ObjectiveTo evaluate the clinical efficacy and safety of pirfenidone in Chinese patients with idiopathic pulmonary fibrosis (IPF). MethodsIn a multicenter,randomized,double-blind,comparative clinical trial,87 patients with IPF were randomly divided into two groups. Group A (43 patients) were treated with pirfenidone (1 200 mg per day) for 48 weeks,while Group B (44 patients) were treated with placebo. Clinical features were compared between two groups including efficacy indicators (pulmonary function,6MWT,and quality of life scores) and safety indicators (incidence of adverse events). ResultsForced vital capacity (FVC) was increased by (90±410)mL in Group A and decreased by (70±310)mL in Group B (P<0.05);In Group A,forced expiratory volume in 1 second was raised by (100±330)mL and (110±240)mL following 12 and 24 weeks after treatment,significantly different from group B (P<0.05). There were significant differences in 6MWT between two groups 36 and 48 weeks after treatment respectively(both P<0.05). Quality of life scores,including the St. George's score (excluding symptoms) and dyspnea score,were significantly higher in Group A than Group B (both P<0.05). There was no significant difference in the incidence of adverse events between Groups A and B (83.72% vs. 72.73%,P>0.05). ConclusionDomestic pirfenidone is clinically effective and safe for the treatment of IPF in Chinese patients.
Objective To explore the correlation and mechanism of ferroptosis with pulmonary fibrosis. Methods Pulmonary fibrosis tissue sequencing data were obtained from Gene Expression Omnibus and FerrDb databases from January 2019 to December 2023. Differentially expressed genes (DEGs) between the normal control group and the pulmonary fibrosis group were analyzed by bioinformatic method, and DEGs related to pulmonary iron addiction were extracted. The hub genes were screened by enrichment analysis, protein-protein interaction (PPI) analysis and random forest algorithm. The mouse model of pulmonary fibrosis was made for exercise intervention, and the expression of hub genes was verified by real-time quantitative reverse transcription polymerase chain reaction. Results A comparison of 103 patients with idiopathic pulmonary fibrosis and 103 normal lung tissues showed that 13 up-regulated genes and 7 down-regulated genes were identified as ferroptosis-related DEGs. PPI results showed that there was an interaction between these ferroptosis-related genes. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment and Genome Ontology enrichment analysis showed that ferroptosis-related genes were involved in organic anion transport, hypoxia response, oxygen level reduction response, hypoxia-inducible factor-1 signaling pathway, renal cell carcinoma, and arachidonic acid metabolic signaling pathway. Genes identified by PPI analysis and random forest algorithm included CAV1, NOS2, GDF15, HNF4A, and CDKN2A. Real-time fluorescence quantitative polymerase chain reaction results of mouse fibrotic lung tissue showed that compared with the exercise group, the mRNA levels of NOS2, PTGS2 and GDF15 were up-regulated and the mRNA levels of CAV1 and CDKN2A were down-regulated in the bleomycin group (P<0.05); compared with the bleomycin group, the expression of CAV1 and CDKN2A increased and the expression of NOS2, PTGS2 and GDF15 decreased in the bleomycin + exercise group (P<0.05). Conclusions Bioinformatic analysis identifies 20 potential genes associating with ferroptosis in pulmonary fibrosis. CAV1, NOS2, GDF15, and CDKN2A influence the development of pulmonary fibrosis by modulating ferroptosis. Treadmill training can reduce ferroptosis in fibrotic tissues, thereby reducing lung inflammation.
