Suppressing epithelial-mesenchymal-transition blue light therapy for reducing macrophage-mediated cancerous pulmonary fibrosis: An in-vitro study.

Lung cancer is the leading killer among all types of cancer globally. As a key factor, epithelial-mesenchymal transition (EMT) plays a crucial role in pathological fibrosis and lung cancer metastasis. This study endeavors to investigate the effect of blue light at specific wavelengths of 405 nm and 415 nm (54 J/cm2 ) on EMT induced by TGF-ß1 in A549 cells. The results revealed that the blue light irradiation reduced the morphological characteristics of EMT in the A549 cells, and cell-to-cell connections were weakened significantly. Molecular analysis showed upregulation of epithelial marker E-cadherin and downregulation of EMT marker vimentin. Additionally, exposure to blue light irradiation at 405 nm and 415 nm significantly decelerated the ability of invasion and migration. Moreover, cell viability was also investigated. Based on these findings, blue light can serve as a useful therapeutic option for inhibiting EMT in cases of lung cancer and fibrotic lung disease.

Component analysis and anti-pulmonary fibrosis effects of Rosa sterilis juice.

Rosa sterilis is a new variety of Rosa roxburghii Tratt, and is rich in bioactive substances, but its role in pulmonary fibrosis has not been elucidated. The purpose of this study was to investigate the potential components of Rosa sterili juice (RSJ) and its anti-pulmonary fibrosis effects. We employed HPLC-Q-Exactive Orbitrap-MS, HPLC, and ICP-MS to analyze the composition of RSJ, and carried out free radical scavenging assays to determine its antioxidant activity. Then, the anti-pulmonary fibrosis effect of RSJ was evaluated using the bleomycin-induced mice model and the TGF-ß1-induced cell model. A total of 49 components were identified in RSJ, and the vitamin C content was 11.29 ± 0.05 mg mL-1. Catechin was the most abundant phenol, and potassium was the highest mineral element in RSJ. Attractively, we found that RSJ alleviated bleomycin-induced inflammation infiltration and tissue injury, and inhibited TGF-ß1-induced epithelial-mesenchymal transition and fibroblast differentiation through the Smad2/3 signaling pathway. In conclusion, we discovered a new health-protective activity of Rosa sterilis, and the high levels of polyphenols, flavonoids, and vitamin C may be the basic anti-fibrosis substances.

Protective Effect of Combined Moxibustion and Decoction Therapy on Bleomycin-Induced Pulmonary Fibrosis in Rats under Nuclear Factor-κB/Transforming Growth Factor-ß1/Smads Signaling Pathway.

it was aimed to discuss the effect of moxibustion (Mox) combined with Bu Fei Qu Yu (BFQY) decoction under the nuclear factor-κB (NF-κB)/transforming growth factor-ß1 (TGF-ß1)/Smads signaling pathway in the treatment of pulmonary fibrosis (PF). The PF rat models were prepared with bleomycin (BLM). They were divided into the normal (Nor) group, the PF model group (BLM puncture perfusion), the Mox group (grain-sized Mox at the back-shu points and Xuxiao points), the BFQY group (intragastrical BFQY decoction), and the Mox combined with BFQY decoction (Mox+BFQY) group. Lung tissue sections were prepared, and the hematoxylin-eosin (HE) staining and Masson staining were performed to observe the inflammatory response and the degree of PF. The contents of hydroxyproline (HYP), glutathione (GSH), and malondialdehyde (MDA), and the expressions of NF-κB p65, TGF-ß1, Smad2, and Smad7 in lung tissues were detected. Compared with those in the Nor group, the inflammatory response score, PF degree score, HYP, GSH, and MDA contents, NF-κB p65, TGF-ß1, and Smad2 expressions were significantly increased in the PF group, but Smad7 expression decreased (P<0.05). The above symptoms were significantly improved in the Mox, BFQY, and Mox+ BFQY groups (P<0.05). The effect was more remarkable in the Mox+BFQY group, and there was no significant difference in each index compared with those in the Nor group (P>0.05). Thus, the combined therapy of Mox and decoction had an effect on PF through the NF-κB/TGF-ß1/Smads pathway.

