Relative incidence of interstitial lung diseases in Brazil / Incidência relativa de doenças pulmonares intersticiais no Brasil

ABSTRACT Objective: To assess the relative frequency of incident cases of interstitial lung diseases (ILDs) in Brazil. Methods: This was a retrospective survey of new cases of ILD in six referral centers between January of 2013 and January of 2020. The diagnosis of ILD followed the criteria suggested by international bodies or was made through multidisciplinary discussion (MDD). The condition was characterized as unclassifiable ILD when there was no specific final diagnosis following MDD or when there was disagreement between clinical, radiological, or histological data. Results: The sample comprised 1,406 patients (mean age = 61 ± 14 years), and 764 (54%) were female. Of the 747 cases exposed to hypersensitivity pneumonitis (HP)-related antigens, 327 (44%) had a final diagnosis of HP. A family history of ILD was reported in 8% of cases. HRCT findings were indicative of fibrosis in 74% of cases, including honeycombing, in 21%. Relevant autoantibodies were detected in 33% of cases. Transbronchial biopsy was performed in 23% of patients, and surgical lung biopsy, in 17%. The final diagnoses were: connective tissue disease-associated ILD (in 27%), HP (in 23%), idiopathic pulmonary fibrosis (in 14%), unclassifiable ILD (in 10%), and sarcoidosis (in 6%). Diagnoses varied significantly among centers (c2 = 312.4; p < 0.001). Conclusions: Our findings show that connective tissue disease-associated ILD is the most common ILD in Brazil, followed by HP. These results highlight the need for close collaboration between pulmonologists and rheumatologists, the importance of detailed questioning of patients in regard with potential exposure to antigens, and the need for public health campaigns to stress the importance of avoiding such exposure.

RESUMO Objetivo: Avaliar a frequência relativa de casos incidentes de doenças pulmonares intersticiais (DPI) no Brasil. Métodos: Levantamento retrospectivo de casos novos de DPI em seis centros de referência entre janeiro de 2013 e janeiro de 2020. O diagnóstico de DPI seguiu os critérios sugeridos por órgãos internacionais ou foi feito por meio de discussão multidisciplinar (DMD). A condição foi caracterizada como DPI não classificável quando não houve um diagnóstico final específico após a DMD ou houve discordância entre dados clínicos, radiológicos ou histológicos. Resultados: A amostra foi composta por 1.406 pacientes (média de idade = 61 ± 14 anos), sendo 764 (54%) do sexo feminino. Dos 747 casos expostos a antígenos para pneumonite de hipersensibilidade (PH), 327 (44%) tiveram diagnóstico final de PH. Houve relato de história familiar de DPI em 8% dos casos. Os achados de TCAR foram indicativos de fibrose em 74% dos casos, incluindo faveolamento, em 21%. Autoanticorpos relevantes foram detectados em 33% dos casos. Biópsia transbrônquica foi realizada em 23% dos pacientes, e biópsia pulmonar cirúrgica, em 17%. Os diagnósticos finais foram: DPI associada à doença do tecido conjuntivo (em 27%), PH (em 23%), fibrose pulmonar idiopática (em 14%), DPI não classificável (em 10%) e sarcoidose (em 6%). Os diagnósticos variaram significativamente entre os centros (c2 = 312,4; p < 0,001). Conclusões: Nossos achados mostram que DPI associada à doença do tecido conjuntivo é a DPI mais comum no Brasil, seguida pela PH. Esses resultados destacam a necessidade de uma estreita colaboração entre pneumologistas e reumatologistas, a importância de fazer perguntas detalhadas aos pacientes a respeito da potencial exposição a antígenos e a necessidade de campanhas de saúde pública destinadas a enfatizar a importância de evitar essa exposição.

Riesgo cardiovascular en pacientes con esclerosis sistémica / Cardiovascular Risk in Patients with Systemic Sclerosis

Introducción: El riesgo cardiovascular es importante en la evaluación de los pacientes con esclerosis sistémica. Objetivo: Determinar el riesgo cardiovascular en pacientes con esclerosis sistémica. Métodos: Se realizó un estudio transversal y descriptivo en pacientes protocolizados del Servicio de Reumatología, en el período de enero 2020 a enero 2022. Se recogieron variables demográficas, clínicas, y se aplicó la calculadora de riesgo cardiovascular Framingham. Resultados: Se incluyeron 105 pacientes con edad media de 48,6 ± 15,3 años, el grupo más frecuente de 50 a 59 años (36,2 por ciento), predominó el sexo femenino 92,2 por ciento el color de piel blanca (74,3 por ciento), el tiempo de evolución fue mayor a 5 años (66,7 por ciento) con una media de 10,5 ± 9,3. El valor promedio de la escala de gravedad modificada de Medsger fue 5,1 ± 2,7 y el 72,4 por ciento con afectación leve. El fenómeno de Raynaud y la fibrosis pulmonar fueron más frecuentes con un 89,5 por ciento y 55,2 por ciento. El índice de Rodnan en promedio fue de 13,1 ± 8,0 y los reactantes de fase aguda normales en la mayoría. Los factores de riesgo cardiovascular más frecuentes fueron la HTA (30,2 por ciento) y dislipidemia (19,9 por ciento). El índice de masa corporal que predominó fue de peso adecuado (54,3 por ciento). Predominó el riesgo cardiovascular bajo según score de Framingham (86 por ciento). Existieron diferencias significativas entre las medias del tiempo de evolución y el riesgo cardiovascular (10 ± 6,9 frente a 9,6 ± 8,8 frente a 16,9 ± 10,8; p = 0,032). Conclusiones: El riesgo cardiovascular en los pacientes con esclerosis sistémica fue bajo(AU)