ObjectiveTo systematically review the efficacy and safety of N-acetylcysteine (NAC) for patients with idiopathic pulmonary fibrosis (IPF). MethodsWe electronically searched PubMed, EMbase, The Cochrane Library (Issue 2, 2014), CNKI, WanFang Data and VIP databases from the date of establishment to February 2014 for all randomized controlled trials (RCTs) on the use of NAC in patients with IPF. Manual search in relevant journals were also performed. The data extraction and quality assessment of included RCTs were conducted by two reviewers independently. Then, meta-analysis was conducted using RevMan 5.1 software. ResultsA total of 13 RCTs involving 713 patients were included. The results of meta-analysis indicated that the NAC group was better than the control group in clinical effectiveness (RR=1.34, 95%CI 1.19 to 1.51, P < 0.000 1). After treatment, the lung function was also improved in the NAC group than in the control group in the following index:PaO2 (MD=6.06, 95%CI 3.79 to 8.32, P < 0.000 01), vital capacity (VC) (%) (MD=4.79, 95%CI 0.35 to 9.24, P=0.03) and diffusing capacity of carbon monoxide (Dlco) (%) (MD=5.74, 95%CI 2.67 to 8.81, P=0.000 2). However, no significant difference was found between groups in total lung capacity (TLC) (%) (MD=5.56, 95%CI-1.73 to 12.86, P=0.14). No serious or frequently-happened adverse effect was reported in the NAC group. ConclusionThe current evidence suggests that NAC in long term use could improve clinical conditions, PaO2 and lung function of IPF patients, with less adverse effects.
Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic at the end of December 2019, more than 85% of the population in China has been infected. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mainly affects the respiratory system, especially the lungs. The mortality rate of patients with severe infection is high. A percentage of 6% to 10% of patients will eventually develop into COVID-related acute respiratory distress syndrome (CARDS), which requires mechanical ventilation and extracorporeal membrane oxygenation (ECMO) support. Some patients who survive acute lung injury will subsequently develop post COVID-19 pulmonary fibrosis (PCPF). Both fully treated CARDS and severe PCPF are suitable candidates for lung transplantation. Due to the special course, evaluation strategies are different from those used in patients with common end-stage lung disease. After lung transplantation in COVID-19 patients, special treatment is required, including standardized nucleic acid testing for the novel coronavirus, adjustment strategy of immunosuppressive drugs, and rational use of antiviral drugs, which is a big challenge for the postoperative management of lung transplantation. This consensus was evidence-based written and was reached by experts after multiple rounds of discussions, providing reference for assessment and postoperative management of patients with interstitial pneumonia after COVID-19 infection.
Objective To investigate the preventive therapeutic effects of CPD1, a novel phosphodiesterase 5 inhibitor, on lung pathological phenotype and interstitial fibrosis of lung in pulmonary fibrosis model rats caused by bleomycin (BLM). Methods Rats were randomly divided into a sham surgery group (n=10), a model group (n=14), a CPD1 treatment group (n=13), and a nintedanib positive control drug treatment group (n=13). Pulmonary fibrosis model was constructed by slowly instilling BLM (3 mg/kg) into the left bronchus in the model group and two treatment groups. Two hours after BLM infusion, the rats were treated with CPD1 (20 mg·kg–1·d–1), or positive control drug nintedanib (50 mg·kg–1·d–1) by intragastric administration, respectively, for 2 weeks. To observe the effect of CPD1 treatment on pathological structural damage, collagen deposition, and the expression of fibronectin (Fn), α-smooth muscle actin (α-SMA), Collagen Ⅰ, and E-cadherin (E-Cad) in the affected lung tissues of unilateral pulmonary fibrosis rats. Moreover, to further observed the effects of CPD1 intervention on the expression of transforming growth factor β1 (TGF-β1) and Smad3 in the cell model of human alveolar basal epithelial A549 cells. Results Compared with the control group, the lung tissue structure was seriously damaged in the BLM group, and with expansion of the alveolar space, collapse of the alveolar lumen. Significant widening of the alveolar septum and thickening of the alveolar wall were observed in the BLM group. There was a marked increase in collagen deposition in the thickened walls of the BLM group. Moreover, the expressions of Fn, α-SMA, Collagen Ⅰ, TGF-β and Smad3 were increased, while the expression of E-Cad significantly decreased in the BLM group (all P<0.05). Compared with the BLM group, the lung tissue damage was significantly improved in the CPD1 group rats. Furthermore, CPD1 inhibit the expression of Fn, α-SMA, Collagen Ⅰ, TGF-β and Smad3, and upregulate the expression of E-Cad (all P<0.05). Conclusions Prophylactic treatment with phosphodiesterase 5 inhibitor CPD1 strongly attenuates BLM-induced pulmonary fibrosis by inhibiting the lung injury and inflammation response via targeting TGF-β/Smad pathway, reducing the deposition of extracellular matrix.