Management of Fibrotic Hypersensitivity Pneumonitis.

Fibrotic hypersensitivity pneumonitis (fHP) is a chronic, often progressive fibrosing form of interstitial lung disease caused by inhaled antigenic exposures. fHP can lead to impaired respiratory function, reduced disease-related quality of life, and early mortality. Management of fHP should start with exposure remediation where possible, with systemic immunosuppression and antifibrotic therapy considered in patients with symptomatic or progressive disease. Nonpharmacologic and supportive management should be offered and, in cases of treatment-resistant, progressive illness, lung transplant should be considered.

Efficacy of the combination of modern medicine and traditional Chinese medicine in pulmonary fibrosis arising as a sequelae in convalescent COVID-19 patients: a randomized multicenter trial.

BACKGROUND: The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a significant number of mortalities worldwide. COVID-19 poses a serious threat to human life. The clinical manifestations of COVID-19 are diverse and severe and 20% of infected patients are reported to be in a critical condition. A loss in lung function and pulmonary fibrosis are the main manifestations of patients with the severe form of the disease. The lung function is affected, even after recovery, thereby greatly affecting the psychology and well-being of patients, and significantly reducing their quality of life. METHODS: Participants must meet the following simultaneous inclusion criteria: over 18 years of age, should have recovered from severe or critical COVID-19 cases, should exhibit pulmonary fibrosis after recovery, and should exhibit Qi-Yin deficiency syndrome as indicated in the system of traditional Chinese medicine (TCM). The eligible candidates will be randomized into treatment or control groups. The treatment group will receive modern medicine (pirfenidone) plus TCM whereas the control group will be administered modern medicine plus TCM placebo. The lung function index will be continuously surveyed and recorded. By comparing the treatment effect between the two groups, the study intend to explore whether TCM can improve the effectiveness of modern medicine in patients with pulmonary fibrosis arising as a sequelae after SARS-CoV-2 infection. DISCUSSION: Pulmonary fibrosis is one of fatal sequelae for some severe or critical COVID-19 cases, some studies reveal that pirfenidone lead to a delay in the decline of forced expiratory vital capacity, thereby reducing the mortality partly. Additionally, although TCM has been proven to be efficacious in treating pulmonary fibrosis, its role in treating pulmonary fibrosis related COVID-19 has not been explored. Hence, a multicenter, parallel-group, randomized controlled, interventional, prospective clinical trial has been designed and will be conducted to determine if a new comprehensive treatment for pulmonary fibrosis related to COVID-19 is feasible and if it can improve the quality of life of patients. TRIAL REGISTRATION: This multicenter, parallel-group, randomized controlled, interventional, prospective trial was registered at the Chinese Clinical Trial Registry (ChiCTR2000033284) on 26th May 2020 (prospective registered).

Efecto antifibrótico de Lepidium peruvianum en un modelo de fibrosis pulmonar inducida con nanosílice en ratas / Antifibrotic effect of Lepidium peruvianum on a model of nanosilica-induced lung fibrosis in rats

Objetivo. Demostrar el efecto antifibrótico de Lepidium peruvianum (maca), ecotipo morado, en la fibrosis pulmonar inducida con nanopartículas de sílice en ratas. Materiales y métodos. Estudio experimental, descriptivo, analítico, transversal, realizado en la Facultad de Medicina de la Universidad Nacional Mayor de San Marcos, Lima, Perú. Se utilizaron ratas de la cepa Sprague Dawley, estos animales fueron divididos aleatoriamente en cinco grupos: Blanco (B), Control (C), Prednisona (P), Dosis 1 (D1) y Dosis 2 (D2). En los últimos cuatro grupos, se indujo la fibrosis pulmonar (20 mg de nanosílice/rata). Luego de 7 días se inició el tratamiento, durante 4 semanas se administró el extracto metanólico de Lepidium peruvianum ecotipo morado (D1: 150 mg/kg/d y D2: 1500 mg/kg/d) y prednisona (P: 6,5 mg/kg/d). El análisis estadístico fue realizado usando la prueba ANOVA seguida de la prueba de comparación múltiple Tukey-Kramer. Los estudios realizados incluyeron el análisis del lavado broncoalveolar (recuento celular y actividad de LDH) y del tejido pulmonar (concentración de malondialdehído y evaluación histopatológica). Resultados. El grado de fibrosis en el grupo D2 fue significativamente menor (P<0,01) al grupo C y P. La concentración de malondialdehído fue significativamente mayor (P<0,01) en el grupo C en comparación a los otros grupos. Además, la concentración en el grupo D2 fue significativamente menor (P<0,01) que en el grupo P. La actividad de LDH fue significativamente menor (P<0,01) en D2 en comparación a C y D1. No hubo diferencias significativas del número de células del lavado broncoalveolar entre el grupo D2 y B. Conclusiones. Lepidium peruvianum posee un efecto antifibrótico en la fibrosis pulmonar inducida con nanopartículas de sílice en ratas.