Introduction: Cardiovascular risk is important in the evaluation of patients with systemic sclerosis. Objective: To determine the cardiovascular risk in patients with systemic sclerosis. Methods: A cross-sectional and descriptive study was carried out in protocolized patients of Rheumatology Service, from January 2020 to January 2022. Demographic and clinical variables were collected, and Framingham cardiovascular risk calculator was used. Results: One hundred five patients were included with a mean age of 48.6 ± 15.3 years, the most frequent group was 50 to 59 years (36.2percent), female sex (92.2percent) predominated, as well as white skin color (74.3percent). The evolution time was greater than 5 years (66.7percent) with a mean of 10.5 ± 9.3. The average value of modified Medsger severity scale was 5.1 ± 2.7 and 72.4percent had mild involvement. Raynaud's phenomenon and pulmonary fibrosis were more common at 89.5percent and 55.2percent. Rodnan index on average was 13.1 ± 8.0 and the acute phase reactants were normal in the majority. The most frequent cardiovascular risk factors were HBP (30.2percent) and dyslipidemia (19.9percent). The predominant body mass index was adequate weight (54.3percent). Low cardiovascular risk according to Framingham score prevailed (86percent). There were significant differences between the mean duration of evolution and cardiovascular risk (10 ± 6.9 vs. 9.6 ± 8.8 vs. 16.9 ± 10.8; p = 0.032). Conclusions: The cardiovascular risk in patients with systemic sclerosis was low(AU)

Lung transplantation after paraquat poisoning in an adolescent: one case report and literature review / 器官移植

Objective To summarize the effect of the timing of lung transplantation and related treatment measures on clinical prognosis of patients with paraquat poisoning. Methods Clinical data of a patient with paraquat poisoning undergoing bilateral lung transplantation were retrospectively analyzed. Clinical manifestations, auxiliary examination, diagnosis and treatment of this patient were summarized and analyzed. Results A 17-year-old adolescent was admitted to hospital due to nausea, vomiting, cough and systemic fatigue after oral intake of 20-30 mL of 25% paraquat. After symptomatic support treatment, the oxygen saturation was not improved, and pulmonary fibrosis continued to progress. Therefore, sequential bilateral lung transplantation was performed under extracorporeal membrane oxygenation (ECMO). After postoperative rehabilitation and active prevention and treatment for postoperative complications, the patient was discharged at postoperative 50 d. Conclusions The timing of lung transplantation after paraquat poisoning may be selected when the liver and kidney function start to recover. Active and targeted prevention of potential pathogen infection in perioperative period and early rehabilitation training contribute to improving clinical prognosis of lung transplant recipients.

AA Amyloidosis Secondary to Horton's Disease Complicated by Pulmonary Fibrosis: A Very Challenging Diagnosis and Therapy

AA amyloidosis is a classic and serious complication of many chronic inflammatory processes, whether of infectious, autoimmune, or neoplastic origin. It is frequently complicated by kidney damage, often in the form of a nephrotic syndrome. Giant cell arteritis is a common inflammatory arteritis in the elderly; however, it rarely causes AA amyloidosis. We report a rare case of Horton disease causing AA amyloidosis in an elderly patient with history of myopericarditis and repeated episodes of congestive heart failure. Patient was treated initially with dual therapy based on corticosteroids and anti TNF therapy (Tocilizumab) associated with heart failure therapy recommended by the European society of cardiology (ESC 2021 guidelines on Heart Failure). The initial outcome was favorable but later complicated by the involvement of the lungs; pulmonary fibrosis, responsible for repeated episodes of pleural effusion non controlled in spite of high dose of loop diuretics and repeated pleural punction. Patient died shortly after her second hospitalization due to respiratory insufficiency.

Rendimiento diagnóstico y morbimortalidad de las biopsias pulmonares quirúrgicas en enfermedad pulmonar intersticial difusa

Introducción: Se denomina Enfermedad Pulmonar Intersticial Difusa (EPID) a un conjunto heterogéneo de patologías caracterizadas por inflamación y fibrosis pulmonar. El diagnóstico basado en patrones clínicos o radiológicos puede, ocasionalmente, ser insuficiente para iniciar un tratamiento. La biopsia pulmonar quirúrgica es una alternativa cuando se requiere aumentar la precisión diagnóstica luego de discusión multidisciplinaria. Objetivo: Describir el rendimiento diagnóstico, morbilidad y mortalidad de las biopsias quirúrgicas pulmonares en un hospital público chileno. Pacientes y Método: Cohorte retrospectiva de todos los pacientes a quienes se realizó biopsia quirúrgica por diagnóstico de EPID entre los años 2010 y 2020, indicada por un comité multidisciplinario. Se excluyen procedimientos similares o biopsias con diagnóstico de EPID como hallazgo incidental. Resultados: 38 pacientes intervenidos, mediana de edad de 63 años, 47% femenino. Solo 1 (2,6%) paciente operado de urgencia, y 34 (89,5%) por videotoracoscopía. 5 (13,1%) pacientes presentaron morbilidad, en 4 de ellos fuga aérea, ninguno requiriendo intervención adicional. No hubo rehospitalización, reoperación ni mortalidad a 90 días. En el 95% de los casos se alcanzó un diagnóstico preciso de la EPID tras discusión multidisciplinaria. Discusión: Se observa un alto rendimiento diagnóstico y una baja morbimortalidad en los pacientes estudiados. La baja frecuencia de procedimientos de urgencia y la adecuada indicación en comité multidisciplinario puede haber contribuido a la baja morbilidad. Conclusión: La biopsia pulmonar quirúrgica en un hospital general tiene un alto rendimiento diagnóstico cuando se discute en comité multidisciplinario para precisar el diagnostico en EPID, con una baja morbimortalidad si se seleccionan adecuadamente los pacientes.

