. et al. Clinical and dosimetric predictors of radiation pneumonitis in a large series of patients treated with stereotactic body radiation therapy to the lung // Int. J. Radiat. Oncol. Biol. Phys. 2013. Vol. 85, N 1. P. 190-195.

11. Bocchino M., Agnese S., Fagone E., Svegliati S., Grieco D. et al. Reactive oxygen species are required for maintenance and differentiation of primary lung fibroblasts in idiopathic pulmonary fibrosis // PLoS One. 2010. Vol. 5, N 1. 14003 p.

12. Borie R., Tabeze L., Thabut G., Nunes H., Cottin V. et al. Prevalence and characteristics of TERT and TERC mutations in suspected genetic pulmonary fibrosis // Eur. Respir. J. 2016. Vol. 48, N 6. P. 1721-1731.

13. Borst G.R., Ishikawa M., Nijkamp J., Hauptmann M., Shirato H. et al. Radiation pneumonitis in patients treated for malignant pulmonary lesions with hypofractionated radiation therapy // Radiother. Oncol. 2009. Vol. 91, N 3. P. 307-313.

14. Bromet E.J., Havenaar J.M., Guey L.T. A 25 year retrospective review of the psychological

consequences of the Chernobyl accident // Clin. Oncol. 2011. Vol. 23, N 4. P. 297-305.

15. Brush J., Lipnick S.L., Phillips T., Sitko J., McDonald J.T. et al. Molecular mechanisms of late normal tissue injury // Semin. Radiat. Oncol. 2007. Vol. 17, N 2. P. 121-130.

16. Burnette B., Weichselbaum R.R. Radiation as an immune modulator // Semin. Radiat. Oncol. 2013. Vol. 23, N 4. P. 273-280.

17. Cappuccini F., Eldh T., Bruder D., Gereke M., Jastrow H. et al. New insights into the molecular pathology of radiation-induced pneumopathy // Radiother. Oncol. 2011. Vol. 101, N 1. P. 86-92.

18. Chen H, Xiang H, Wu B, Zhang X., Li M. et al. Manganese superoxide dismutase gene modified mesenchymal stem cells attenuates acute radiation-induced lung injury // Hum. Gene Ther. 2016. N 4. P. 517-529.

19. Claudia C. Advances in mechanisms of repair and remodeling in acute lung injury // Intensive Care Medicine. 2008. Vol. 34, N 4. P. 619-630.

20. Davis B.K., Wen H, Ting J.P. The inflammasome NLRs in immunity, inflammation, and associated diseases // Annu. Rev. Immunol. 2011. Vol. 29. P. 707-735.

21. Diederich S. Chest CT for suspected pulmonary complications of oncologic therapies: how I review and report // Cancer Imaging. 2016. Vol. 16. 7 p.

22. Ding N.H., Li J.J., Sun L.Q. Molecular mechanisms and treatment of radiation-induced lung fibrosis // Curr. Drug Targets. 2013. Vol. 14, N 11. P. 1347-1356.

23. Dorn P., Tieche C.C., Peng R.W., Froment L, Schmid R.A. et al. Schedule-dependent increased efficiency of pemetrexed-ionizing radiation combination therapy elicits a differential DNA damage response in lung cancer cells // Cancer Cell Int. 2016. Vol. 16, N 1. 66 p.

24. Epler G.R., Kelly E.M. Systematic review of postradiotherapy bronchiolitis obliterans organizing pneumonia in women with breast cancer // Oncologist. 2014. Vol. 19, N 12. P. 1216-1226.

25. Fleckenstein K., Gauter-Fleckenstein B., Jackson I., Rabbani 2, Anscher M. et al. Using biological markers to predict risk of radiation injury // Semin. Radiat. Oncol. 2007. Vol. 17, N 2. P. 89-98.

26. Franchi L, Eigenbrod T, Munoz-Planillo R., Nunez G. The inflammasome: a caspase—1— activation platform that regulates immune responses and disease pathogenesis // Nat. Immunol. 2009. Vol. 10, N 3. P. 241—247.

27. Fujino M., Shirato H.,Onishi H., Kawamura H., Takayama K. et al. Characteristics of patients who developed radiation pneumonitis requiring steroid therapy after stereotactic irradiation for lung tumors // Cancer J. 2006. Vol. 12, N 1. P. 41—46.

28. Gao F., Fish B.L., Moulder J.E., Jacobs E.R., Medhora M. Enalapril mitigates radiation— induced pneumonitis and pulmonary fibrosis if started 35 days after whole—thorax irradiation // Radiat. Res. 2013. Vol. 180, N 5. P. 546—552.

29. Garofalo M., Bennett A., Farese A.M., Harper J., Ward A. et al. The delayed pulmonary syndrome following acute high—dose irradiation: a rhesus macaque model // Health Phys. 2014. Vol. 106, N 1. P. 56—72.

30. Ghafoori P., Marks L.B., Vujaskovic Z., Kelsey C.R. Radiation—induced lung injury. Assessment, management, and prevention // Oncology (Williston Park). 2008. Vol. 22, N 1. P. 37—47.

31. Ghobadi G., Bartelds B., van der Veen S.J., Dickinson M.G., Brandenburg S. et al. Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension // Thorax. 2012. Vol. 67, N 4. P. 334—341.

32. Ghosh S.N., Wu Q., Mader M., Fish B.L., Moulder J.E. et al. Vascular injury after whole thoracic x—ray irradiation in the rat // Int. J. Radiat. Oncol. Biol. Phys. 2009. Vol. 74, N 1. P. 192—199.

33. Goertz O., Poettgen C., Akbari A., Kolbenschlag J., Langer S. et al. New model for long—term investigations of cutaneous microcirculatory and inflammatory changes following irradiation // J. Radiat. Res. 2015. Vol. 56, N 3. P. 456—461.

34. Gong H.Y., Hu W.G., Hu Q.Y., Li X.P., Song Q.B. Radiation—induced pulmonary injury accelerated pulmonary metastasis in a mouse model of breast cancer // Oncol. Lett. 2015. Vol. 10, N 6. P. 3613—3618.

35. Groves A.M., Johnston C.J., Misra R.S., Williams J.P., Finkelstein J.N. Effects of IL—4 on pulmonary fibrosis and the accumulation and phenotype of macrophage subpopulations

following thoracic irradiation // Int. J. Radiat. Biol. 2016. Vol. 92, N 12. P. 754-765.