Objective. To demonstrate the antifibrotic effect of Lepidium peruvianum (maca), purple ecotype, on lung fibrosis induced with silica nanoparticles in rats. Materials and methods. Experimental, descriptive, analytical, cross-sectional study. Done in the Faculty of Medicine, San Marcos University, Lima, Peru. Rats of the Sprague Dawley strain were used, these animals were randomly divided into 5 groups: Blank (B), Control (C), Prednisone (P), Dose 1 (D1), and Dose 2 (D2). The pulmonary fibrosis was induced (nanosilica 20 mg/rat) in the last four groups. After 7 days the treatment was started, for 4 weeks the methanol extract of Lepidium peruvianum purple ecotype (D1: 150 mg/kg/d and D2: 1500 mg/kg/d) was administered and Prednisone (P: 6.5 mg/kg/d). The degree of inflammation and fibrosis was quantified by analysis of bronchoalveolar lavage (cell count and LDH activity) and lung tissue (malondialdehyde concentration and histopathologic evaluation). Statistical analysis was performed using the ANOVA test followed by the Tukey-Kramer multiple comparison test. The main outcome measures were the analysis of bronchoalveolar lavage (cell count and LDH activity) and lung tissue (malondialdehyde concentration and histopathological evaluation). Results. The degree of fibrosis in the D2 group was significantly lower (P <0.01) than group C and P. The malondialdehyde concentration was significantly higher (P <0.01) in group C compared to the others. In addition, the concentration in the D2 group was significantly lower (P <0.01) than group P. LDH activity was significantly lower (P <0.01) in D2 compared to C and D1. There were no significant differences in cell number of BAL between D2 and B. Conclusions. Lepidium peruvianum has an antifibrotic effect in pulmonary fibrosis induced by silica nanoparticles in rats.

Anti-fibrosis effect for Hirsutella sinensis mycelium based on inhibition of mTOR p70S6K phosphorylation.

Hirsutella sinensis, cultured in vitro, is an attractive substitute for Cordyceps sinensis as health supplement. The aim of this study was to demonstrate whether H. sinensis mycelium (HSM) attenuates murine pulmonary fibrosis induced by bleomycin and to explore the underlying molecular mechanisms. Using lung fibrosis modle induced by intratracheal instillation of bleomycin (BLM; 4 mg/kg), we observed that the administration of HSM reduced HYP, TGF-ß1 and the production of several pro-fibrosis cytokines (α-smooth muscle actin, fibronectin and vimentin) in fibrotic mice lung sections. Histopathological examination of lung tissues also demonstrated that HSM improved BLM-induced pathological damage. Concurrently, HSM supplementation markedly reduced the chemotaxis of alveolar macrophages and potently suppressed the expression of inflammatory cytokines. Also, HSM influenced Th1/Th2 and Th17/Treg imbalance and blocked the phosphorylation of mTOR pathway in vivo. Alveolar epithelial A549 cells acquired a mesenchymal phenotype and an increased expression of myofibroblast markers of differentiation (vimentin and fibronectin) after treatment with TGF-ß1. HSM suppressed these markers and blocked the phosphorylation of mTOR pathway in vitro. The results provide evidence supporting the use of HSM in the intervention of pulmonary fibrosis and suggest that HSM is a potential therapeutic agent for lung fibrosis.

