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Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease, characterized by progressive parenchymal fibrosis and respiratory failure. In a model of bleomycin-induced pulmonary fibrosis, the antifibrotic and anti-inflammatory activity of Longidaze (Bovhyaluronidase Azoxymer), which contains a conjugate of the hyaluronidase enzyme with a high molecular weight synthetic carrier azoxymer bromide, was investigated. Experiments were conducted in male C57BL/6 mice. Longidaze was administered at different doses by intranasal and intramuscular routes. Histology, hematology, and enzyme-linked immunosorbent assay were used in the study. The use of Longidaze reduced pulmonary fibrosis, as evidenced by an improvement in histopathologic damage to the lungs, a decrease in the area of connective tissue, and the levels of profibrotic factors (TGF-ß1, hydroxyproline, collagen I) in lung tissue. In addition, Longidaze inhibited the inflammatory response in pulmonary fibrosis, and decreased the levels of IL-6, TNF-α, and hyaluronic acid in lung tissue and the recruitment of inflammatory cells into lung tissue. The highest therapeutic efficacy was observed with the use of Longidaze at doses of 120 and 1200 U/kg intramuscularly, which was superior to that of the reference drug pirfenidone axunio. The data presented in this study suggest that Longidaze is a new and promising drug for the treatment of IPF that warrants further investigation in patients with fibrotic interstitial lung disease.
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Using a model of Lewis lung carcinoma (LLC) in vitro and in vivo, we previously demonstrated increased antitumor activity in CD8+ T-cells reprogrammed with an MEK inhibitor and PD-1 blocker. In this follow-up study, we carried out the reprogramming of human CD8+ T-cells (hrT-cell) using the MEK inhibitor and PD-1 blocker and targeted LLC cells. The effects of hrT-cell therapy were studied in a mouse model of spontaneous metastasis of a solid LLC tumor. We found antimetastatic activity of hrT-cells, a decrease in the number of cancer cells and cancer stem cells in the lungs, and an increase in the number of T-cells in the blood (including effector T-cells). Thus, reprogramming of human CD8+ T-cells with an MEK inhibitor and PD-1 blocker with targeted training by tumor target cells is a potential platform for developing a new approach to targeted lung cancer therapy.
Assuntos
Carcinoma Pulmonar de Lewis , Neoplasias Pulmonares , Animais , Camundongos , Humanos , Carcinoma Pulmonar de Lewis/terapia , Carcinoma Pulmonar de Lewis/patologia , Camundongos Endogâmicos C57BL , Linfócitos T CD8-Positivos/patologia , Seguimentos , Receptor de Morte Celular Programada 1 , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/secundário , Quinases de Proteína Quinase Ativadas por MitógenoRESUMO
Current methods for diagnosis and treatment of small cell lung cancer (SCLC) have only a modest efficacy. In this pilot study, we analyzed circulating tumor cells (CTCs) and cancer stem cells (CSCs) in patients with SCLC to search for new diagnostic and prognostic markers and novel approaches to improve the treatment of the disease. In other forms of lung cancer, we showed a heterogeneity of blood CTCs and CSCs populations, as well as changes in other cell populations (ALDH+, CD87+CD276+, and EGF+Axl+) in smokers. A number of CTCs and CSCs in patients with SCLC have been shown to be resistant to chemotherapy (CT). High cytotoxic activity and resistance to apoptosis of reprogrammed CD3+CD8+ T-lymphocytes (rTcells) in relation to naive CD3+CD8+ T-lymphocytes was demonstrated in a smoking patient with SCLC (Patient G) in vitro. The target for rTcells was patient G's blood CSCs. Reprogramming of CD3+CD8+ T-lymphocytes was carried out with the MEK1/2 inhibitor and PD-1/PD-L1 pathway blocker nivolumab. The training procedure was performed with a suspension of dead CTCs and CSCs obtained from patient's G blood. The presented data show a new avenue for personalized SCLC diagnosis and targeted improvement of chemotherapy based on the use of both CTCs and CSCs.