36. Hamada N., Fujimichi Y. Classification of radiation effects for dose limitation purposes: history, current situation and future prospects // J. Radiat. Res. 2014. Vol. 55, N 4. P. 629-640.

37. Han G., Zhang H., Xie C.H., Zhou Y.F. Th2-like immune response in radiation-induced lung fibrosis // Oncol. Rep. 2011. Vol. 26, N 2. P. 383-388.

38. Haston C.K., Begin M., Dorion G., Cory S.M. Distinct loci influence radiation-induced alveolitis from fibrosing alveolitis in the mouse // Cancer Res. 2007. Vol. 67, N 22. P. 1079610803.

39. Hirai Y., Kodama Y., Cullings H.M., Miyazawa C., Kanamura N. Electron spin resonance analysis of tooth enamel does not indicate exposure to large radiation doses in a large proportion of distally-exposed a-bomb survivors // Radiat. Res. 2011. Vol. 52. P. 600608.

40. Hiyama K., Tanimoto K., Nishimura Y., Tsugane M., Fukuba I. et al. Exploration of the genes responsible for unlimited proliferation of immortalized lung fibroblasts // Exp. Lung Res. 2008. Vol. 34, N 7. P. 373-390.

41. Hong Z.Y, Eun S.H., Park K., Choi W.H., Lee J.I. et al. Development of a small animal model to simulate clinical stereotactic body radiotherapy-induced central and peripheral lung injuries // J. Radiat. Res. 2014. Vol. 55, N 4. P. 648-657.

42. Hong Z.Y., Song K.H., Yoon J.H., Cho J., Story M.D. An experimental model-based exploration of cytokines in ablative radiation-induced lung injury in vivo and in vitro // Lung. 2015. Vol. 193, N 3. P. 409-419.

43. Hu Y., Li J., Su X. Fatal pneumonitis associated with postoperative intensity-modulated radiotherapy in lung cancer: case report and review // Oncol. Lett. 2013. Vol. 5, N 2. P. 714-716.

44. Jang S.S., Kim H.G., Han J.M., Lee J.S., Choi M.K. et al. Modulation of radiation-induced alterations in oxidative stress and cytokine expression in lung tissue by Panax ginseng extract // Phytother. Res. 2015. Vol. 29, N 2. P. 201-209.

45. Jenkins P., Welsh A. Computed tomography appearance of early radiation injury

to the lung: correlation with clinical and dosimetric factors // Int. J. Radiat. Oncol. Biol. Phys. 2011. Vol. 81, N 1. P. 97-103.

46. Jiang X., Qu C., Chang P., Zhang C., Qu Y. et al. Intravenous delivery of adipose-derived mesenchymal stromal cells attenuates acute radiation-induced lung injury in rats // Cytotherapy. 2015. Vol. 17, N 5. P. 560-570.

47. Kalash R., Berhane H., Au J., Rhieu B.H., Epperly M.W. et al. Differences in irradiated lung gene transcription between fibrosis-prone C57BL/6NHsd and fibrosis-resistant C3H/HeNHsd mice // In Vivo. 2014. Vol. 28, N 2. P. 147-171.

48. Kano A., Ujita M., Kobayashi M., Sunakawa Y., Shirahama J. et al. Radiographic and CT features of radiation-induced organizing pneumonia syndrome after breast-conserving therapy // Jpn J. Radiol. 2012. Vol. 30, N 2. P. 128-136.

49. Kerr G.D., Egbert S.D., Al-Nabulsi I., Bailiff I.K., Beck H.L. et al. Workshop report on atomic bomb dosimetry-review of dose related factors for the evaluation of exposures to residual radiation at Hiroshima and Nagasaki // Health Phys. 2015. Vol. 109, N 6. P. 581-600.

50. Kerr G.D., Egbert S.D., Al-Nabulsi I., Beck H.L., Cullings H.M. et al. Workshop report on atomic bomb dosimetry-residual radiation exposure: recent research and suggestions for future studies // Health Phys. 2013. Vol. 105, N 2. P. 140-149.

51. Khalil A.A., Hoffmann L., Moeller D.S., Farr K.P., Knap M.M. New dose constraint reduces radiation-induced fatal pneumonitis in locally advanced non-small cell lung cancer patients treated with intensity-modulated radiotherapy // Acta Oncol. 2015. Vol. 54, N 9. P. 1343-1349.

52. Kim B.Y., Jin H., Lee Y.J., Kang G.Y., Cho J. et al. Focal exposure of limited lung volumes to high-dose irradiation down-regulated organ development-related functions and up-regulated the immune response in mouse pulmonary tissues // BMC Genet. 2016. Vol. 17. 29 p.

53. Li M., Abdollahi A., Grone H.J., Lipson K.E., Belka C. et al. Late treatment with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse model // Radiat. Oncol. 2009. Vol. 4. 66 p.

54. Liang H., Deng L, Chmura S., Burnette B., Liadis N. et al. Radiation-induced equilibrium is a

balance between tumor cell proliferation and T cell-mediated killing // J. Immunol. 2013. Vol. 190, N 11. P. 5874-5881.

55. Liu Y., Xia T., Zhang W., Zhong Y., Zhang L. et al. Variations of circulating endothelial progenitor cells and transforming growth factor-beta-1 (TGF-01) during thoracic radiotherapy are predictive for radiation pneumonitis // Radiat. Oncol. 2013. Vol. 8. 189 p.

56. Maddams J., Parkin D.M., Darby S.C. The cancer burden in the United Kingdom in 2007 due to radiotherapy // Int. J. Cancer. 2011. Vol. 129, N 12. P. 2885-2893.

57. Maebayashi T., Ishibashi N., Aizawa T., Sakaguchi M., Sato T. et al. Radiation pneumonitis changes over time after stereotactic body radiation therapy for lung tumors: Post-treatment Cavity (Sunny-side-up Egg-like) Changes // Anticancer Res. 2016. Vol. 36, N 10. P. 5563-5570.

58. Marples B., Downing L, Sawarynski K.E., Finkelstein J.N., Williams J.P. et al. Pulmonary injury after combined exposures to low-dose low-LET radiation and fungal spores // Radiat. Res. 2011. Vol. 175, N 4. P. 501-509.

59. Mazeron R., Etienne-Mastroianni B., Perol D., Arpin D., Vincent M. et al. Predictive factors of late radiation fibrosis: a prospective study in non-small cell lung cancer // Int. J. Radiat. Oncol. Biol. Phys. 2010. Vol. 77, N 1. P. 38-43.