Background: Interstitial Lung Disease (ILD) is a heterogeneous group of diseases characterized by inflammation and fibrosis of the lung. Diagnosis based exclusively on clinical or radiologic patterns may be inaccurate, and if a reliable diagnosis cannot be made, surgical lung biopsy can be strongly considered to increase the diagnostic yield after multidisciplinary committee. Objective: To review the diagnostic results, morbidity, and mortality of surgical biopsies in a chilean public health institution. Patients and Method: Retrospective cohort of patients operated for diagnostic purposes for ILD between 2010 - 2020. Surgical biopsies done for other diagnoses were excluded. Results: 38 patients were included, with a median age of 63 years, 47% were female. Only 1 patient (2.6%) underwent emergency surgery and 89.5% underwent minimally invasive surgery techniques. 5 patients had some morbidity (13.1%), 4 of them being air leak. All complications were successfully managed conservatively. We had no readmission, reoperations, or 90-day mortality in this cohort. In 95% of the cases an accurate diagnosis of ILD was reached after multidisciplinary discussion. Discussion: In our experience surgical lung biopsy has a high diagnostic yield and a low morbidity and mortality. A low number of emergency procedures and accurate surgical indication by an expert committee could explain the low morbidity. Conclusion: Surgical lung biopsy in a general hospital reach a high diagnostic performance when discussed in a multidisciplinary committee to specify the diagnosis in ILD, with low morbidity and mortality if patients are properly selected.

A review on post-COVID-19 pulmonary fibrosis and the role of nintedanib in its management

Pulmonary fibrosis as a complication of COVID-19 has been widely reported. Several studies have reported prolonged respiratory symptoms in significant numbers of people lasting months after the acute episode of COVID-19 infection. Nintedanib is being explored as a potential therapeutic agent in the treatment of post-COVID-19 pulmonary fibrosis. However, the exact role of nintedanib in the treatment of post-COVID-19 pulmonary fibrosis is not clear. Objectives of this article are to perform a scoping review of the literature on the mechanism of pulmonary fibrosis, role of nintedanib in the treatment of post-COVID-19 pulmonary fibrosis, and emerging treatments in the treatment of post-COVID-19 pulmonary fibrosis. The United States Clinical Trials Registry and Clinical Trials Registry of India were searched to identify studies evaluating the role of nintedanib in post-COVID-19 pulmonary fibrosis. Embase and PubMed databases were searched and relevant articles were reviewed. Over all 26 article in PubMed and 67 articles in Embase were reviewed. There are several ongoing studies evaluating the safety and efficacy of nintedanib in the treatment of post-COVID-19 pulmonary fibrosis. Some studies have shown promising results for nintedanib while results from several large ongoing clinical trials are awaited. Use of nintedanib in post-COVID-19 pulmonary fibrosis is promising based on the preliminary evidence from the present studies. However, the current evidence is limited and more evidence is awaited from the ongoing randomized clinical trials evaluating the safety and efficacy of nintedanib in the management of post-COVID-19 pulmonary fibrosis.

The role and treatment strategy of epithelial-mesenchymal transition in radiation-induced pulmonary fibrosis / 中华放射医学与防护杂志

Radiation-induced pulmonary fibrosis (RIPF) is one of the most serious late complications after nuclear radiation accident, bone marrow transplantation pretreatment and thoracic tumor radiotherapy. The formation process of RIPF is complicated and the pathogenesis has not been fully elucidated. Recent studies have shown that radiation-induced epithelial-mesenchymal transition (EMT) of lung epithelial cells is an indispensable segment of RIPF. This article reviews the role of radiation-induced lung EMT in the occurrence and development of RIPF and related drugs with EMT as a potential therapeutic target, providing ideas for the development of therapeutic drugs for RIPF in the future.

CEP33779 ameliorates pulmonary fibrosis associated with rheumatoid arthritis via the cross-talk between JAK2 and TGF-β 1 signaling pathway / 中华风湿病学杂志