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Neoplasias Pulmonares , Células Neoplásicas Circulantes , Carcinoma de Pequenas Células do Pulmão , Antígenos B7 , Antígeno B7-H1/metabolismo , Fator de Crescimento Epidérmico , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Células Neoplásicas Circulantes/patologia , Células-Tronco Neoplásicas/metabolismo , Nivolumabe , Projetos Piloto , Receptor de Morte Celular Programada 1 , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
CD8+ T-lymphocytes play a key role in antitumor immune response. Patients with lung cancer often suffer from T-lymphocyte dysfunction and low T-cell counts. The exhaustion of effector T-lymphocytes largely limits the effectiveness of therapy. In this study, reprogrammed T-lymphocytes used MEK inhibitors and PD-1 blockers to increase their antitumor activity. Antitumor effects of reprogrammed T-lymphocytes were shown in vitro and in vivo in the Lewis lung carcinoma model. The population of T- lymphocytes with persistent expression of CCR7 was formed as a result of reprogramming. Reprogrammed T-lymphocytes were resistant to apoptosis and characterized by high cytotoxicity against Lewis lung carcinoma (LLC) cells in vitro. Administration of reprogrammed T-lymphocytes to C57BL/6 mice with LLC reduced the number of lung metastases. The antitumor effect resulted from the elimination of tumor cells and cancer stem cells, and the effect of therapy on cytotoxic T-lymphocyte counts. Thus, reprogramming of T-lymphocytes using MEK inhibitors is a promising approach for targeted therapy of lung cancer.
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Despite the increasing urgency of the problem of treating small cell lung cancer (SCLC), information on the causes of its development is fragmentary. There is no complete understanding of the features of antitumor immunity and the role of the microenvironment in the development of SCLC resistance. This impedes the development of new methods for the diagnosis and treatment of SCLC. Lung cancer and chronic obstructive pulmonary disease (COPD) have common pathogenetic factors. COPD is a risk factor for lung cancer including SCLC. Therefore, the search for effective approaches to prevention, diagnosis, and treatment of SCLC in patients with COPD is an urgent task. This review provides information on the etiology and pathogenesis of SCLC, analyses the effectiveness of current treatment options, and critically evaluates the potential of chimeric antigen receptor T cells therapy (CART therapy) in SCLC. Moreover, we discuss potential links between lung cancer and COPD and the role of endothelium in the development of COPD. Finally, we propose a new approach for increasing the efficacy of CART therapy in SCLC.
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New drug targets, markers of disease prognosis, and more efficient treatment options are an unmet clinical need in breast cancer (BC). We have conducted a pilot study including patients with luminal B stage breast cancer IIA-IIIB. The presence and frequency of various populations of cancer stem cells (CSC) and somatic stem cells were assessed in the blood, breast tumor tissue, and normal breast tissue. Our results suggest that patients with BC can be divided into two distinct groups based on the frequency of aldehyde dehydrogenase positive cells (ALDH1+ cells) in the blood (ALDH1hi and ALDH1low). In the ALDH1hi cells group, the tumor is dominated by epithelial tumor cells CD44+CD24low, CD326+CD44+CD24-, and CD326-CD49f+, while in the ALDH1low cells group, CSCs of mesenchymal origin and epithelial tumor cells (CD227+CD44+CD24- and CD44+CD24-CD49f+) are predominant. In vitro CSCs of the ALDH1low cells group expressing CD326 showed high resistance to cytostatics, CD227+ CSCs of the ALDH1hi cells group are sensitive to cytostatics. Epithelial precursors of a healthy mammary gland were revealed in normal breast tissue of patients with BC from both groups. The cells were associated with a positive effect of chemotherapy and remission in BC patients. Thus, dynamic control of their presence in blood and assessment of the sensitivity of CSCs to cytostatics in vitro can improve the effectiveness of chemotherapy in BC.
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Concentration of hyaluronic acid (HA) in the lungs increases in idiopathic pulmonary fibrosis (IPF). HA is involved in the organization of fibrin, fibronectin, and collagen. HA has been proposed to be a biomarker of fibrosis and a potential target for antifibrotic therapy. Hyaluronidase (HD) breaks down HA into fragments, but is a subject of rapid hydrolysis. A conjugate of poloxamer hyaluronidase (pHD) was prepared using protein immobilization with ionizing radiation. In a model of bleomycin-induced pulmonary fibrosis, pHD decreased the level of tissue IL-1ß and TGF-ß, prevented the infiltration of the lung parenchyma by CD16+ cells, and reduced perivascular and peribronchial inflammation. Simultaneously, a decrease in the concentrations of HA, hydroxyproline, collagen 1, total soluble collagen, and the area of connective tissue in the lungs was observed. The effects of pHD were significantly stronger compared to native HD which can be attributed to the higher stability of pHD. Additional spiperone administration increased the anti-inflammatory and antifibrotic effects of pHD and accelerated the regeneration of the damaged lung. The potentiating effects of spiperone can be explained by the disruption of the dopamine-induced mobilization and migration of fibroblast progenitor cells into the lungs and differentiation of lung mesenchymal stem cells (MSC) into cells of stromal lines. Thus, a combination of pHD and spiperone may represent a promising approach for the treatment of IPF and lung regeneration.