60. Medhora M., Gao F., Jacobs E.R., Moulder J.E. Radiation damage to the lung: mitigation by angiotensin-converting enzyme (ACE) inhibitors // Respirology. 2012. Vol. 17, N. 1. P. 66-71.

61. Mehrad B., Strieter R.M. Fibrocytes and the pathogenesis of diffuse parenchymal lung disease // Fibrogenesis & Tissue Repair. 2012. Vol. 5, N 1. 22 p.

62. Molthen R.C., Wu Q., Fish B.L., Moulder J.E., Jacobs E.R. et al. Mitigation of radiation induced pulmonary vascular injury by delayed treatment with captopril // Respirology. 2012. Vol. 17, N 8. P. 1261-1268.

63. Moore B.B., Hogaboam C.M. Murine models of pulmonary fibrosis // Am J. Physiol. Lung Cell. Mol. Physiol. 2008. Vol. 294. P. 152160.

64. Murofushi K.N., Oguchi M., Gosho M., Kozuka T., Sakurai H. Radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome in breast cancer patients is

associated with age // Radiat. Oncol. 2015. Vol. 10. 103 p.

65. Nuovo G.J., Garofalo M., Valeri N., Roulstone V., Volinia S. et al. Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples // Mod. Pathol. 2012. Vol. 25, N 10. P. 1333-1344.

66. Ochiai S., Nomoto Y., Yamashita Y., Murashima S., Hasegawa D. et al. Radiation-induced organizing pneumonia after stereotactic body radiotherapy for lung tumor // J. Radiat. Res. 2015. Vol. 56, N 6. P. 904-911.

67. Oie Y., Saito Y., Kato M., Ito F., Hattori H. et al. Relationship between radiation pneumonitis and organizing pneumonia after radiotherapy for breast cancer // Radiat. Oncol. 2013. Vol. 8. 56 p.

68. Palmer J.D., Zaorosky N.G., Witek M., Lu

B. Molecular markers to predict clinical outcome and radiation-induced toxicity in lung cancer // J. Thorac. Dis. 2014. Vol. 6, N 4. P. 387-398.

69. Park K.J., Oh Y.T., Kil W.J., Park W., Kang S.H. et al. Bronchoalveolar lavage findings of radiation induced lung damage in rats // J. Radiat. Res. 2009. Vol. 50, N 3. P. 177-182.

70. Paun A., Haston C.K. Genomic and genome-wide association of susceptibility to radiation-induced fibrotic lung disease in mice // Radiother. Oncol. 2012. Vol. 105, N 3. P. 350-357.

71. Paun A., Kunwar A., Haston C.K. Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice // Radiat. Oncol. 2015. Vol. 10. 45 p.

72. Pietrofesa R.A., Solomides C.C., Christofidou-Solomidou M. Flaxseed mitigates acute oxidative lung damage in a mouse model of repeated radiation and hyperoxia exposure associated with space exploration // J. Pulm. Respir. Med. 2014. Vol. 4, N 6. P. 215-224.

73. Porcel J.M., Azzopardi M., Koegelenberg

C.F., Maldonado F. et al. The diagnosis of pleural effusions // Expert Rev. Respir. Med. 2015. Vol. 9, N 6. P. 801-815.

74. Preston D.L., Ron E., Tokuoka S., Funamoto S., Nishi N. et al. Solid cancer incidence in atomic bomb survivors: 1958-1998 // Radiat. Res. 2007. Vol. 168, N 1. P. 1-64.

75. Rube C.E., Palm J., Erren M., Fleckenstein J., Konig J. et al. Cytokine plasma levels: reliable predictors for radiation pneumonitis? // PLoS One. 2008. Vol. 3, N 8. 2898 p.

76. Ryerson C.J., Hartman T., Elicker B.M., Ley B., Lee J.S. et al. Clinical features and outcomes in combined pulmonary fibrosis and emphysema in idiopathic pulmonary fibrosis // Chest. 2013. Vol. 144, N 1. P. 234-240.

77. Saintigny P., Burger J.A. Recent advances in non-small cell lung cancer biology and clinical management // Discov. Med. 2012. Vol. 13, N 71. P. 287-297.

78. Saito-Fujita T., Iwakawa M., Nakamura E, Nakawatari M., Fujita H. et al. Attenuated lung fibrosis in interleukin 6 knock-out mice after C-ion irradiation to lung // J. Radiat. Res. 2011. Vol. 52, N 3. P. 270-277.

79. Schallenkamp J.M., Miller R.C., Brinkmann D.H., Foote T., Garces Y.I. Incidence of radiation pneumonitis after thoracic irradiation: Dosevolume correlates // Int. J. Radiat. Oncol. Biol. Phys. 2007. Vol. 67, N 2. P. 410-416.

80. Shank B. Toxicity due to total body irradiation // Hum. Radiat. Injury. 2010. N 1. P. 133-139.

81. Shi A, Zhu G, Wu H, Yu R, Li F. et al. Analysis of clinical and dosimetric factors associated with severe acute radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent chemotherapy and intensity-modulated radiotherapy // Radiat. Oncol. 2010. Vol. 5. 35 p.

82. Siva S., MacManus M., Kron T., Best N., Smith J. et al. A pattern of early radiation-induced inflammatory cytokine expression is associated with lung toxicity in patients with non-small cell lung cancer // PLoS One. 2014. Vol. 9, N 10. 560 p.

83. Sohn S.H., Lee J.M., Park S., Yoo H., Kang J.W. et al. The inflammasome accelerates radiation-induced lung inflammation and fibrosis in mice // Environ. Toxicol. Pharmacol. 2015. Vol. 39, N 2. P. 917-926.

84. Stewart F.A., Akleyev A.V., Hauer-Jensen M., Hendry J.H., Kleiman N.J. et al. ICRP Publication 118: ICRP Statement on tissue reactions, early and late effects of radiation in normal tissues and organs-threshold doses for tissue reactions in a radiation protection context // Ann. ICRP. 2012. Vol. 41, N 1/2. 322 p.

85. Terashima T., Iwami E., Chubachi S., Ikemura S., Nakajima T. et al. A case of small cell lung cancer treated with concurrent

chemoradiotherapy with carboplatin plus etoposide in a hemodialysis patient // Gan To Kagaku Ryoho. 2016. Vol. 43, N 1. P. 99-101.