Objective:Rat model of RA complicated with pulmonary fibrosis were constructed to observe the degree of improvement of pulmonary fibrosis in RA rats by JAK2 inhibitor CEP33779 and the possible mechanisms.Methods:①The RA models were constructed by subcutaneous injection of 0.2 ml (1 mg/ml) of bovine type Ⅱ collagen into the tail of the rats on the day of modeling development (d0); intratracheal injection of 100 μl bleomycin (2.5 mg/kg) was used to induce pulmonary fibrosis model at d13. In vivo study: model rats were randomly divided into the normal group, pulmonary fibrosis group, pulmonary fibrosis CEP treatment group, RA complicated with pulmonary fibrosis group, and RA complicated pulmonary fibrosis CEP treatment group. Rats in the treatment group was given CEP (10 ml/kg) qd by gavage from d14 to week 4. The right hind foot of the rats was measured for joints swelling and the arthritis index score were measured, lung compliance (Cst) and lung specific gravity were measured. In addition, the pathological changes of the left lung were observed by HE and Masson staining, and the extracellular matrix level of the right lung was measured by protein immunoblotting (WB). ② In vitro study: TGF-β 1 (10 ng/ml) was applied to stimulate human embryonic lung fibroblasts (HFL1) for 24 h and 48h, and p-JAK2 expression was detected by immunofluorescence. After HFL1 inoculation of culture plates, the control group, TGF-β 1 stimulation group, TGF-β 1+ LY2109761 (TGFβ-R1/2 inhibitor group, 0.5 mmol/L and 2 mmol/L) group, TGF-β 1+CEP (0.1 mmol/L and 1.0 mmol/L) group were co-incubated for 48 h, and the expression levels of TGFβ-R2, α-SMA, JAK2, and Col 1 were measured by WB. Comparisons between multiple groups were made by Tukey′s test, and comparisons between the two groups were analyzed by independent t-test. Results:① In vivo study, compared with the control group (1.45±0.04), joint swelling was increased at d13 [(2.54±0.16) in RA+PF+Vehicle group, t=16.02, P<0.001], and the mean arthritis index score and toe volume were decreased 3 days after CEP treatment(d16) [(2.89±0.11), t=5.78, P<0.001; (1.92±0.13), t=6.85, P<0.001]. For rats with pulmonary fibrosis, all had different degrees of lung enlargement, increased lung specific gravity, decreased Cst, and increased lung inflammation and fibrosis[(0.96±0.06), t=19.76, P<0.001; (0.26±0.09), t=17.64, P<0.001; (3.63±1.51), t=6.00, P<0.001; (1.75±0.71), t=5.84, P<0.001]. After CEP gavage, rats that had RA complicated with pulmonary fibrosis had reduced lung swelling, decreased lung specific gravity, increased Cst [(0.82±0.05), t=5.76, P<0.001; (0.43±0.18), t=2.31, P=0.038], and the scores of pulmonary fibrosis and inflammation [(3.00±1.00); (1.56±0.52)] all showed a trend of decrease, but did not reach statistical difference CEP inhibited the expression of TGF-β 1, TGFβ-R2, α-SMA, Fn and JAK2 in lung tissue of pulmonary fibrosis rats, and the differences among the five groups were statistically significant ( F=9.02, P=0.017; F=4.86, P=0.048; F=6.57, P=0.032; F=11.26, P=0.010; F=13.32, P=0.007). ② In vitro study, TGF-β 1 stimulated HFL1 showed stronger phosphorylated JAK2 (p-JAK2) fluorescent signal WB showed a significant increase in the expression of TGFβ-R2, α-SMA, JAK2 and Col1, and after LY and CEP intervention, the above proteins were reduced in a concentration-dependent manner, with statistically significant differences among all five groups ( F=337.30, P<0.001; F=20.61, P<0.001; F=100.60, P<0.001; F=180.90, P<0.001). Conclusion:JAK2 inhibitors can ameliorate RA-related pulmonary fibrosis, and the mechanism may be through interfering with the "crosstalk" between JAK2 and TGF-β 1 signaling pathway.

Risk factors of early death after lung transplantation in patients with idiopathic pulmonary fibrosis complicated with pulmonary arterial hypertension / 中华危重病急救医学

Objective:To investigate the risk factors of early death after lung transplantation in patients with idiopathic pulmonary fibrosis (IPF) complicated with pulmonary arterial hypertension (PAH).Methods:A retrospective cohort study was conducted. The clinical data of 134 patients with IPF and PAH who underwent lung transplantation at Wuxi People's Hospital Affiliated to Nanjing Medical University from January 2017 to December 2020 were collected. The donor's gender, age, duration of mechanical ventilation, and cold ischemia time, the recipient's gender, age, body mass index (BMI), smoking, history of hypertension and diabetes, preoperative usage of hormones, mean pulmonary arterial pressure (mPAP), cardiac echocardiography and cardiac function, serum creatinine (SCr), N-terminal pro-brain natriuretic peptide (NT-proBNP) as well as surgical type, extracorporeal membrane oxygenation (ECMO) treatment, duration of operation, and plasma and red blood cell infusion ratio were collected. The cumulative survival rates of patients at 30, 60, and 180 days after lung transplantation were calculated by Kaplan-Meier method. The univariate and multivariate Cox proportional hazards regression models were used to analyze the effects of donor, recipient, and surgical factors on early survival in donors after lung transplantation.Results:The majority of donors were male (80.6%). There was 63.4% of the donors older than 35 years old, 80.6% of the donors had mechanical ventilation duration less than 10 days, and the median cold ischemia time was 465.00 (369.25, 556.25) minutes. The recipients were mainly males (83.6%). Most of the patients were younger than 65 years old (70.9%). Most of them had no hypertension (75.4%) or diabetes (67.9%). The median mPAP of recipients was 36 (30, 43) mmHg (1 mmHg≈0.133 kPa). There were 73 patients with single lung transplantation (54.5%), and 61 with double lung transplantation (45.5%). The survival rates of 134 IPF patients with PAH at 30, 60, 180 days after lung transplantation were 81.3%, 76.9%, and 67.4%, respectively. Univariate Cox proportional risk regression analysis showed that recipient preoperative use of hormone [hazard ratio ( HR) = 2.079, 95% confidence interval (95% CI) was 1.048-4.128], mPAP ≥ 35 mmHg ( HR = 2.136, 95% CI was 1.129-4.044), NT-proBNP ≥ 300 ng/L ( HR = 2.411, 95% CI was 1.323-4.392), New York Heart Association (NYHA) cardiac function classification Ⅲ-Ⅳ ( HR = 3.021, 95% CI was 1.652-5.523) were the risk factors of early postoperative death in patients with IPF complicated with PAH (all P < 0.05). In the multivariable Cox proportional risk regression analysis, recipient preoperative hormone usage (model 1: HR = 2.072, 95% CI was 1.044-4.114, P = 0.037; model 2: HR = 2.098, 95% CI was 1.057-4.165, P = 0.034), NT-proBNP ≥ 300 ng/L ( HR = 2.246, 95% CI was 1.225-4.116, P = 0.009) and NYHA cardiac function classification Ⅲ-Ⅳ ( HR = 2.771, 95% CI was 1.495-5.134, P = 0.001) were independent risk factors of early postoperative death in patients with IPF. Conclusions:Preoperative hormone usage, NT-proBNP ≥ 300 ng/L, NYHA cardiac function classification Ⅲ-Ⅳ are independent risk factors for early death in patients with IPF and PAH after lung transplantation. For these patients, attention should be paid to optimize their functional status before operation. Preoperative reduction of receptor hormone usage and improvement of cardiac function can improve the early survival rate of such patients after lung transplantation.

