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Autopsy data from 80 patients who died of the COVID-19 infection were analysed. Using macro- and microscopic studies, specific features of pathological processes in various organs were identified. The obtained experimental data, along with information from literature sources, allowed conclusions to be drawn about the mechanisms of damaging internal organs and body systems, as well as assumptions to be made about individual links in the pathogenesis of COVID-19. The thanatogenesis of the disease and the main causes of death are discussed, including acute cardiopulmonary failure, acute renal failure, pulmonary thromboembolism, shock involving multiple organ failure and sepsis. The critical importance of autopsy is emphasized, which provides valuable information on the morphological substrate for this infection closely associated with possible clinical manifestations.

The review of the literature deals with the participation of Clara cells now called club cells (CCs) of the epithelium in the respiratory and terminal bronchioles in the pathogenesis and morphogenesis of chronic inflammatory diseases, precancer, and cancer of the lung, which develop in the respiratory segments. The review summarizes data on the histophysiology of CCs and their participation in the pathogenesis and morphogenesis of chronic interstitial lung diseases, pneumoconiosis, chronic obstructive diseases, adenomatosis, and adenocarcinoma of the lung. In this area, there is a bronchioloalveolar junction area (BAJA), one of the most important stem cell niches. CCs are located in the BAJA; they are progenitor tissue stem cells and play an important role in the regeneration of the epithelium of the respiratory bronchioles and alveoli. Pathology of CCs in the BAJA leads to the maintenance of chronic inflammation, to the destruction of the lung elastic frame, and to impaired epithelial regeneration, interstitial fibrosis, and adenomatosis. In this case, decompensated inflammation, pathological regeneration, and fibrosis develop, which, along with the action of carcinogenic agents, can contribute to the accumulation of mutations and epigenetic rearrangements in the CCs, which subsequently results in atypical adenomatous hyperplasia and adenocarcinoma of the lung.Обзор литературы посвящен участию клеток Клара, или, как их сейчас принято называть, булавовидных клеток (БК) эпителия респираторных и терминальных бронхиол в пато- и морфогенезе хронических воспалительных заболеваний, предрака и рака легкого, развивающихся на территории респираторных отделов. Обобщены данные о гистофизиологии БК и их участии в патогенезе и морфогенезе хронических интерстициальных заболеваний легких, пневмокониозов, хронических обструктивных болезней, аденоматоза и аденокарциномы легкого. В данной области располагается одна из самых важных ниш стволовых клеток - зона бронхиолоальвеолярного перехода (ЗБАП). БК располагаются в ЗБАП, являются прогениторными тканевыми стволовыми клетками и играют важную роль в регенерации эпителия респираторных бронхиол и альвеол. Патология БК в ЗБАП приводит к поддержанию хронического воспаления, разрушению эластического каркаса легкого, нарушениям регенерации эпителия, интерстициальному фиброзу и аденоматозу. При этом развиваются декомпенсированное воспаление, патологическая регенерация и фиброз, которые наряду с действием канцерогенных агентов могут способствовать накоплению мутаций и эпигенетических перестроек в БК, что впоследствии заканчивается возникновением атипической аденоматозной гиперплазии и аденокарциномы легкого.