86. Todd N.W., Luzina I.G., Atamas S.P. Molecular and cellular mechanisms of pulmonary fibrosis // Fibrogenesis & Tissue Repair. 2012. Vol. 5, N 1. 11 p.

87. Ulubay G., Kupeli E, Er Dedekarginoglu B., Savas Bozbas S., Alekberov M. et al. Postoperative pleural effusions after orthotopic heart transplant: cause, clinical manifestations, and course // Exp. Clin. Transplant. 2016. Vol. 14, N 3. P. 125-129.

88. Uzbekov D., Hoshi M., Shichijo K., Chaizhunusova N., Shabdarbaeva D. et al. Radiation effects on morphofunctional state of the respiratory system // Astana medical journal. 2016. N 4 (90). P. 56-62.

89. Uzbekov D., Shichijo K., Chaizhunusova N., Shabdarbaeva D., Sayakenov N. et al. Radiation effects on the pulmonary histological structure of experimental rats // XII International scientific-practical conference «Ecology. Radiation. Health» dedicated to academician B. Atchabarov and 25 years from the date of closing of Semipalatinsk nuclear test site // Science & Healthcare. Semey, 2016. 185 p.

90. Van der Veen S.J., Ghobadi G., de Boer R.A., Faber H., Cannon M.V. et al. ACE inhibition attenuates radiation-induced cardiopulmonary damage // Radiother. Oncol. 2015 Vol. 114, N 1. P. 96-103.

91. Walkin L., Herrick S.E., Summers A., Brenchley P.E., Hoff C.M. et al. The role of mouse strain differences in the susceptibility to fibrosis: a systematic review // Fibrogenesis & Tissue Repair. 2013. Vol. 6, N 1. 18 p.

92. Wang D., Shi J., Liang S., Lu S., Qi X. et al. Dose-volume histogram parameters for predicting radiation pneumonitis using receiver operating characteristic curve // Clin. Transl. Oncol. 2013. Vol. 15, N 5. P. 364-369.

93. Wang L.P., Wang Y.W., Wang B.Z., Sun G.M., Wang X.Y. et al. Expression of interleukin-17A in lung tissues of irradiated mice and the influence of dexamethasone // Scientific World Journal. 2014. Vol. 2014. 251067 p.

94. Westbury C.B., Yarnold J.R. Radiation fibrosis - current clinical and therapeutic perspectives // Clin. Oncol. (R. Coll. Radiol). 2012. Vol. 24, N 10. P. 657-672.

95. Williams J.P., Brown S.L., Georges G.E., Hauer-Jensen M., Hill R.P. et al. Animal models for medical countermeasures to radiation exposure // Radiat. Res. 2010. Vol. 173, N 4. P. 557—578.

96. Xie L., Zhou J., Zhang S., Chen Q., Lai R. et al. Integrating microRNA and mRNA expression profiles in response to radiation— induced injury in rat lung // Radiat. Oncol. 2014. Vol. 9. 111 p.

97. Xu L., Xiong S., Guo R., Yang Z., Wang Q. et al. Transforming growth factor 03 attenuates the development of radiation—induced pulmonary fibrosis in mice by decreasing fibrocyte recruitment and regulating IFN—y/IL—4 balance // Immunol. Lett. 2014. Vol. 162, N 1 (A). P. 27—33.

98. Yamada M., Kasagi F., Mimori Y., Miyachi T, Ohshita T. et al. Incidence of dementia among atomic—bomb survivors — radiation effects research foundation adult health study // J. Neurol. Sci. 2009. Vol. 281, N 1—2. P. 11—14.

99. Yang S., Zhang M., Chen C., Cao Y., Tian Y. et al. Triptolide mitigates radiation—induced pulmonary fibrosis // Radiat. Res. 2015. Vol. 184, N 5. P. 509—517.

100. Zhang R., Ghosh S.N., Zhu D., North P.E., Fish B.L. et al. Structural and functional alterations in the rat lung following whole thoracic irradiation with moderate doses: injury and recovery // Int. J. Radiat. Biol. 2008. Vol. 84, N 6. P. 487—497.

References:

1. Apsalikov K.N., Gusev B.I., Muldagaliev T.Zh., Kenzhina L.B., Belikhina T.I. Ob"ektivizatsiya markerov radiatsionnogo povrezhdeniya v gruppakh radiatsionnogo riska, predstavlennykh eksponirovannym radiatsiei naseleniem VKO i ikh potomkami [Objectification markers of radiation damage in radiation risk groups represented by the radiation—exposed population of East Kazakhstan region and their offsprings]. Nauka i Zdravoohranenie [Science & Healthcare]. 2011. N 4. pp. 20—22. [in Russian]

2. Apsalikov R.K. Otsenka meditsinskikh poter' sredi lits, prozhivayushchikh na territoriyakh, prilegayushchikh k semipalatinskomu yadernomu poligonu v otdalennom periode [Evaluation of health loss among people living in the areas adjacent to the Semipalatinsk nuclear test site in

the long term]. Nauka i Zdravoohranenie [Science & Healthcare]. 2013. N 5. pp. 49-52. [in Russian]

3. Zhetpisbaev B.A., Madieva M.R., Saidakhmetova A.S., Tanatova Z.A., Orazbaeva A.K. i dr. Narushenie metabolizma v legkikh i miokarde pri radiatsionnom porazhenii organizma v eksperimente [Disorder of metabolism in the lungs and the myocardium during radiation injury of the organism in an experiment]. Nauka i Zdravoohranenie [Science & Healthcare]. 2009. T. 2, N 4. pp. 153-154. [in Russian]

4. Zhetpisbaev B.A., Madieva M.R., Saidakhmetova A.S., Tanatova Z.A., Orazbaeva A.K. i dr. Sostoyanie perekisnogo okisleniya lipidov v legkikh i miokarde posle fraktsionirovannogo gamma-oblucheniya [The condition of lipid peroxidation in lung and myocardium after fractionated gammairradiation]. Nauka i Zdravoohranenie [Science & Healthcare]. 2009. T. 2, N 4. pp. 127-128. [in Russian]

5. Zhetpisbaev B.A., Serimkhanova B.T., Argynbekova A.S., Musainova A.K., Orazbaeva A.K. i dr. Meditsinskie posledstviya vliyaniya maloi dozy radioaktivnogo zagryazneniya okruzhayushchei sredy [Medical outcomes of low dose effects of the environmental radioactive contamination]. Nauka i Zdravoohranenie [Science & Healthcare]. 2010. T. 1, N 1. pp. 7-11. [in Russian]