Effect of donor age on short-term survival of patients with idiopathic pulmonary fibrosis after lung transplantation / 器官移植

Objective To evaluate the effect of donor age on short-term survival of patients with idiopathic pulmonary fibrosis (IPF) after lung transplantation. Methods Clinical data of 235 IPF donors and recipients of lung transplantation were retrospectively analyzed. Univariate and multivariate Cox proportional hazard regression models were employed to analyze the correlation between donor age and short-term mortality rate of IPF patients after lung transplantation. Kaplan-Meier was used to draw the survival curve. Results Univariate Cox regression analysis showed that donor age was correlated with the 1-year fatality of IPF patients after lung transplantation. The 1-year fatality of recipients after lung transplantation was increased by 0.020 times if donor age was increased by 1 year (P=0.009). Oxygenation index of the donors, preoperative oxygenation index, preoperative lung allocation score, preoperative N-terminal pro brain natriuretic peptide, pattern of transplantation, pattern of intraoperative extracorporeal membrane oxygenation and intraoperative blood transfusion volume of the recipients were correlated with 1-year fatality after lung transplantation (all P < 0.1). Multivariate Cox regression analysis demonstrated that there was no correlation between donor age and 30-, 90-, 180-d and 1-year fatality of IPF patients after lung transplantation (all P > 0.05). Sensitivity analysis showed that there was no significant difference in 30-, 90-, 180-d and 1-year fatality after lung transplantation among donors aged < 18, 18-33, 34-49 and ≥50 years (all P > 0.05). Conclusions Donor age exerts no effect upon short-term survival of IPF patients after lung transplantation. Considering the mechanical ventilation time, oxygenation index, infection and other factors of donors, the age range of lung transplant donors may be expanded.

Medicated Serum of Bupleuri Radix Regulates HFL1 Apoptosis and Fibroblast-myofibroblast Transition via Smad3/Rheb Axis / 中国实验方剂学杂志

ObjectiveTransforming growth factor-β1 （TGF-β1） was used to stimulate human fetal lung fibroblast 1 （HFL1） for simulating the pathological process of idiopathic pulmonary fibrosis （IPF） and thereby the effects and mechanism of medicated serum of Bupleuri Radix against IPF were investigated. MethodTGF-β1 （10 μg·L-1） was employed to stimulate HFL1， and cells were treated with medicated serum of Bupleuri Radix （5%， 10%， 15%， 20%） for 24 h. Then cell proliferation rate was determined with cell counting kit-8 （CCK-8）. Subsequently， cells were classified into the control group （20% blank serum）， TGF-β1 group （20% blank serum and 10 μg·L-1 TGF-β1）， TGF-β1 + medicated serum of Bupleuri Radix group （5% blank serum， 15% medicated serum， and 10 μg·L-1 TGF-β1）， and TGF-β1 + SIS3 group （3 μmol·L-1 SIS3， 20% blank serum， 10 μg·L-1 TGF-β1）. Based on in situ end labeling （TUNEL） staining， the apoptosis rate was examined， and mRNA expression of apoptosis-related proteins B-cell lymphoma 2 （Bcl-2）， Bcl-2 associated X protein （Bax） and myofibroblast marker α-smooth muscle actin （α-SMA） was detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. The protein expression of α-SMA， Ras homolog enriched in brain （Rheb）， and phosphorylated （p）-Smad3 was determined by immunofluorescence. Expression of Rheb， p-Smad3， and Smad3 was examined by Western blot. ResultThe cell proliferation rate of TGF-β1 group increased compared with that of the control group （P<0.05）. The cell proliferation rate of TGF+15% medicated serum of Bupleuri Radix group and TGF+20% medicated serum of Bupleuri Radix group decreased compared with that of the TGF-β1 group （P<0.01）. Compared with the control group， TGF-β1 group showed decrease in apoptosis rate， increase in mRNA expression of Bcl-2 and α-SMA， reduction in Bax mRNA expression， and rise of α-SMA and Rheb protein expression and p-Smad3 level （P<0.05）. Compared with TGF-β1 group， TGF-β1 + medicated serum of Bupleuri Radix group and TGF-β1 + SIS3 group demonstrated high apoptosis rate， low Bcl-2 and α-SMA mRNA expression， high Bax mRNA expression， and low α-SMA and Rheb protein expression and p-Smad3 level （P<0.05）. ConclusionMedicated serum of Bupleuri Radix can inhibit TGF-β1-induced HFL1 proliferation and fibroblast-myofibroblast transition and promote fibroblast apoptosis by regulating the Smad3/Rheb axis.