MOXIBUSTION HAS A POSITIVE EFFECT ON PULMONARY FIBROSIS: AN ALTERNATIVE APPROACH.

BACKGROUND: An increasing number of people suffered idiopathic fibrosis (IPF) and the current treatment was far from clinical satisfaction. Moxibustion, another effective and safe unconventional therapy, had been introduced to treat this refractory disease. The study aimed to investigate the effect of moxibustion on a bleomycin A5-induced pulmonary fibrosis model. MATERIALS AND METHODS: Sprague-dawley (SD) rats were randomly allocated to the blank group, model group, moxibustion group, and prednisone group, for which they received no treatment, modeling, moxibustion treatment and prednisone treatment. After four-week treatment, the rats were euthanized for Hematoxylin and Eosin (H.E.) staining, and TGF-ß1 and IFN-γ protein and mRNA detection in lungs. RESULTS: In the model group, TGF-ß1 was significantly increased and IFN-γ was significantly decreased at both protein and mRNA levels in comparison to the blank group. In the moxibustion and prednisone group, however, TGF-ß1 was decreased and IFN-γ was increased at both protein and mRNA levels in comparison to the model groups. Compared with prednisone, moxibustion showed comparable effect in lowing TGF-ß1 (P>0.05) and better effect in up-regulating IFN-γ (P>0.05). CONCLUSION: The study concludes moxibustion protected pulmonary fibrosis by downregulating TGF-ß1 and upregulating IFN-γ cytokines at both mRNA and protein levels, and the effect was comparable to prednisone. Moxibustion could be used as a therapeutic alternative treatment for pulmonary fibrosis.

Acupuncture Treatment for Dyspnea due to Combined Pulmonary Fibrosis and Emphysema: A Case Report.

OBJECTIVE: Combined idiopathic pulmonary fibrosis with pulmonary emphysema (CPFE) is a syndrome with a characteristic presentation of upper lobe emphysema and lower lobe fibrosis. Dyspnea on exertion (DOE) is a major symptom of CPFE. We report a patient with DOE due to CPFE who was successfully treated with acupuncture. DESIGN: Case report. CASE PRESENTATION: A 72-year-old Japanese man with a 4-year history of DOE was diagnosed with CPFE 2 years previously in another hospital. He received standard Western medicine treatment, which included bronchodilators. However, his DOE did not improve. Consequently, he visited our hospital for acupuncture treatment and received acupuncture treatment once a week for 1 year. RESULTS: After 10 weeks of acupuncture treatment, the results of the 6-minute walk test (6-minute walking distance, 379 m; lowest oxygen saturation, 86%; modified Borg dyspnea scale score: 2 units) were better than those at baseline (352 m, 84%, 4 units, respectively). These values were sustained at both 30 weeks (470 m, 88%, 1 unit) and 60 weeks (473 m, 85%, 2 units). Serum interstitial biomarkers, Krebs von den Lungen and surfactant protein-D, decreased after commencement of acupuncture therapy. CONCLUSION: A patient with CPFE showed improvements in dyspnea scores, exercise tolerance, and serum biomarkers during a 1-year course of acupuncture treatment. Use of acupuncture might be an effective adjunct therapy in relieving DOE due to CPFE. A large, well-designed cohort study that includes patients with CPFE treated with acupuncture should be conducted.

[The effectiveness of magnetic therapy of grade I-II radiation pneumofibrosis].

Radiation therapy of malignant tumours of the chest organs may result in radiation damage of the lungs. To prevent and reduce radiation-induced lung injuries, new types of radiation therapy have been developed, a number of various modifiers investigated, the methods of pharmacotherapy and physiotherapy proposed. The present study involved 37 patients presenting with radiation pneumofibrosis, including 7 ones with lung cancer and 30 patients with breast cancer. Based on the results of clinical, radiographic, and functional investigations, grade 1 and II pneumofibrosis was diagnosed in 20 and 17 patients respectively. After the application of an alternating magnetic field during 15 days, all the patients experience the overall regression of clinical symptoms and disorders of respiratory biomechanics. However, it seems premature to draw a definitive conclusion about the effectiveness of magnetic therapy of grade 1 and II radiation pneumofibrosis before the extensive in-depth investigations are carried out based on a large clinical material including the results of long-term follow-up studies and continuous monitoring.