6. Manambaeva Z.A., Apsalikov B.A., Zhabagin K.T., Ospanov E.A., Kamzin K.Zh. Rezul'taty luchevoi terapii raka legkikh i primeneniya preduktala [The results of the lung cancer radiotherapy and application preductal]. Nauka i Zdravoohranenie [Science & Healthcare]. 2012. N 5. pp. 124-125. [in Russian]

7. Rakhypbekov T.K., Hoshi M., Stepanenko V.F., Zhumadilov K.Sh., Chaizhunusova N.Zh. i dr. Radiatsionno-biologicheskii eksperiment na komplekse issledovatel'skikh reaktorov «Baikal-1» [Radiation-chemical experiment on complex of research reactors "Baikal-1"]. Chelovek. Energiya. Atom [Human. Energy. Atom]. 2015. N 2 (24). pp. 43-45. [in Russian]

8. Stepanenko V.F., Rakhypbekov T.K., Kaprin A.D., Ivanov S.A., Otani K. i dr. Obluchenie eksperimental'nykh zhivotnykh aktivirovannoi neitronami radioaktivnoi pyl'yu: razrabotka i realizatsiya metoda - pervye rezul'taty mezhdunarodnogo mnogotsentrovogo

issledovaniya [Irradiation of laboratory animals by neutron activated dust: development and application of the method - first results of international multicenter study]. Radiatsiya i risk [Radiation and risk]. 2016. T. 25, N 4. pp. 112125. [in Russian]

9. Abuo El Naga I., Abd Rabou M. The possible protective role of bone marrow transplantation on irradiated mothers and their fetuses. Stem Cell. 2012. Vol. 3, N 3. pp. 8-30.

10. Baker R., Han G., Sarangkasiri S., DeMarco M., Turke C. et al. Clinical and dosimetric predictors of radiation pneumonitis in a large series of patients treated with stereotactic body radiation therapy to the lung. Int. J. Radiat. Oncol. Biol. Phys. 2013. Vol. 85, N 1. pp. 190-195.

11. Bocchino M., Agnese S., Fagone E., Svegliati S., Grieco D. et al. Reactive oxygen species are required for maintenance and differentiation of primary lung fibroblasts in idiopathic pulmonary fibrosis. PLoS One. 2010. Vol. 5, N 1. 14003 p.

12. Borie R., Tabeze L., Thabut G., Nunes H., Cottin V. et al. Prevalence and characteristics of TERT and TERC mutations in suspected genetic pulmonary fibrosis. Eur. Respir. J. 2016. Vol. 48, N 6. pp. 1721-1731.

13. Borst G.R., Ishikawa M., Nijkamp J., Hauptmann M., Shirato H. et al. Radiation pneumonitis in patients treated for malignant pulmonary lesions with hypofractionated radiation therapy. Radiother. Oncol. 2009. Vol. 91, N 3. pp. 307-313.

14. Bromet E.J., Havenaar J.M., Guey L.T. A 25 year retrospective review of the psychological consequences of the Chernobyl accident. Clin. Oncol. 2011. Vol. 23, N 4. pp. 297-305.

15. Brush J., Lipnick S.L., Phillips T., Sitko J., McDonald J.T. et al. Molecular mechanisms of late normal tissue injury. Semin. Radiat. Oncol. 2007. Vol. 17, N 2. pp. 121-130.

16. Burnette B., Weichselbaum R.R. Radiation as an immune modulator. Semin. Radiat. Oncol. 2013. Vol. 23, N 4. pp. 273-280.

17. Cappuccini F., Eldh T., Bruder D., Gereke M., Jastrow H. et al. New insights into the molecular pathology of radiation-induced pneumopathy. Radiother. Oncol. 2011. Vol. 101, N 1. pp. 86-92.

18. Chen H., Xiang H., Wu B., Zhang X., Li M. et al. Manganese superoxide dismutase gene

modified mesenchymal stem cells attenuates acute radiation-induced lung injury. Hum. Gene Ther. 2016. N 4. pp. 517-529.

19. Claudia C. Advances in mechanisms of repair and remodeling in acute lung injury. Intensive Care Medicine. 2008. Vol. 34, N 4. pp. 619-630.

20. Davis B.K., Wen H., Ting J.P. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu. Rev. Immunol. 2011. Vol. 29. pp. 707-735.

21. Diederich S. Chest CT for suspected pulmonary complications of oncologic therapies: how I review and report. Cancer Imaging. 2016. Vol. 16. 7 p.

22. Ding N.H., Li J.J., Sun L.Q. Molecular mechanisms and treatment of radiation-induced lung fibrosis. Curr. Drug Targets. 2013. Vol. 14, N

11. pp. 1347-1356.

23. Dorn P., Tieche C.C., Peng R.W., Froment L., Schmid R.A. et al. Schedule-dependent increased efficiency of pemetrexed-ionizing radiation combination therapy elicits a differential DNA damage response in lung cancer cells. Cancer Cell Int. 2016. Vol. 16, N 1. 66 p.

24. Epler G.R., Kelly E.M. Systematic review of postradiotherapy bronchiolitis obliterans organizing pneumonia in women with breast cancer. Oncologist. 2014. Vol. 19, N 12. pp. 1216-1226.

25. Fleckenstein K., Gauter-Fleckenstein B., Jackson I., Rabbani Z., Anscher M. et al. Using biological markers to predict risk of radiation injury. Semin. Radiat. Oncol. 2007. Vol. 17, N 2. pp. 89-98.

26. Franchi L., Eigenbrod T., Munoz-Planillo R., Nunez G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat. Immunol. 2009. Vol. 10, N 3. pp. 241-247.

27. Fujino M., Shirato H., Onishi H., Kawamura H., Takayama K. et al. Characteristics of patients who developed radiation pneumonitis requiring steroid therapy after stereotactic irradiation for lung tumors. Cancer J. 2006. Vol.

12, N 1. pp. 41-46.

28. Gao F., Fish B.L., Moulder J.E., Jacobs E.R., Medhora M. Enalapril mitigates radiation-induced pneumonitis and pulmonary fibrosis if started 35 days after whole-thorax irradiation. Radiat. Res. 2013. Vol. 180, N 5. pp. 546-552.