Assuntos
Ácido Hialurônico/metabolismo , Hialuronoglucosaminidase/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/efeitos dos fármacos , Espiperona/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Hialuronoglucosaminidase/administração & dosagem , Hialuronoglucosaminidase/farmacocinética , Hidroxiprolina/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/enzimologia , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Queratinas/metabolismo , Pulmão/enzimologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Poloxâmero/química , Receptores de IgG/metabolismo , Espiperona/administração & dosagem , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Endothelial dysfunction and destruction of the pulmonary microcirculation are important pathogenic factors in chronic obstructive pulmonary disease (COPD). In COPD, bronchial obstruction is associated with endothelial dysfunction. Thus, new pharmacological treatment options aimed at restoring the pulmonary endothelium represent a clinical need in COPD therapy. Notch1 has been shown to protect cells against apoptosis, inflammation, and oxidative stress caused by cigarette smoke extract (CSE). Therefore, drug which effect on Notch1 may be a potential therapeutic target for COPD in the future. METHODS: In this study, we assessed the potential of spiperone to mediate regeneration of pulmonary endothelium in model of pulmonary emphysema induced by a CSE and lipopolysaccharide (LPS) in female C57BL/6 mice. RESULTS: Spiperone increased the number of capillaries as well as the expression of the CD31 in the alveolar tissue compared to the controls. Moreover, application of spiperone prevented alveolar wall destruction (DI), and reduced the area of emphysema. Lastly, we demonstrated that spiperone positively influenced mobilization and migration of endothelial progenitor cells (EPC, CD45-CD34+CD31+), CD309+-endothelial cells, and angiogenesis precursors (CD45-CD117+CD309+) into the lung. Spiperone administration significantly reduced the number Notch1 positive CD309+-endothelial cells and Notch1+ EPCs. CONCLUSION: Overall, our results suggest that spiperone mediates endothelial regeneration in an animal model of COPD. Thus, it could represent a novel therapeutic approach for treatment of emphysema associated with COPD.
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Fumar Cigarros , Células Progenitoras Endoteliais , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Animais , Fumar Cigarros/efeitos adversos , Células Progenitoras Endoteliais/metabolismo , Endotélio/metabolismo , Endotélio/patologia , Feminino , Humanos , Lipopolissacarídeos/farmacologia , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/tratamento farmacológico , Regeneração , Espiperona/metabolismo , Espiperona/farmacologia , Espiperona/uso terapêuticoRESUMO
Metabolic syndrome can lead to several challenging complications including degeneration of the pancreas and hypogonadism. Recently, we have shown that Bisamide Derivative of Dicarboxylic Acid (BDDA) can contribute to pancreatic restoration in mice with metabolic disorders via its positive effects on lipid and glucose metabolism, and by increasing the numbers of pancreatic stem cells. In the present study, we hypothesized that BDDA might also be effective in restoring hypogonadism caused by metabolic syndrome. Experiments were performed on male C57BL/6 mice with hypogonadism, where metabolic disorders have been introduced by a combination of streptozotocin treatment and high fat diet. Using a combination of histological and biochemical methods along with a flow cytometric analysis of stem and progenitor cell markers, we evaluated the biological effects of BDDA on testicular tissue, germ cells, spermatogonial stem cells in vitro and in vivo, as well as on fertility. We demonstrate that in mice with metabolic disorders, BDDA has positive effects on spermatogenesis and restores fertility. We also show that BDDA exerts its therapeutic effects by reducing inflammation and by modulating spermatogonial stem cells. Thus, our results suggest that BDDA could represent a promising lead compound for the development of novel therapeutics able to stimulate regeneration of the testicular tissue and to restore fertility in hypogonadism resulting from complications of metabolic syndrome.