Novel therapeutic strategies for lung disorders associated with airway remodelling and fibrosis.

Inflammatory cell infiltration, cytokine release, epithelial damage, airway/lung remodelling and fibrosis are central features of inflammatory lung disorders, which include asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome and idiopathic pulmonary fibrosis. Although the lung has some ability to repair itself from acute injury, in the presence of ongoing pathological stimuli and/or insults that lead to chronic disease, it no longer retains the capacity to heal, resulting in fibrosis, the final common pathway that causes an irreversible loss of lung function. Despite inflammation, genetic predisposition/factors, epithelial-mesenchymal transition and mechanotransduction being able to independently contribute to airway remodelling and fibrosis, current therapies for inflammatory lung diseases are limited by their ability to only target the inflammatory component of the disease without having any marked effects on remodelling (epithelial damage and fibrosis) that can cause lung dysfunction independently of inflammation. Furthermore, as subsets of patients suffering from these diseases are resistant to currently available therapies (such as corticosteroids), novel therapeutic approaches are required to combat all aspects of disease pathology. This review discusses emerging therapeutic approaches, such as trefoil factors, relaxin, histone deacetylase inhibitors and stem cells, amongst others that have been able to target airway inflammation and airway remodelling while improving related lung dysfunction. A better understanding of the mode of action of these therapies and their possible combined effects may lead to the identification of their clinical potential in the setting of lung disease, either as adjunct or alternative therapies to currently available treatments.

Clinical case: Combined pulmonary fibrosis and emphysema with pulmonary hypertension--clinical management.

BACKGROUND: Combined idiopathic pulmonary fibrosis (IPF) with pulmonary emphysema (CPFE) is a syndrome with a characteristic presentation of upper lobe emphysema and lower lobe fibrosis. While CPFE is a strong determinant of secondary precapillary pulmonary hypertension (PH), there is limited evidence regarding the management of patients with CPFE and PH. CASE PRESENTATION: A 63 year-old male presented in 2006 with dyspnoea on exertion having quit smoking in 2003. Clinical examination, together with high resolution computed tomography, bronchoalveolar lavage, and echocardiographic assessments, suggested a diagnosis of CPFE without PH. In 2007, the patient received intravenous cyclophosphamide, N-acetylcysteine, and short-term anticoagulation treatment. Due to remission of acute exacerbations, the patient received triple combination therapy (prednisone, N-acetylcysteine and azathioprine). Upon progressive clinical worsening, long-term supplemental oxygen therapy was initiated in 2009. Repeated right heart catheterisation in 2011 confirmed PH and worsening pulmonary haemodynamics, and off-label ambrisentan therapy was initiated. Dyspnoea remained at follow-up, although significant haemodynamic improvement was observed. CONCLUSION: CFPE is a distinct but under-recognized and common syndrome with a characteristic presentation. Further studies are needed to ascertain the etiology, morbidity, and mortality of CPEF with or without PH, and to evaluate novel management options.

Rehabilitation and palliative care in lung fibrosis.

The idiopathic interstitial pneumonias are a heterogeneous group of diffuse parenchymal lung diseases with varying degrees of inflammation and fibrosis, like interstitial pulmonary fibrosis. Functional exercise tolerance and quality of life have been shown to be significantly affected in patients with lung fibrosis. Moreover, interstitial pulmonary fibrosis is a progressive disease with poor prognosis and limited response to conventional pharmacological treatment like immunosuppressive agents. So, in patients with lung fibrosis there seems a clear indication to refer them for comprehensive pulmonary rehabilitation programmes and to initiate palliative care in an early phase of the disease. In the current review we will present a rationale for pulmonary rehabilitation in patients with lung fibrosis and the effects of this type of non-pharmacological intervention on exercise capacity and quality of life. In addition, we will discuss possibilities for palliative care in these patients.

[Therapeutic effects of aerosolized signal transducer and activator of transcription 1 antisense oligonucleotide administered at different time points on bleomycin-induced pulmonary fibrosis: experiment with rats].