29. Garofalo M., Bennett A., Farese A.M., Harper J., Ward A. et al. The delayed pulmonary syndrome following acute high-dose irradiation: a rhesus macaque model. Health Phys. 2014. Vol. 106, N 1. pp. 56-72.

30. Ghafoori P., Marks L.B., Vujaskovic Z., Kelsey C.R. Radiation-induced lung injury. Assessment, management, and prevention. Oncology (Williston Park). 2008. Vol. 22, N 1. pp. 37-47.

31. Ghobadi G., Bartelds B., van der Veen S.J., Dickinson M.G., Brandenburg S. et al. Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension. Thorax. 2012. Vol. 67, N 4. pp. 334-341.

32. Ghosh S.N., Wu Q., Mader M., Fish B.L., Moulder J.E. et al. Vascular injury after whole thoracic x-ray irradiation in the rat. Int. J. Radiat. Oncol. Biol. Phys. 2009. Vol. 74, N 1. pp. 192-199.

33. Goertz O., Poettgen C., Akbari A., Kolbenschlag J., Langer S. et al. New model for long-term investigations of cutaneous microcirculatory and inflammatory changes following irradiation. J. Radiat. Res. 2015. Vol. 56, N 3. pp. 456-461.

34. Gong H.Y., Hu W.G., Hu Q.Y., Li X.P., Song Q.B. Radiation-induced pulmonary injury accelerated pulmonary metastasis in a mouse model of breast cancer. Oncol. Lett. 2015. Vol. 10, N 6. pp. 3613-3618.

35. Groves A.M., Johnston C.J., Misra R.S., Williams J.P., Finkelstein J.N. Effects of IL-4 on pulmonary fibrosis and the accumulation and phenotype of macrophage subpopulations following thoracic irradiation. Int. J. Radiat. Biol. 2016. Vol. 92, N 12. pp. 754-765.

36. Hamada N., Fujimichi Y. Classification of radiation effects for dose limitation purposes: history, current situation and future prospects. J. Radiat. Res. 2014. Vol. 55, N 4. pp. 629-640.

37. Han G., Zhang H., Xie C.H., Zhou Y.F. Th2-like immune response in radiation-induced lung fibrosis. Oncol. Rep. 2011. Vol. 26, N 2. pp. 383-388.

38. Haston C.K., Begin M., Dorion G., Cory S.M. Distinct loci influence radiation-induced alveolitis from fibrosing alveolitis in the mouse. Cancer Res. 2007. Vol. 67, N 22. pp. 1079610803.

39. Hirai Y., Kodama Y., Cullings H.M., Miyazawa C., Kanamura N. Electron spin resonance analysis of tooth enamel does not indicate exposure to large radiation doses in a large proportion of distally—exposed A—bomb survivors. Radiat. Res. 2011. Vol. 52. pp. 600— 608.

40. Hiyama K., Tanimoto K., Nishimura Y., Tsugane M., Fukuba I. et al. Exploration of the genes responsible for unlimited proliferation of immortalized lung fibroblasts. Exp. Lung Res. 2008. Vol. 34, N 7. pp. 373—390.

41. Hong Z.Y, Eun S.H., Park K., Choi W.H., Lee J.I. et al. Development of a small animal model to simulate clinical stereotactic body radiotherapy—induced central and peripheral lung injuries. J. Radiat. Res. 2014. Vol. 55, N 4. pp. 648—657.

42. Hong Z.Y., Song K.H., Yoon J.H., Cho J., Story M.D. An experimental model—based exploration of cytokines in ablative radiation— induced lung injury in vivo and in vitro. Lung. 2015. Vol. 193, N 3. pp. 409—419.

43. Hu Y., Li J., Su X. Fatal pneumonitis associated with postoperative intensity— modulated radiotherapy in lung cancer: case report and review. Oncol. Lett. 2013. Vol. 5, N 2. pp. 714—716.

44. Jang S.S., Kim H.G., Han J.M., Lee J.S., Choi M.K. et al. Modulation of radiation—induced alterations in oxidative stress and cytokine expression in lung tissue by Panax ginseng extract. Phytother. Res. 2015. Vol. 29, N 2. pp. 201—209.

45. Jenkins P., Welsh A. Computed tomography appearance of early radiation injury to the lung: correlation with clinical and dosimetric factors. Int. J. Radiat. Oncol. Biol. Phys. 2011. Vol. 81, N 1. pp. 97—103.

46. Jiang X., Qu C., Chang P., Zhang C., Qu Y. et al. Intravenous delivery of adipose—derived mesenchymal stromal cells attenuates acute radiation—induced lung injury in rats. Cytotherapy. 2015. Vol. 17, N 5. pp. 560—570.

47. Kalash R., Berhane H., Au J., Rhieu B.H., Epperly M.W. et al. Differences in irradiated lung gene transcription between fibrosis—prone C57BL/6NHsd and fibrosis—resistant C3H/HeNHsd mice. In Vivo. 2014. Vol. 28, N 2. pp. 147—171.

48. Kano A., Ujita M., Kobayashi M., Sunakawa Y., Shirahama J. et al. Radiographic and CT features of radiation-induced organizing pneumonia syndrome after breast-conserving therapy. Jpn J. Radiol. 2012. Vol. 30, N 2. pp. 128-136.

49. Kerr G.D., Egbert S.D., Al-Nabulsi I., Bailiff I.K., Beck H.L. et al. Workshop report on atomic bomb dosimetry-review of dose related factors for the evaluation of exposures to residual radiation at Hiroshima and Nagasaki. Health Phys. 2015. Vol. 109, N 6. pp. 581-600.

50. Kerr G.D., Egbert S.D., Al-Nabulsi I., Beck H.L., Cullings H.M. et al. Workshop report on atomic bomb dosimetry-residual radiation exposure: recent research and suggestions for future studies. Health Phys. 2013. Vol. 105, N 2. pp. 140-149.

51. Khalil A.A., Hoffmann L., Moeller D.S., Farr K.P., Knap M.M. New dose constraint reduces radiation-induced fatal pneumonitis in locally advanced non-small cell lung cancer patients treated with intensity-modulated radiotherapy. Acta Oncol. 2015. Vol. 54, N 9. pp. 1343-1349.