S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2-3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.

A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis

Pulmonary fibrosis (PF) is a pathological change caused by repeated injuries and repair dysfunction of the alveolar epithelium. Our previous study revealed that the residues Asn3 and Asn4 of peptide DR8 (DHNNPQIR-NH2) could be modified to improve stability and antifibrotic activity, and the unnatural hydrophobic amino acids α-(4-pentenyl)-Ala and d-Ala were considered in this study. DR3penA (DHα-(4-pentenyl)-ANPQIR-NH2) was verified to have a longer half-life in serum and to significantly inhibit oxidative damage, epithelial-mesenchymal transition (EMT) and fibrogenesis in vitro and in vivo. Moreover, DR3penA has a dosage advantage over pirfenidone through the conversion of drug bioavailability under different routes of administration. A mechanistic study revealed that DR3penA increased the expression of aquaporin 5 (AQP5) by inhibiting the upregulation of miR-23b-5p and the mitogen-activated protein kinase (MAPK) pathway, indicating that DR3penA may alleviate PF by regulating MAPK/miR-23b-5p/AQP5. Safety evaluation showed that DR3penA is a peptide drug without obvious toxicity or acute side effects and has significantly improved safety compared to DR8. Thus, our findings suggest that DR3penA, as a novel and low-toxic peptide, has the potential to be a leading compound for PF therapy, which provides a foundation for the development of peptide drugs for fibrosis-related diseases.

Study on the anti-pulmonary fibrosis effect of linarin in vivo and in vitro and its mechanism / 中国药房

OBJECTIVE To investigate the anti-pulmonary fibrosis effect of linarin in vivo and in vitro， and investigate its mechanism preliminarily. METHODS C57BL/6J mice were randomly divided into normal group （carboxymethylcellulose sodium）， model group （carboxymethylcellulose sodium）， positive control group （pirfenidone， 200 mg/kg）， linarin low-dose and high-dose groups （12.5， 25 mg/kg）， with 8 mice in each group. Except for normal group， pulmonary fibrosis model was induced in other groups. After modeling， they were given relevant medicine intragastrically， once a day， for consecutive 14 d. The general situation of mice was observed， and their lung indexes were measured； the levels of tumor necrosis factor-α （TNF-α） and transforming growth factor-β1（ TGF-β1） in serum and interleukin-6 （IL-6） in lung tissue were determined. Hematoxylin-eosin （HE） staining and Masson staining were used to observe the histopathological morphology of lung. The pulmonary fibrosis was scored according to Ashcroft score standard. The expressions of α-smooth muscle actin （α-SMA） and （type Ⅰ collagen， Collagen Ⅰ）， phosphorylated extracellular signal-regulated kinase （p-ERK1/2） and TGF-β1 in lung tissues were detected. HFL1 cells were stimulated by TGF- β1 to form pulmonary fibrosis model in vitro， which were divided into normal group， model group and linarin low-， medium- and high-concentration groups （3.7， 7.4， 14.8 mg/L）. After being cultured for 48 h， the protein expressions of α-SMA， Collagen Ⅰ and p-ERK1/2 in HFL1 cells were detected. RESULTS In vivo， compared with normal group， the lung index of model group and the levels of TNF- α， TGF- β1 and IL-6 were significantly increased （P＜0.01）. There were a large number of inflammatory infiltration and cellular fibrosis lesions in the alveoli， and a large number of collagen depositions. The scores of HE staining and Masson staining were significantly increased （P＜0.01）. The protein expressions of α-SMA， Collagen Ⅰ， p-ERK1/2 and TGF-β1 in lung tissue were up-regulated significantly （P＜0.01）. Compared with model group， above indexes of mice were improved significantly in linarin high-dose group （P＜0.05 or P＜0.01）， and most of indexes （except for lung index） were improved significantly in linarin low-dose group （P＜0.05 or P＜0.01）. In vitro， compared with blank group， the density of cells in the model group increased， and obvious proliferation and other changes occurred； protein expressions of α-SMA， Collagen Ⅰ and p-ERK1/2 were significantly up-regulated （P＜0.05 or P＜0.01）. Compared with model group， the cell density of each concentration group was decreased and the morphology gradually returned to normal； the expressions of above proteins in linarin high-concentration group and the protein expression of p-ERK1/2 in linarin medium-concentration group were down-regulated significantly（P＜0.05 or P＜0.01）. CONCLUSIONS Linarin may regulate ERK and inflammatory pathways to reduce the inflammatory response， thereby exerting anti-pulmonary fibrosis effect.