The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches (SCN) in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic idiopathic interstitial pneumonias (IIP), including idiopathic pulmonary fibrosis (IPF), desquamative interstitial pneumonia (DIP), cryptogenic organizing pneumonia (COP) with bronchiolitis obliterans (BO), and nonspecific interstitial pneumonia (NSIP).The study was performed using open transthoracic (n=181) and transbronchial (n=71) lung biopsies from 194 patients (118 cases (61%) with IPF, 35 (18%) with NSIP, 23 (12%) with DIP, 18 (9%) with COP + BO). The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas ("Novocastra", 1:100), vimentin (Vimentin) ("LabVision" 1:100), SMA ("LabVision", 1:100), TGF-β, TNF-α, CD34, Ost-4, and CD117 ("Dako", 1:50), CD68, and EMA ("Dako", 1:100). Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies ("Dako" LSAB + KIT, PEROXIDASE) were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics.The compared IIPs were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage.The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus.В работе представлены материалы собственного исследования по изучению морфологических и молекулярно-биологических особенностей повреждения зон ниш стволовых клеток (НСК) респираторных отделов легких и значения возникших в них изменений в патогенезе хронических идиопатических интерстициальных пневмоний (ИИП), включая идиопатический легочный фиброз (ИЛФ), десквамативную интерстициальную пневмонию (ДИП), криптогенную организующуюся пневмонию с облитерирующим бронхиолитом (КОП с ОБ) и неспецифическую пневмонию (НСИП). Материал и методы. Работа выполнена на материале открытых трансторакальных (181) и трансбронхиальных (71) биопсий легких от 194 пациентов: ИЛФ - 118 (61%) случаев, НСИП - 35 (18%), ДИП - 23 (12%), КОП с ОБ - 18 (9%) случаев. Серийные парафиновые срезы окрашивали гематоксилином и эозином и пикрофуксином по ван Гизону, ставили иммуногистохимические реакции на выявление MMP 1, 2, 7, Apo-Cas ("Novocastra", 1:100), Виментин (Vimentin) ("LabVision", 1:100), SMA ("LabVision", 1:100), TGFΒ , TNFα, CD34, Oсt-4 и СD117 ("Dako", 1:50), CD68, EMA ("Dako", 1:100). В качестве вторичных антител применяли биотинилированные антитела к иммуноглобулинам мыши и кролика ("Dako" LSAB + KIT, PEROXIDASE). Все полученные количественные и полуколичественные данные обработаны методом вариационной статистики. Результаты. Показано, что сравниваемые ИИП отличаются локализацией и выраженностью инициального и вторичного повреждения респираторных ацинусов, обусловленными степенью агрессивности воспалительного инфильтрата и распространенностью повреждения на различные зоны НСК, участвующие в регенерации легочной ткани. Маркерной клеткой глубокого повреждения НСК можно считать мезенхимальную клетку с миофибробластической дифференцировкой связанную, вероятно, с мезенхимальной стволовой клеткой, что может подтверждаться экспрессией этими клетками Oct-4, Vimentin, SMA, CD117, CD34. Заключение. Авторы утверждают, что клиническое течение и выраженность морфологических изменений при ИИП легких непосредственно зависит от тяжести и глубины повреждения зон НСК респираторного ацинуса.

Fifty-six primary neuroendocrine lung tumors were examined morphologically and histologically and their apoptosis level was determined. Malignant carcinomas were characterized by increased apoptotic index and enhanced expression ofBcl-2, Bak, p53, and Ki-67 compared to typical carcinoid. However, apoptosis in these tumors was not completed. Proteins of the Bcl family play an important role in the regulation of spontaneous apoptosis in neuroendocrine lung tumors. Bcl-2 accumulating in the nucleus is a morphological analogue of phosphorylated inactive form of this protein, which does not inhibit apoptosis. Expression of Bcl-2 and Bax decreases in small-cell lung carcinoma (SCLC) with metastases indicating attenuation of apoptosis and development of metastatic clones resistant to apoptosis induces.

Sarcoidosis is a group of diseases with chronic immune inflammation and granulomas formation in the lung, lymph nodes, and others organs. Under progress of disease remodeling of the lung tissue occurs and at 20-25% of patient with sarcoidosis lung fibrosis is developed. We studied biopsies from 50 patients with sarcoidosis and 10 biopsies of pathological intact lung tissue as a control group. Roentgenologic, morphologic and immunohistochemical methods with using of mono- and polyclonal antibody to MMP 1, 2, 9 and TIMP-1, PCNA, aSMA, apo-CAS were realized. The expression levels of growth factors, apoptosis, MMPs, TIMPs were different in various clinic-morphological courses of sarcoidosis. As a rule under sarcoidosis deep remodeling of lung tissue didn't occur in spite of granulomatous inflammation. Granulomatous process, alveolitis (bronchiolitis) and sclerotic changes resulted in alteration of the lung. Cells of sarcoidosis granulomas, produced low level of MMPs and TIMP can't induce evident fibrosis and so hypertension is absent or becomes apparent in the slight form. It apparently can be link with localization of pathologic process in lung tissue without any alterations in the bronchoalveolar zone. Alveolitis under sarcoidosis conditions is notable for low activity of inflammation and doesn't result in interstitial fibrosis developing.