OBJECTIVE: To investigate the curative effects of inhaling signal transducer and activator of transcription 1 (STAT1) antisense oligonucleotide (ASON) on alveolitis and pulmonary fibrosis and the best administration time. METHODS: Twenty-five adult female Wistar rats were randomly divided into 5 equal groups: BLM group, undergoing intra-tracheal perfusion of BLM so as to establish animal models of alveolitis and pulmonary fibrosis and then inhaling aerosolized normal saline (NS); NS group undergoing intra-tracheal perfusion of NS and then inhaling aerosolized NS; ASON 0 d group, undergoing intra-tracheal perfusion of BLM and then inhaling aerosolized STAT1 ASON 3 ml immediately; ASON 7 d group, undergoing intra-tracheal perfusion of BLM and then inhaling STAT1 ASON 3 ml 7 days later; and ASON 14 d group undergoing intra-tracheal perfusion of BLM and then inhaling aerosolized STAT1 ASON 3 ml 14 days later. Aerosolized inhalation was repeated once every other day for 4 times. Twenty-eight days after intra-tracheal perfusion the rats were sacrificed with their lungs taken out to undergo pathological examination. NS was infused into the right lungs to get bronchoalveolar lavage fluid (BALF). ELISA was used to examine the concentrations of transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) in the BALF. RESULTS: The pathology result of the lung tissues showed that compared with the BLM and ASON 14 d groups, the alveolitis and pulmonary fibrosis of the ASON 0 d group were obviously milder. The scores of alveolitis and pulmonary fibrosis of the ASON 0 d group were (1.80 +/- 0.84) and (2.60 +/- 0.55) respectively, both significantly lower than those of the BLM group [(2.40 +/- 0.55) and (4.40 +/- 0.55) respectively] and those of the ASON 7 d group [(2.20 +/- 0.45) and (3.00 +/- 0.71) respectively] (all P < 0.05). The scores of pulmonary fibrosis of the ASON 7 d group was significantly lower than those of the BLM and ASON 14 d groups (both P < 0.05). The concentrations of TGF-beta and TNF-alpha in BALF of the ASON 0 d group were (48.11 +/- 3.46) pg/ml and (1.93 +/- 0.14) ng/ml respectively, both significantly lower than those of the BLM group [(57.67 +/- 2.46) pg/ml and (2.45 +/- 0.25) ng/ml respectively, both P < 0.05]. The concentration of TGF-beta in BALF of the ASON 0 d group was significantly lower than those of the ASON 7 d and ASON 14 d groups [(51.42 +/- 3.57) pg/ml and (55.8 3 +/- 1.79) pg/ml respectively, both P < 0.05]. The concentration of TGF-beta in BALF of the ASON7 d group was significantly lower than those of the BLM and ASON 14 d groups (both P < 0.05). CONCLUSIONS: STAT1 ASON administered in the early stage helps depress the pulmonary fibrosis procedure, and the earlier the drug is administrated the better effect would be obtained. Aerosolized STAT1 ASON can be used as a therapeutic method for pulmonary fibrosis.

[Pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis with inspiratory muscle training]. / Rehabilitacja oddechowa chorych z idiopatycznym sródmiazszowym wlóknieniem pluc za pomoca programu z cwiczeniami miesni wdechowych.

INTRODUCTION: Evaluation of effectiveness of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis (IPF) has not yet been presented in medical literature. The objective of the study is to analyze the influence of inspiratory muscle training on dyspnea (oxygen cost diagram [OCD], baseline dyspnea index [BDI]), quality of life (SF-36), results of 6 MWT (distance, dyspnea in Borg's scale), maximal inspiratory pressure (MIP), and lung function tests (IC, TLC, VC, FEV1, DLCO(SB), DLCO/VA) in patients with IPF. MATERIAL AND METHODS: Investigations were conducted before, after 6 and 12 weeks of pulmonary rehabilitation performed in 2 groups of patients: study group (GB)--16 patients--with inspiratory muscle training added to general body conditioning and in control group (GK)--14 patients--who performed only general body conditioning. RESULTS: After 12 weeks of rehabilitation in SG we noticed the significant decrease of dyspnoea before (p = 0.028) and after (p = 0.012) 6 MWT, increase of distance in 6 MWT (p = 0.001), increase of MIP (p = 0.006), decrease of dyspnoea in BDI (p = 0.001) and improvement of quality of life (SF-36/PCS; p = 0.030) in comparison to baseline values. In the GK we observed increase of distance in 6MWT (p = 0.001) and improvement in quality of life (SF-36/PCS; p = 0.016). No improvement in sensation of dyspnea during 6MWT, BDI and MIP was noticed in the GK. CONCLUSION: Adding inspiratory muscle training increases effectiveness of pulmonary rehabilitation in IPF patients.