After pirfenidone and nintedanib showed efficacy, drug treatment for idiopathic pulmonary fibrosis began to focused on anti-fibrosis. Current research on idiopathic pulmonary fibrosis mainly focus on the pathogenesis and therapeutic targets, and more targeted drugs are gradually entering clinical trials. This article summarizes the results of recent studies on the treatment of idiopathic pulmonary fibrosis with pirfenidone and nintedanib alone or in combination by searching the literature, and reviews the mechanism and test results of the new target anti-fibrosis drugs based on molecular biology that are currently undergoing clinical research in various phases, and aims to provide a basis for how to choose drugs to treat idiopathic pulmonary fibrosis.
Objective To improve the knowledge and diagnostic accuracy of combined pulmonary fibrosis and emphysema (CPFE) syndrome in connective tissue diseases (CTD) by summarizing the clinical characteristics of 20 CTD patients with CPFE and reviewing literatures. Methods The medical records of 20 CTD patients with CPFE from January 2011 to June 2015 were retrospectively analyzed. Results There were 11 males and 9 females. The average age was 47 years. Among them, 4 patients were smokers and 15 patients were nonsmokers. The average duration of CTD was 3.5 years with an average onset age of 41 years. Respiratory symptoms were reported in 17 patients and Velcro rale was found in 9 patients; The most common type of CTD disease in these 20 patients was inflammatory myopathy (9 patients, 45%) followed by systemic sclerosis (SSc) (4 patients, 20%). High resolution computerized tomography of lung showed typical radiological features of CPFE containing fibrosis lesions predominantly distributed in the subpleural (14 patients) and basal (18 patients) parts and emphysema mainly located in upper zones. Relatively normal results of lung volume and ventilation function, and markedly reduced carbon monoxide transfer capacity were observed. One patient was confirmed with pulmonary hypertension and 1 patient died from severe inflammation and acute respiratory distress syndrome. Conclusions The CPFE syndrome can be identified in CTD patients as an entity with male predominance, especially among patients with inflammatory myopathy and SSc. Higher risk of secondary pulmonary hypertension and acute lung injury in these patients may increase mortality. Early differentiation of CPFE from pure interstitial lung disease in CTD patients could be helpful in improving prognosis.
ObjectiveTo understand the genetic polymorphisms of MUC5B and TOLLIP in Chinese patients with idiopathic pulmonary fibrosis (IPF), and to explore whether gene polymorphism variation in Chinese IPF patients can be used as a genetic biomarker for accurate treatment and prognosis judgment.MethodsA total of one hundred and twenty-six patients with IPF were enrolled in this study. The baseline characteristics, total lung capacity (TLC), forced vital capacity (FVC), carbon monoxide diffusion function (DLCO), imaging changes of the patients were followed up. The levels of serum sputum glycosylated antigen-6 (Krebs Von den Lungen-6, KL-6) and B lymphocyte chemotactic factor C-X-C motif chemokine 13 (CXCL13) were detected by chemiluminescent enzyme immunoassay and enzyme-linked immunosorbent assay. The gene MUC5B rs35705950 and TOLLIP rs5743890, rs5743894 single nucleotide polymorphism (SNP) were determined by polymerase chain reaction.ResultsOne hundred and twenty-six patients with IPF were found with AA type by TOLLIP rs5743890 and rs5743894 SNP, accounting for 100.0%; MUC5B rs35705950 SNP was expressed as 116 patients (92.1%) with GG type, and 10 patients (7.9%) with GT type, no TT patients were detected. There was no significant difference in clinical characteristics between the two groups in age and non-smokers (P>0.05). Compared with group G, annual decrease of lung function (FVC, DLCO, and TLC), serum biomarkers (KL-6 and CXCL13), annual increase of reticular and honeycombing lesions, and mortality were significantly lower in group T (P<0.05). The median survival time of IPF patients carrying the MUC5B SNP rs35705950 minor allele (gene phenotype GT) heterozygous was significantly higher than that of homozygous IPF patients with a genetic phenotype of GG.ConclusionsThere are genetic polymorphisms in Chinese patients with IPF. MUC5B rs35705950 and TOLLIP rs5743890, rs5743894 gene subtypes have low mutation rates in the cohort. Compared with homozygous patients of MUC5B SNP rs35705950, heterozygous patients have smaller changes in lung function and radiological image, lower levels of serum KL-6 and CXCL13, and better prognosis.