The aim of the investigation was to study the specific features of morphological manifestations and the molecular bases of lung tissue remodeling in progressive idiopathic pulmonary fibrosis (IPF). The investigation used open and transbronchial biopsy specimens from 110 patients with IPE/idiopathic pneumonia syndrome in 1997 to 2008. Immunohistochemical analysis was carried out on serial paraffin-embedded lung tissue slices from 20 patients with IPF and 20 control patients. Immunohistochemical staining for the detection of antigens in the paraffin-embedded slices was made using the antibodies to MMP-1, MMP-2, MMP-7, TIMP-4, Apo-CAS, PCNA, PDGF, EGFR, CD34, and SMA. Nonparametric statistical methods were employed. Our findings have indicated that in early-stage IPF, there are proliferating myofibroblasts in the myofibroblastic foci, mainly in the bronchioloalveolar transitional zone (BATZ), which express PCNA and PDGF. Both in early- and late-stage IPF, there were signs of increased readiness of the alveolar and bronchiolar epithelium of BATZ for apoptosis, as judged from Apo-CAS expression. At the same time no Apo-CAS expression was recorded in the myofibroblasts. In the early stage of the disease, the expression of MMP-1, MMP-2, MMP-7, and TIMP-4 in the epitheliocytes, macrophages, fibroblasts, and myofibroblasts was higher than that in the late stage of IPF. At the same time, late-stage IPF was characterized by the higher expression in all lung tissue cells than was early-stage IPF. There was also a significant increase in vessel density in both early and late stages of IPF as compared with intact lung tissue particularly in the BATZ in the control group. Thus, lung tissue remodeling in the progression of IPF from the early to late stage of the disease comprises interrelated processes that are largely localized in the BATZ, such as immune inflammation with pathological reparation, neoangiogenesis, apoptosis, and proliferation of epitheliocytes and myofibroblasts, which lead to the development of interstitial fibrosis and adenomatosis of the lung.

The purpose of the study was to examine the specific features of morphological manifestations and molecular mechanisms of controlling the processes of proliferation, apoptosis, cell differentiation, neoangiogenesis, and fibrosis, which result in lung tissue rearrangement in different types of idiopathic fibrosing alveolitis (IFA). Open and transbronchial biopsy specimens obtained from 103 patients with IFA and intact lung tissue biopsy specimens taken from those clinically diagnosed as having sarcoidosis as a control group were examined. The serial paraffin sections immunohistochemically revealed the following antigens: cytokeratins 5, 6, 7, 8, 19 (Uni-Heidelberg, DAKO), MMP 1, MMP 2, MMP 7, and TIMP 4, Apo-protein (Novocastra), Ki67, PCNA, PDGF, EGFR, CD34, SMA (smooth muscle actin), FGFb (LabVision). Biotin-conjugated antibodies to murine and rabbit immunoglobulins (Dako LSAB + KIT, PEROXIDASE) were used as secondary antibodies. The nuclei were stained with hematoxylin. Positive and negative control tests were carried out. The results of immunohistochemical tests were estimated in percentage of cells showing positive reactions (Ki67, PCNA), as well as those of a semiquantitative analysis in scores and statistical analyses (Mann-Whitney U-test, Fisher's test, and Spearman's rank correlation coefficient) were employed. OIP was ascertained to differ from other IFA in higher values of the cytokines under study, as well as in the predominant rearrangement of the lung interstice and dysregeratory epithelial changes at the site of respiratory bronchiolar transformation. At the same time there was an intensive proliferation of the epithelium and stromal cells (high expression of PCNA, PDGF by hyperplastic alveolocytes, alveolar macrophages, fibroblasts and myofibroblasts), and neogenesis (the high density of newly formed vessels with endothelial expression of CD34). Elevated alveolocytic apoptosis (from Apo-protein expression) was also observed. Cell proliferation and neoangiogenesis was attained by high MMPs expression. The practical value of the study is that the expression of the study markers may serve as a criterion for differential diagnosis and determination of prognosis in different types of IFA.

Structure, topography and numbers of endocrinocytes in bulbourethral glands of mature men were studied using immunohistochemical demonstration of chromogranin A. Chromogranin-positive cells were found to be predominantly localized in the epithelium of excretory ducts, while they were sparse in the terminal secretory portions. Endocrinocytes in bulbourethral glands were shown to possess argyrophobic properties and to be stained with antibodies against common cytokeratin. The possibility of epithelial histogenesis of bulbourethral gland endocrinocytes is discussed.