Research progress of the regulation effect of traditional Chinese medicine monomer of flavonoids on the pulmonary fibrosis signaling pathway / 中国药房

Pulmonary fibrosis is a chronic， progressive and irreversible interstitial lung disease. At present， there is no specific drug for the treatment of pulmonary fibrosis， and many TCM monomers have potential therapeutic value for pulmonary fibrosis， among which flavonoids are the main representative. For example， total flavones of Astragalus memeranaceus and scutellarin can reduce inflammatory cell infiltration， lung injury and extracellular matrix （ECM） deposition by interfering with transforming growth factor-β1/drosophila MAD protein signaling pathway. Total flavonoids of Oxytropis falcata Bunge and salidroside can inhibit lung inflammation by mediating JAK/signal transduction and transcriptional activator signaling pathway， and prevent the epithelial interstitial transition （EMT） process. Quercetin and Ginkgo biloba leaf extract can reduce the apoptosis of macrophages by inhibiting the nuclear factor-κB signaling pathway and play an anti-pulmonary fibrosis role. Urushetin and proanthocyanidins can promote the morphological recovery of myofibroblasts and reduce ECM deposition through the phosphatidylinositol 3-kinase/protein kinase B/mammalian target protein of rapamycin signaling pathway. Naringin and luteolin can inhibit scorch death of macrophage and inflammation response， and improve lung function and lung tissue injury through NOD-like receptor heat protein domain related protein 3 signaling pathway. The ethanol extract of Phyllanthus emblica and calycosin can improve the inflammatory injury and fibrosis of lung tissue by activating the signaling pathway of nuclear transcription factor erythro2-related factor 2/antioxidant response element. Isogliquiritin can inhibit the phenotypic transformation of epithelial cells and reverse EMT progression by inhibiting extracellular signal-regulating kinase signaling pathway. In the future， scholars should consider developing appropriate drug carriers to improve their bioavailability and further study drug targets and pathways， to provide evidence for the development of traditional Chinese medicine monomers of flavonoids into clinical practice.

Biomechanical Characteristics of Idiopathic Pulmonary Fibrosis / 医用生物力学

Idiopathic pulmonary fibrosis (IPF) is a common chronic interstitial fibrotic disease. During the fibrosis process, myofibroblasts are abnormally activated, collagen is deposited in large quantities and the biomechanical characteristics of lung tissue are significantly altered. In this paper, a systematic review about the changes in lung tissues, cellular biomechanical properties and biomechanical signals during the process of IPF was presented, and the in vitro reproduction of biomechanical features and therapeutic strategies for targeting biomechanics wassummarized, so as to provide references for clinical prevention and treatment of IPF.

Identification the key factor of pulmonary fibrosis following silica nanoparticles exposure based on bioinformatics analysis / 中华劳动卫生职业病杂志

Objective: To investigate the main mechanisms of pulmonary fibrosis following silica nanoparticles (SiNPs) exposure through constructing the macrophage-fibroblast model in vitro, which simulated the process of pulmonary fibrosis. Methods: In January 2021, human mononuclear leukemia cells (THP-1) were treated with 0, 25, 50, 100 μg/ml SiNPs for 24 h. The supernatant of THP-1 cells was collected and applied to human embryonic lung fibroblast cells (MRC-5) which divided into control and low, medium and high dose groups at the logarithmic growth stage for 24 h. MRC-5 cell viability was detected by CCK8. The hydroxyproline (Hyp), interleukin 6 (IL-6), interleukin 1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) expression were detected in the supernatants of MRC-5. The changed proteins were detected by liquid-phase mass spectrometry in high dose group. GeneCard database were applied to identity the differential pulmonary fibrosis proteins in high dose group. Gene Ontology (GO) was performed to identity the key biological process in differential pulmonary fibrosis proteins of high dose group. The String database was used to construct the protein-protein interactions (PPI) network of differential pulmonary fibrosis proteins. The APP of CytoHubba was applied to calculate the key protein of differential pulmonary fibrosis proteins in PPI network. Correlation coefficients between key differential pulmonary fibrosis proteins were calculated using Pearson correlation analysis. Western blotting was applied to detect the expression of key proteins of differential pulmonary fibrosis proteins in different groups. Results: CCK8 results showed that MRC-5 cell viability was increasing in low, medium and high dose groups compared with control group (P<0.05). The expression levels of Hyp and IL-1β in different group were increased compared with control group, the expression levels of IL-6 and TNF-α were increased in high dose group compared with control group (P<0.05). GeneCard database identified 26 differential pulmonary fibrosis proteins, which were mainly involved in extracellular matrix hydrolysis, cell inflammatory response, tissue repair, cell proliferation, inflammation response by GO analysis. The APP of CytoHubba was calculated that matrix metalloproteinase 9 (MMP9) and tissue inhibitor metalloproteinase 1 (TIMP1) played an important role in PPI network. The results of correlation analysis showed that MMP9 was correlated with the expression of matrix metalloproteinase 1 (MMP1), matrix metalloproteinase 3 (MMP3), TIMP1 and epidermal growth factor receptor (EGFR) (r=0.97, 0.98, 0.94, 0.93, P<0.05). Western blotting results showed that TIMP1 protein expression was increased in low, medium and high dose groups, while MMP9 protein expression was increased only in high dose group (P<0.05) . Conclusion: Differential expression proteins related with pulmonary fibrosis in MRC-5 cells mainly regulate biological processes of extracellular matrix hydrolysis, tissue repair, and cellular inflammation response following SiNPs exposure. MMP9 and TIMP1 may be the key proteins, which affected the fibrosis process in vitro pulmonary fibrosis model.