[Effects of gene therapy with replication-defective adenovirus ericlosing Egr-1 promoter and Smad7 cDNA on irradiation-induced pulmonary fibrosis: experiment with mice].

OBJECTIVE: To investigate the effects of gene therapy with replication-defective adenovirus enclosing Egr-1 promoter and Smad7 cDNA on irradiation-induced pulmonary fibrosis. METHODS: The recombinant replication-defective adenovirus AD. Egr-Smad7 enclosing Egr-1 promoter and Smad7 cDNA was constructed. 288 C57BL mice were randomly divided into 6 groups: AD. Egr-Smad7 group (Group RA, receiving intratracheal instillation of AD. Egr-Smad7 of the dose of 10(9) pfu/0.1 ml), AD. Egr-Smad7 + radiation group (Group RAR, receiving intratracheal instillation of AD. Egr-Smad7 of the dose of 10(9) pfu/0.1 ml and then radiation to the chest 14 h later), replication-defective adenovirus group (Group AV, receiving intratracheal instillation of replication-defective adenovirus of the dose of 10(9) pfu/0.1 ml), replication-defective adenovirus + irradiation group (Group AVR, receiving intratracheal instillation of replication-defective adenovirus of the dose of 10(9) pfu/0.1 ml and then radiation to the chest 14 h later), blank control group (Group C), and pure irradiation group (Group R), each group was re-divided into 6 subgroups of 8 mice to be observed 0, 1, 2, 4, 8, and 12 weeks after the treatment. The mice were killed at different time points and their lungs were taken out. The levels of type I collagen, type III collagen, connective tissue growth factor (CTGF), and transforming growth factor-beta1 (TGF-beta1) were detected by ELISA. The level of hydroxyproline was examined by alkaline hydrolysis method. The lung tissues were stained with HE to undergo pathological examination. RESULTS: The TGF-beta1 levels of the irradiation groups all increased, peaking in the second week (all P < 0.05), all significantly higher than those of Group C. However, the TGF-beta1 levels at different time points of Group RAR were all significantly lower then those of the other irradiation groups. The CTGF levels of different groups at different time points were all significantly higher than those of Group C (P < 0.05 or P < 0.01), and the CTGF levels of Groups RA and AV were decreased to almost normal 12 weeks after the irradiation. The levels of type I collagen and type III collagen of the 1 and 2-week subgroups of Group RAR were significantly lower than those of Group C (all P < 0.01), then gradually increased, and were slightly higher than those Group C 12 weeks later. The levels of type I collagen and type III collagen at different time points of the other groups were all significantly higher than those of Group C (P < 0.05 or P < 0.01). However, The levels of type I collagen at different time points of Group RAR were all lower than those of the other groups except Group C, and the levels of type III collagen in the first to eighth weeks after irradiation of Group RAR were all lower than those of the other groups except Group C. The hydroxyproline level of the 1 and 2 week subgroups of Group RAR were significantly lower than those of Group C (all P < 0.01), and then gradually increased. The hydroxyproline levels of the other irradiation groups all gradually increased significantly, peaking at the 12 th week (all P < 0.01). 1 approximately 2 weeks after irradiation Groups RAR, RA, and AV showed remarkable pulmonary congestion changes, even more remarkable then those in Group R, 8 approximately 12 week later, fibrosis changes were found in Group R and AVR, and 12 weeks later the histological structure of lung of Group AV, RAR, and RA returned almost normal. CONCLUSION: Radioactive rays induce Egr-1 promoter to regulated the expression of exogenous Smad7 gene that blocks the signal transduction of TGF-beta. Thus use of AD. Egr-Smad7 may become a novel strategy of gene therapy in prevention and treatment of pulmonary fibrosis.