Study is devoted to investigation of fluorescent and photodynamic properties of near-infrared photosensitizer bacteriochloriphyllide-serine. The peculiarities of its fluorescence excited by different lasers, dynamics and selectivity of accumulation were investigated. Photodynamic therapy of mice and investigation of tissue de-oxygenation during tumor irradiation were performed. It was shown that bacteriochloriphyllide-serine is an effective photosensitizer for PDT and fluorescent diagnostics of tumors.

Effect of transition from multiple administration of short acting nitrates to once daily use of isosorbide-5-mononitrate on angina class and quality of life was studied in 280 patients with stable angina pectoris. Transition to isosorbide-5-mononitrate was associated with increases of (in units) exercise tolerance (Delta=-6.6+/-0.35, p0.001), satisfaction from treatment (Delta=-2.1+/-0.12, p0.001), degree of psychological discomfort (Delta=-2.8+/-0.21, p0.001), decreases of numbers of attacks of angina (Delta=-4.0+/-0.22, p0.001) and side effects (Delta=-4.1+/-0.29, p0.001), increase of average distance of walking without chest pain or dyspnea (from 372.1+/-415.1 to 586+/-663.5 m), shortening of duration of episodes of angina (from 4.7+/-4.0 to 4.1+/-7.2 min), significant lowering of angina class (p0.0001). Thus in patients with ischemic heart disease long acting formulation of isosorbide-5-mononitrate provided rapid onset and stability of therapeutic action what eventually resulted in effective prevention of attacks of angina and improvement of quality of life.

Surgical material of the lungs and their parts from 31 patients and open biopsies were studied. Proliferative activity (Ki-67, PCNA) and oncomarkers expression (bcl-2, p-53, c-myc, b-TGF, chromogranin-A) were studied immunohistochemically in the foci of various epithelial changes. It is established that a wide spectrum of alterations in pulmonary tissue is associated with variability of precursor cells and may have nosological features.

Neuroendocrine lung tumors (NELT) from 50 patients were studied immunohistochemically. Malignant carcinoid and small-cell lung carcinoma (SCC) have a higher level of apoptosis than ordinary carcinoid. An increase of apoptosis index in NELT coincides with an increase in NELT proliferative activity (Ki-67, Bcl-2, c-myc, p-53) as compared to a typical carcinoid. Phagocytosis of apoptotic bodies was absent in SCC. Classic SCC differs from combined SCC by a higher apoptosis index and lower expression of p-53 and Bcl-2. Metastatic SCC differs from SCC without metastases by lower apoptosis level and higher level of proliferative indices (Ki-67, Bcl-2) of tumor cells. Development of unbalance between apoptosis and proliferation may result from mitosis and apoptosis pathology.

Clinicomorphological analysis of 15 lung carcinomas of patients who had been exposed for a long time to the radiation after the Chernobyl accident was performed. The material consisted of 10 surgical and 5 autopsy cases and was studied at the light, electron microscopic and immunohistochemical level. There were 6 peripheral, 8 central carcinomas and one massive tumor. Fibrous areas with many dust particles were found in peripheral carcinomas. In central tumors chronic obstructive bronchitis with epithelial dysplasia and metaplasia was observed. Carcinoma was represented by various histologic types: small cell (4 cases), combined small cell with squamous differentiation (5 cases), adenocarcinoma (5 cases), adenosquamous type (1 case). Peculiar calcium deposits in both stroma and parenchyma were found in tumors with glandular differentiation. Morphogenesis of calcium microdeposits may be connected with dust radioactive particles elimination. Central carcinoma had, in the majority of cases, a neuroendocrine differentiation and can be related to some types of small cell carcinoma. Peripheral cancer was mostly of a glandular differentiation and was, as a rule, carcinoma in the scar. Lung carcinomas studied had peculiar molecular-genetic features: lack or low bcl-2 expression, low Ki-67 expression and a high degree of c-myc expression. Tumors were characterized by a low apoptosis index independently of a histologic type. Apoptosis was not complete: lack of apoptotic bodies phagocytosis this resulting in postapoptotic detritus formation.