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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease characterized by interstitial fibrosis and progressive respiratory failure. Pirfenidone and nintedanib slow down but do not stop the progression of IPF. Thus, new compounds with high antifibrotic activity and simultaneously regenerative activity are an unmet clinical need. Recently, we showed that Treamid can help restoring the pancreas and testicular tissue in mice with metabolic disorders. We hypothesized that Treamid may be effective in antifibrotic therapy and regeneration of damaged lung tissue in pulmonary fibrosis. In this study, experiments were performed on male C57BL/6 mice with bleomycin-induced pulmonary fibrosis. We applied histological and immunohistochemical methods, ELISA, and assessed the expression of markers of endothelial and epithelial cells in primary cultures of CD31+ and CD326+ lung cells. Finally, we evaluated esterase activity and apoptosis of lung cells in vitro. Our data indicate that Treamid exhibits antifibrotic activity in mice with pulmonary fibrosis and has a positive effect on capillaries of the lungs. Treamid also increases the number of endothelial progenitor cells in the lungs of animals with pulmonary fibrosis. Lastly, Treamid increases esterase activity and decreases apoptosis of CD31+ lung cells in vitro. Based on these findings, we suggest that Treamid may represent a promising compound for the development of new antifibrotic agents, which are capable of stimulating regeneration of lung endothelium in IPF patients.
Assuntos
Ácidos Dicarboxílicos/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Bleomicina/toxicidade , Capilares/efeitos dos fármacos , Capilares/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Fibrose , Humanos , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/fisiopatologia , Indóis/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piridonas/farmacologia , Regeneração/efeitos dos fármacos , Regeneração/fisiologiaRESUMO
In clinical practice, the metabolic syndrome can lead to multiple complications, including diabetes. It remains unclear which component of the metabolic syndrome (obesity, inflammation, hyperglycemia, or insulin resistance) has the strongest inhibitory effect on stem cells involved in beta cell regeneration. This makes it challenging to develop effective treatment options for complications such as diabetes. In our study, experiments were performed on male C57BL/6 mice where metabolic disorders have been introduced experimentally by a combination of streptozotocin-treatment and a high-fat diet. We evaluated the biological effects of Bisamide Derivative of Dicarboxylic Acid (BDDA) and its impact on pancreatic stem cells in vivo. To assess the impact of BDDA, we applied a combination of histological and biochemical methods along with a cytometric analysis of stem cell and progenitor cell markers. We show that in mice with metabolic disorders, BDDA has a positive effect on lipid and glucose metabolism. The pancreatic restoration was associated with a decrease of the inhibitory effects of inflammation and obesity factors on pancreatic stem cells. Our data shows that BDDA increases the number of pancreatic stem cells. Thus, BDDA could be used as a new compound for treating complication of the metabolic syndrome such as diabetes.
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Amidas/química , Citocinas/sangue , Ácidos Dicarboxílicos/química , Hipoglicemiantes/farmacologia , Lipídeos/sangue , Doenças Metabólicas/tratamento farmacológico , Animais , Hipoglicemiantes/química , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/patologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
In clinical practice, the metabolic syndrome (MetS) is often associated with chronic obstructive pulmonary disease (COPD). Although gender differences in MetS are well documented, little is known about sex-specific differences in the pathogenesis of COPD, especially when combined with MetS. Consequently, it is not clear whether the same treatment regime has comparable efficacy in men and women diagnosed with MetS and COPD. In the present study, using sodium glutamate, lipopolysaccharide, and cigarette smoke extract, we simulated lipid metabolism disorders, obesity, hyperglycemia, and pulmonary emphysema (comorbidity) in male and female C57BL/6 mice. We assessed the gender-specific impact of lipid metabolism disorders and pulmonary emphysema on angiogenic precursor cells (endothelial progenitor cells (EPC), pericytes, vascular smooth muscle cells, cells of the lumen of the nascent vessel), as well as the biological effects of pegylated glucagon-like peptide 1 (pegGLP-1) in this experimental paradigm. Simulation of MetS/COPD comorbidity caused an accumulation of EPC (CD45-CD31+CD34+), pericytes, and vascular smooth muscle cells in the lungs of female mice. In contrast, the number of cells involved in the angiogenesis decreased in the lungs of male animals. PegGLP-1 had a positive effect on lipids and area under the curve (AUC), obesity, and prevented the development of pulmonary emphysema. The severity of these effects was stronger in males than in females. Furthermore, PegGLP-1 stimulated regeneration of pulmonary endothelium. At the same time, PegGLP-1 administration caused a mobilization of EPC (CD45-CD31+CD34+) into the bloodstream in females and migration of precursors of angiogenesis and vascular smooth muscle cells to the lungs in male animals. Gender differences in stimulatory action of pegGLP-1 on CD31+ endothelial lung cells in vitro were not observed. Based on these findings, we postulated that the cellular mechanism of in vivo regeneration of lung epithelium was at least partly gender-specific. Thus, we concluded that a pegGLP-1-based treatment regime for metabolic disorder and COPD should be further developed primarily for male patients.