Meta-analysis of Ac-SDKP inhibition of Pulmonary fibrosis in animal models / 中华劳动卫生职业病杂志

Objective: To systematically study the anti-fibrotic effect of N-acetyl-seryl-as partyl-lysyl-proline (Ac-SDKP) on pulmonary fibrosis. Methods: In May 2021, a computer search was performed on CNKI, Wanfang Knowledge Service Platform, VIP.com, China Biomedical Literature Database, Pubmed, OVID and other databases. The retrieval time was from January 2008 to May 2021. Randomized controlled experiments on the inhibition of pulmonary fibrosis by Ac-SDKP were screened. The control group was the pulmonary fibrosis model group and the experimental group was the Ac-SDKP treatment group. The quality of the literature was assessed using the syrcle risk of bias assessment tool, and data were extracted. Data analysis was Performed using revman 5.4 software. Results: 18 papers were included, with a total of 428 animal models. The results of meta analysis showed that the contents of α-smooth muscle actin (α-SMA), type I collagen, type Ⅲ collagen, transforming growth factor-β (TGF-β) and Nodule area in the exPerimental group were lower than those in the control grouP. [SMD=-2.44, 95%CI (-3.71--1.17), P=0.000][SMD=-5.36, 95%CI (-7.13--3.59), P=0.000] [SMD=-3.07, 95%CI (-4.13--2.02), P<0.000][SMD=-2.88, 95%CI (-3.63--2.14), P=0.000] [SMD=-1.80, 95%CI (-2.42--1.18), P=0.000], the content of hydroxy proline in the experimental group was higher than that in the control group [SMD=7.62, 95%CI (4.90-10.33), P=0.000], all indexes included in the literature were statistically significant. Conclusion: Ac-SDKP has obvious inhibitory effect on the process of pulmonary fibrosis, and may become a new clinical drug for the treatment of pulmonary fibrosis.

Research Progress of Macrophages in Development of Radiation Pneumonitis and Pulmonary Fibrosis / 肿瘤防治研究

Radiation pneumonitis and pulmonary fibrosis are important dose-limiting side effects of radiotherapy that influence the prognosis and quality of life of patients with thoracic cancer. The disorder of the immune system plays a key role, especially macrophages. With the discovery of underlying molecular mechanisms, including the chemotaxis and polarization of macrophages, the infiltration of inflammatory cells, the release of inflammatory and pro-fibrotic factors, extracellular matrix deposition and the remodeling of lung structure, increasing strategies are under investigation to facilitate the prevention or treatment of lung injury via targeting macrophages. In this paper, the role of macrophages in the development of radiation pneumonitis, pulmonary fibrosis, and potential drug use strategies were reviewed.

Effect of pirfenidone on paraquat-induced pulmonary fibrosis in rats / 中华劳动卫生职业病杂志

Objective: To construct paraquat (PQ) poisoning rat model and to explore the effect of pirfenidone (PFD) on PQ-induced pulmonary fibrosis. Methods: In April 2017, male 6-8 week-old Wistar rats were selected, and PQ was administered intraperitoneally at one time. PFD was administered by gavage 2 hours after poisoning. The daily gavage doses were 100, 200 and 300 mg/kg, and the rats were divided into physiological saline group, PQ group, PQ+PFD 100 group, PQ+PFD 200 group, PQ+PFD 300 group, with 10 rats in each group at each observation time point. The pathological changes of lung tissue at different time points (the 1st, 3rd, 7th, 14th, 28th, 42nd and 56th days) after poisoning and the effect of PFD intervention with different dose on PQ-induced pulmonary fibrosis were observed. Pathological evaluation of lung tissue was performed by Ashcroft scale method. The PQ+PFD 200 group was selected to further explore the pathological changes of lung tissue, the contents of hydroxyproline and malondialdehyde in lung tissue were determined.And the tumor necrosis factor (TNF) -α, interleukin (IL) -6, transforming growth factor (TGF) -β1, fibroblast growth factor (FGF) -B, platelet-derived growth factor (PDGF) -AB, insulin-like growth factor (IGF) -1 and PQ concentrations in serum and lung tissue were determined. Results: On the 1st to 7th day after PQ exposure, rats developed lung inflammation, which was aggravated on the 7th to 14th day, and pulmonary fibrosis appeared on the 14th to 56th day. Compared with PQ group, the Ashcroft scores of lung fibrosis in PQ+PFD 200 group and PQ+PDF 300 group decreased significantly in 7th and 28th day (P<0.05), while the Ashcroft score of lung fibrosis in PQ+PFD 100 group had no significant difference (P>0.05). After PQ exposure, the content of hydroxyproline in lung tissue increased gradually and reached the peak value on the 28th day. Compared with the PQ group, the contents of hydroxyproline in the PQ+PFD 200 group decreased at the 7th, 14th and 28th day, and the contents of malondialdehyde decreased at the 3rd and 7th day, the differences were statistically significant (P<0.05). The levels of TNF-α, IL-6 in rat serum and lung tissue reached the peak value on the 7th day after PQ exposure, and the levels of TGF-β1, FGF-B and IGF-1 in rat serum and lung tissue reached the peak value on the 14th day after PQ exposure, and the level of PDGF-AB in rat serum and lung tissue reached the peak value on the 28th day after PQ exposure. Compared with PQ group, the level of serum IL-6 in PQ+PFD 200 group decreased significantly on the 7th day, and serum TGF-β1, FGF-B, PDGF-AB and IGF-1 on the 14th and 28th day were decreased significantly (P<0.05). The levels of TNF-α, IL-6 in lung tissue of rats in PQ+PFD 200 group on the 7th day decreased significantly, and the levels of TGF-β1, FGF-B and IGF-1 in lung tissue of rats on the 14th day were significantly decreased, and the level of PDGF-AB in lung tissue of rats on the 28th day were significantly decreased (P<0.05) . Conclusion: PFD partially alleviates the PQ-induced lung inflammation and fibrosis by inhibiting oxidative stress, reducing the levels of pro-inflammatory and pro-fibrotic cytokines in serum and lung tissue, but does not affect the concentrations of PQ in serum and lung tissue.