52. Kim B.Y., Jin H., Lee Y.J., Kang G.Y., Cho J. et al. Focal exposure of limited lung volumes to high-dose irradiation down-regulated organ development-related functions and up-regulated the immune response in mouse pulmonary tissues. BMC Genet. 2016. Vol. 17. 29 p.

53. Li M., Abdollahi A., Grone H.J., Lipson K.E., Belka C. et al. Late treatment with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse model. Radiat. Oncol. 2009. Vol. 4. 66 p.

54. Liang H., Deng L., Chmura S., Burnette B., Liadis N. et al. Radiation-induced equilibrium is a balance between tumor cell proliferation and T cell-mediated killing. J. Immunol. 2013. Vol. 190, N 11. pp. 5874-5881.

55. Liu Y., Xia T., Zhang W., Zhong Y., Zhang L. et al. Variations of circulating endothelial progenitor cells and transforming growth factor-beta-1 (TGF-ß1) during thoracic radiotherapy are predictive for radiation pneumonitis. Radiat. Oncol. 2013. Vol. 8. 189 p.

56. Maddams J., Parkin D.M., Darby S.C. The cancer burden in the United Kingdom in 2007 due to radiotherapy. Int. J. Cancer. 2011. Vol. 129, N 12. pp. 2885-2893.

57. Maebayashi T., Ishibashi N., Aizawa T., Sakaguchi M., Sato T. et al. Radiation pneumonitis changes over time after stereotactic body radiation therapy for lung tumors: Post-treatment Cavity (Sunny-side-up Egg-like) Changes. Anticancer Res. 2016. Vol. 36, N 10. pp.5563-5570.

58. Marples B., Downing L., Sawarynski K.E., Finkelstein J.N., Williams J.P. et al. Pulmonary injury after combined exposures to low-dose low-lEt radiation and fungal spores. Radiat. Res. 2011. Vol. 175, N 4. pp. 501-509.

59. Mazeron R., Etienne-Mastroianni B., Perol D., Arpin D., Vincent M. et al. Predictive factors of late radiation fibrosis: a prospective study in non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 2010. Vol. 77, N 1. pp. 38-43.

60. Medhora M., Gao F., Jacobs E.R., Moulder J.E. Radiation damage to the lung: mitigation by angiotensin-converting enzyme (ACE) inhibitors. Respirology. 2012. Vol. 17, N. 1. pp. 66-71.

61. Mehrad B., Strieter R.M. Fibrocytes and the pathogenesis of diffuse parenchymal lung disease. Fibrogenesis & Tissue Repair. 2012. Vol. 5, N 1. 22 p.

62. Molthen R.C., Wu Q., Fish B.L., Moulder J.E., Jacobs E.R. et al. Mitigation of radiation induced pulmonary vascular injury by delayed treatment with captopril. Respirology. 2012. Vol. 17, N 8. pp. 1261-1268.

63. Moore B.B., Hogaboam C.M. Murine models of pulmonary fibrosis. Am J. Physiol. Lung Cell. Mol. Physiol. 2008. Vol. 294. pp. 152-160.

64. Murofushi K.N., Oguchi M., Gosho M., Kozuka T., Sakurai H. Radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome in breast cancer patients is associated with age. Radiat Oncol. 2015. Vol. 10. 103 p.

65. Nuovo G.J., Garofalo M., Valeri N., Roulstone V., Volinia S. et al. Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples. Mod. Pathol. 2012. Vol. 25, N 10. pp. 1333-1344.

66. Ochiai S., Nomoto Y., Yamashita Y., Murashima S., Hasegawa D. et al. Radiation-induced organizing pneumonia after stereotactic body radiotherapy for lung tumor. J. Radiat. Res. 2015. Vol. 56, N 6. pp. 904-911.

67. Oie Y., Saito Y., Kato M., Ito F., Hattori H. et al. Relationship between radiation pneumonitis and organizing pneumonia after radiotherapy for breast cancer. Radiat. Oncol. 2013. Vol. 8. 56 p.

68. Palmer J.D., Zaorosky N.G., Witek M., Lu

B. Molecular markers to predict clinical outcome and radiation-induced toxicity in lung cancer. J. Thorac. Dis. 2014. Vol. 6, N 4. pp. 387-398.

69. Park K.J., Oh Y.T., Kil W.J., Park W., Kang S.H. et al. Bronchoalveolar lavage findings of radiation induced lung damage in rats. J. Radiat. Res. 2009. Vol. 50, N 3. pp. 177-182.

70. Paun A., Haston C.K. Genomic and genome-wide association of susceptibility to radiation-induced fibrotic lung disease in mice. Radiother. Oncol. 2012. Vol. 105, N 3. pp. 350357.

71. Paun A., Kunwar A., Haston C.K. Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice. Radiat. Oncol. 2015. Vol. 10. 45 p.

72. Pietrofesa R.A., Solomides C.C., Christofidou-Solomidou M. Flaxseed mitigates acute oxidative lung damage in a mouse model of repeated radiation and hyperoxia exposure associated with space exploration. J. Pulm. Respir. Med. 2014. Vol. 4, N 6. pp. 215-224.

73. Porcel J.M., Azzopardi M., Koegelenberg

C.F., Maldonado F. et al. The diagnosis of pleural effusions. Expert Rev. Respir. Med. 2015. Vol. 9, N 6. pp. 801-815.

74. Preston D.L., Ron E., Tokuoka S., Funamoto S., Nishi N. et al. Solid cancer incidence in atomic bomb survivors: 1958-1998. Radiat. Res. 2007. Vol. 168, N 1. pp. 1-64.

75. Rube C.E., Palm J., Erren M., Fleckenstein J., König J. et al. Cytokine plasma levels: reliable predictors for radiation pneumonitis? PLoS One. 2008. Vol. 3, N 8. 2898 p.

76. Ryerson C.J., Hartman T., Elicker B.M., Ley B., Lee J.S. et al. Clinical features and outcomes in combined pulmonary fibrosis and emphysema in idiopathic pulmonary fibrosis. Chest. 2013. Vol. 144, N 1. pp. 234-240.

77. Saintigny P., Burger J.A. Recent advances in non-small cell lung cancer biology and clinical management. Discov. Med. 2012. Vol. 13, N 71. pp. 287-297.

78. Saito-Fujita T., Iwakawa M., Nakamura E., Nakawatari M., Fujita H. et al. Attenuated lung fibrosis in interleukin 6 knock-out mice after C-

ion irradiation to lung. J. Radiat. Res. 2011. Vol. 52, N 3. pp. 270-277.