Objective To clarify the specific clinical predictive efficacy of CT and serological indicators for the progression of connective tissue disease-associated interstitial lung disease (CTD-ILD) to progressive pulmonary fibrosis (PPF). Methods Patients who were diagnosed with CTD-ILD in Chest Hospital of Zhengzhou University Between January 2020 and December 2021 were recruited in the study. Clinical data and high-resolution CT results of the patients were collected. The patients were divided into a stable group and a progressive group (PPF group) based on whether PPF occurred during follow-up. COX proportional hazards regression was used to identify risk factors affecting the progression of CTD-ILD to PPF, and a risk prediction model was established based on the results of the COX regression model. The predictive efficacy of the model was evaluated through internal cross-validation. Results A total of 194 patients diagnosed with CTD-ILD were enrolled based on the inclusion and exclusion criteria. Among them, 34 patients progressed to PPF during treatment, and 160 patients did not progress. The variables obtained at lambda$1se in LASSO regression were ANCA associated vasculitis, lymphocytes, albumin, erythrocyte sedimentation rate, and serum ferritin. Multivariate COX regression analysis showed that the extent of fibrosis, serum ferritin, albumin, and age were independent risk factors for the progression of CTD-ILD to PPF (all P<0.05). A prediction model was established based on the results of the multivariate COX regression analysis. The area under the receiver operator characteristic curve at 6 months, 9 months, and 12 months was 0.989, 0.931, and 0.797, respectively, indicating that the model has good discrimination and sensitivity, and good predictive efficacy. The calibration curve showed a good overlap between predicted and actual values. Conclusions The extent of fibrosis, serum ferritin, albumin, and age are independent risk factors for the progression of CTD-ILD to PPF. The model established based on this and externally validated shows good predictive efficacy.
Objective To explore the prognostic significance of baseline clinical and pulmonary physiological variables on idiopathic pulmonary fibrosis ( IPF) . Methods Patients diagnosed with IPF according to 2011 ATS/ERS/JRS/ALAT statementwere selected from Nanjing DrumTower Hospital between January 1, 2002 and July 31, 2010. The baseline characteristics were abstracted, including age, gender, smoking history, corticosteroid, delay before diagnosis, body mass index, finger clubbing, oxygenation index ( PaO2 /FiO2 ) , C-reaction protein, erythrocyte sedimentation rate ( ESR) , serum lactate dehydrogenase ( LDH) , albumin, vital capacity ( VC) , forced vital capacity ( FVC) , total lung capacity ( TLC) , and singlebreath diffusing capacity of the lung for carbon monoxide ( DLCO) . The relationships between all factors and survival were examined with a univariate Cox proportional-hazard model. Kaplan-Meier method was used to assess the survival probabilities between groups with different baseline characteristics. Results Eighty-four patients were included in this study, with the median survival time of 34. 7 months. PaO2 /FiO2 , FVC% pred, VC% pred, TLC% pred, and DLCO% pred showed significant associations with the mortality of IPF ( hazard ratios 0. 940-0. 994, P lt; 0. 01) . The Kaplan-Meier analyses for above variables also showed significant differences ( P lt;0. 05) . Besides, the statistical difference of survival probability could be found between the patients with elevated serumLDH and those with normal LDH ( 27. 0 months vs. 43. 1 months, P =0. 014) . Conclusions Baseline oxygenation and pulmonary function parameters may indicate the prognosis of IPF patients. Serum LDH may provide clinicians with additional prognostic information.