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Células Progenitoras Endoteliais/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Síndrome Metabólica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Animais , Fumar Cigarros/efeitos adversos , Modelos Animais de Doenças , Células Progenitoras Endoteliais/citologia , Feminino , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Humanos , Lipopolissacarídeos/efeitos adversos , Masculino , Síndrome Metabólica/induzido quimicamente , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Enfisema Pulmonar/induzido quimicamente , Caracteres Sexuais , Glutamato de Sódio/efeitos adversos , Resultado do TratamentoRESUMO
In clinical practice, there are patients with a combination of metabolic syndrome (MS) and chronic obstructive pulmonary disease (COPD). The pathological mechanisms linking MS and COPD are largely unknown. It remains unclear whether the effect of MS (possible obesity) has a major impact on the progression of COPD. This complicates the development of effective approaches for the treatment of patients with a diagnosis of MS and COPD. Experiments were performed on female C57BL/6 mice. Introduction of monosodium glutamate and extract of cigarette smoke was modeled to simulate the combined pathology of lipid disorders and emphysema. Biological effects of glucagon-like peptide 1 (GLP-1) and GLP-1 on endothelial progenitor cells (EPC) in vitro and in vivo were evaluated. Histological, immunohistochemical methods, biochemical methods, cytometric analysis of markers identifying EPC were used in the study. The CD31⺠endothelial cells in vitro evaluation was produced by Flow Cytometry and Image Processing of each well with a Cytation™ 3. GLP-1 reduces the area of emphysema and increases the number of CD31⺠endothelial cells in the lungs of mice in conditions of dyslipidemia and damage to alveolar tissue of cigarette smoke extract. The regenerative effects of GLP-1 are caused by a decrease in inflammation, a positive effect on lipid metabolism and glucose metabolism. EPC are proposed as pathogenetic and diagnostic markers of endothelial disorders in combination of MS with COPD. Based on GLP-1, it is proposed to create a drug to stimulate the regeneration of endothelium damaged in MS and COPD.
Assuntos
Peptídeo 1 Semelhante ao Glucagon/genética , Síndrome Metabólica/genética , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Animais , Fumar Cigarros/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Células Progenitoras Endoteliais/metabolismo , Citometria de Fluxo , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Pulmão/efeitos dos fármacos , Pulmão/patologia , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/tratamento farmacológico , Camundongos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/patologia , Glutamato de Sódio/toxicidadeRESUMO
Hyaluronidases are groups of enzymes that degrade hyaluronic acid (HA). To stop enzymatic hydrolysis we modified testicular hyaluronidase (HYAL) by activated polyethylene oxide with the help of electron-beam synthesis. As a result we received pegylated hyaluronidase (pegHYAL). Spiperone is a selective D2 dopamine receptor antagonist. It was demonstrated on the model of a single bleomycin damage of alveolar epithelium that during the inflammatory phase monotherapy by pegHYAL or spiperone reduced the populations of hematopoietic stem /progenitor cells in the lung parenchyma. PegHYAL also reduced the levels of transforming growth factor (TGF)-ß, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α in the serum and lungs, while spiperone reduced the level of the serum IL-1ß. Polytherapy by spiperone and pegHYAL caused the increase of the quantity of hematopoietic stem/ progenitor cells in the lungs. Such an influx of blood cell precursors was observed on the background of considerable fall level of TGF-ß and the increase level of TNF-α in the serum and lungs. These results show pegHYAL reduced the bleomycin-induced fibrosis reaction (production and accumulation of collagen) in the lung parenchyma. This effect was observed at a single and repetitive bleomycin damage of alveolar epithelium, the antifibrotic activity of pegHYAL surpassing the activity of testicular HYAL. The antifibrotic effect of pegHYAL is enhanced by an additional instillation of spiperone. Therapy by pegHYAL causes the flow of CD31â CD34â CD45â CD44+ CD73+ CD90+ CD106+-cells into the fibrous lungs. These cells are incapable of differentiating into fibroblast cells. Spiperone instillation separately or together with pegHYAL reduced the MSC-like cells considerably. These data enable us to assume, that pegHYAL is a new and promising instrument both for preventive and therapy of toxic pneumofibrosis. The blockage of D2 dopamine receptors with the following change of hyaluronan matrix can be considered as a new strategy in treatment of pneumofibrosis.