79. Schallenkamp J.M., Miller R.C., Brinkmann D.H., Foote T., Garces Y.I. Incidence of radiation pneumonitis after thoracic irradiation: Dosevolume correlates. Int. J. Radiat. Oncol. Biol. Phys. 2007. Vol. 67, N 2. pp. 410-416.

80. Shank B. Toxicity due to total body irradiation. Hum. Radiat. Injury. 2010. N 1. pp. 133-139.

81. Shi A., Zhu G., Wu H., Yu R., Li F. et al. Analysis of clinical and dosimetric factors associated with severe acute radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent chemotherapy and intensity-modulated radiotherapy. Radiat. Oncol. 2010. Vol. 5. 35 p.

82. Siva S., MacManus M., Kron T., Best N., Smith J. et al. A pattern of early radiation-induced inflammatory cytokine expression is associated with lung toxicity in patients with non-small cell lung cancer. PLoS One. 2014. Vol. 9, N 10. 560 p.

83. Sohn S.H., Lee J.M., Park S., Yoo H., Kang J.W. et al. The inflammasome accelerates radiation-induced lung inflammation and fibrosis in mice. Environ. Toxicol. Pharmacol. 2015. Vol. 39, N 2. pp. 917-926.

84. Stewart F.A., Akleyev A.V., Hauer-Jensen M., Hendry J.H., Kleiman N.J. et al. ICRP Publication 118: ICRP Statement on tissue reactions, early and late effects of radiation in normal tissues and organs-threshold doses for tissue reactions in a radiation protection context. Ann. ICRP. 2012. Vol. 41, N 1/2. 322 p.

85. Terashima T., Iwami E., Chubachi S., Ikemura S., Nakajima T. et al. A case of small cell lung cancer treated with concurrent chemoradiotherapy with carboplatin plus etoposide in a hemodialysis patient. Gan To Kagaku Ryoho. 2016. Vol. 43, N 1. pp. 99-101.

86. Todd N.W., Luzina I.G., Atamas S.P. Molecular and cellular mechanisms of pulmonary fibrosis // Fibrogenesis & Tissue Repair. 2012. Vol. 5, N 1. 11 p.

87. Ulubay G., Kupeli E., Er Dedekarginoglu B., Savas Bozbas S., Alekberov M. et al. Postoperative pleural effusions after orthotopic heart transplant: cause, clinical manifestations, and course. Exp. Clin. Transplant. 2016. Vol. 14, N 3. pp. 125-129.

88. Uzbekov D., Hoshi M., Shichijo K., Chaizhunusova N., Shabdarbaeva D. et al. Radiation effects on morphofunctional state of the respiratory system. Astana medical journal. 2016. N 4 (90). pp. 56-62.

89. Uzbekov D., Shichijo K., Chaizhunusova N., Shabdarbaeva D., Sayakenov N. et al. Radiation effects on the pulmonary histological structure of experimental rats // XII International scientific-practical conference «Ecology. Radiation. Health» dedicated to academician B. Atchabarov and 25 years from the date of closing of Semipalatinsk nuclear test site. Science & Healthcare. Semey, 2016. 185 p.

90. Van der Veen S.J., Ghobadi G., de Boer R.A., Faber H., Cannon M.V. et al. ACE inhibition attenuates radiation-induced cardiopulmonary damage. Radiother. Oncol. 2015. Vol. 114, N 1. pp. 96-103.

91. Walkin L., Herrick S.E., Summers A., Brenchley P.E., Hoff C.M. et al. The role of mouse strain differences in the susceptibility to fibrosis: a systematic review. Fibrogenesis & Tissue Repair. 2013. Vol. 6, N 1. 18 p.

92. Wang D., Shi J., Liang S., Lu S., Qi X. et al. Dose-volume histogram parameters for predicting radiation pneumonitis using receiver operating characteristic curve. Clin. Transl. Oncol. 2013. Vol. 15, N 5. pp. 364-369.

93. Wang L.P., Wang Y.W., Wang B.Z., Sun G.M., Wang X.Y. et al. Expression of interleukin-17A in lung tissues of irradiated mice and the influence of dexamethasone. Scientific World Journal. 2014. Vol. 2014. 251067 p.

94. Westbury C.B., Yarnold J.R. Radiation fibrosis - current clinical and therapeutic perspectives. Clin. Oncol. (R. Coll. Radiol). 2012. Vol. 24, N 10. pp. 657-672.

95. Williams J.P., Brown S.L., Georges G.E., Hauer-Jensen M., Hill R.P. et al. Animal models for medical countermeasures to radiation exposure. Radiat. Res. 2010. Vol. 173, N 4. pp. 557-578.

96. Xie L., Zhou J., Zhang S., Chen Q., Lai R. et al. Integrating microRNA and mRNA expression profiles in response to radiation-induced injury in rat lung. Radiat. Oncol. 2014. Vol. 9. 111 p.

97. Xu L., Xiong S., Guo R., Yang Z., Wang Q. et al. Transforming growth factor 03 attenuates the development of radiation-induced pulmonary fibrosis in mice by decreasing fibrocyte recruitment and regulating IFN-y/IL-4 balance. Immunol. Lett. 2014. Vol. 162, N 1 (A). pp. 27-33.

98. Yamada M., Kasagi F., Mimori Y., Miyachi T., Ohshita T. et al. Incidence of dementia among atomic-bomb survivors - radiation effects research foundation adult health study. J. Neurol. Sci. 2009. Vol. 281, N 1-2. pp. 11-14.

99. Yang S., Zhang M., Chen C., Cao Y., Tian Y. et al. Triptolide mitigates radiation-induced pulmonary fibrosis. Radiat. Res. 2015. Vol. 184, N 5. pp. 509-517.

100. Zhang R., Ghosh S.N., Zhu D., North P.E., Fish B.L. et al. Structural and functional alterations in the rat lung following whole thoracic irradiation with moderate doses: injury and recovery. Int. J. Radiat. Biol. 2008. Vol. 84, N 6. pp. 487-497.

Correspondence:

Uzbekov Darkhan - PhD student in «Medicine» speciality of Semey State Medical University, Department of Pathological anatomy and Forensic medicine, Semey, Kazakhstan. Address: East Kazakhstan region, 071400, Semey city, Shakarim street, 13 A - 72. Phone: +77222569782, +77055301026 E-mail: darkhan.uzbekov@mail.ru