Pulmonary hypertension in systemic sclerosis.

Pulmonary arterial hypertension occurs in up to 15% of patients who have systemic sclerosis (SSc) and has a high mortality. It can develop as an isolated complication or secondary to pulmonary fibrosis. There have been significant advances in assessment and therapy for this complication. Patients should be screened regularly by Doppler-echocardiography and pulmonary function tests. Right heart catheterization provides important diagnostic and prognostic information. Drawing from experience with treating primary pulmonary hypertension, treatment in the context of SSc is now possible. Patients should receive oral anticoagulation and oxygen supplementation. Calcium channel blockers are rarely effective, but parenteral prostacyclin analogs improve functional capacity and pulmonary hemodynamics. The oral endothelin-receptor blocker, bosentan, was shown to be an effective therapy for established symptomatic pulmonary hypertension in SSc. The next major challenge is to improve diagnosis and treatment of early stage or presymptomatic pulmonary hypertension with the goal of preventing this important cause of premature SSc-related mortality.

Intracellular glutathione and bronchoalveolar cells in fibrosing alveolitis: effects of N-acetylcysteine.

Extracellular glutathione deficiency and exaggerated oxidative stress may contribute to the pathogenesis of fibrosing alveolitis (FA). High-dose N-acetylcysteine (NAC) supplementation partially reverses extracellular glutathione depletion and oxidative damage, but effects on intracellular glutathione are unknown. Intracellular total glutathione (GSHt) and activation of bronchoalveolar lavage cells (BAC) obtained from 18 FA patients (9 males, aged 52+/-2 yrs), before and after 12 weeks of oral NAC (600 mg t.i.d.), were assessed. Eight healthy nonsmokers (2 males, aged 36+/-6 yrs) served as a control group. Intracellular GSHt was decreased in FA (1.57+/-0.20 nmol 1x10(6) BAC(-1) versus 2.78+/-0.43 nmol x 10(6) BAC(-1)). After NAC treatment, the intracellular GSHt content increased (1.57+/-0.20 versus 1.87+/-0.19 nmol x 1 x 10(6) BAC(-1)). The spontaneous oxidative activity of BAC decreased after NAC treatment (2.7+/-0.8 versus 1.0+/-0.2 nmol x 1 x 10(6) BAC(-1) x h(-1)). Interleukin-8 concentration (82.1+/-31.5 versus 80.0+/-22.6 pg x mL bronchoalveolar fluid (BALF), nonsignificant (NS)) and myeloperoxidase activity (1.93+/-0.64 versus 1.55+/-0.47 mU x mL(-1) BALF, NS) did not change significantly, but were found to be inversely correlated to intracellular GSHt. In conclusion, high-dose N-acetylcysteine supplementation increases intracellular glutathione levels slightly. This increase is associated with a mild reduction of oxidative activity but not with a reduction of bronchoalveolar cell activation in these patients.

[The immunomodulating action of cyclosporin A in vitro and in vivo on the lymphocytes of patients with alveolitis]. / Immunomoduliruiushchee deistvie tsiklosporina A in vitro i in vivo na limfotsity bol'nykh al'veolitami.

The paper presents the first results of using cyclosporin A (CsA) to treat lymphocytes during their extracorporeal immunomodulation (EIL) in patient with fibrotic alveolitis of various etiology. Two-hour lymphocytic incubation in the medium containing 0.1-10 micrograms per ml of CsA was sufficient for CsA to show its in vitro immunosuppressive effect, which resulted in a substantial inhibition of a proliferative lymphocytic response to mitogens and antigens. Administration of CsA-treated lymphocytes induced no profound structural changes in lymphocytic subpopulations (CD3, CD4, CD8), but it was followed by a reduction in the baseline high proliferative lymphocytic response to PHA. The clinical effect, alveolitis alleviation was noted in all patients. It is suggested that clinical effects may be produced by a local concentration of the treated lymphocytes and their transferred CsA as well.