Shared biomarkers and mechanisms in idiopathic pulmonary fibrosis and non-small cell lung cancer.

BACKGROUND: Epidemiological evidence has indicated the occurrence of idiopathic pulmonary fibrosis (IPF) with coexisting lung cancer is not a coincidence. The pathogenic mechanisms shared between IPF and non-small cell lung cancer (NSCLC) at the transcriptional level remain elusive and need to be further elucidated. METHODS: IPF and NSCLC datasets of expression profiles were obtained from the GEO database. Firstly, to detect the shared dysregulated genes positively correlated with both IPF and NSCLC, differentially expressed analysis and WGCNA analysis were carried out. Functional enrichment and the construction of protein-protein network were employed to reveal pathogenic mechanisms related to two diseases mediated by the shared dysregulated genes. Then, the LASSO regression was adopted for screening critical candidate biomarkers for two disorders. Moreover, ROC curves were applied to evaluate the diagnostic value of the candidate biomarkers in both IPF and NSCLC. RESULTS: The 20 shared dysregulated genes positively correlated with both IPF and NSCLC were identified after intersecting differentially expressed analysis and WGCNA analysis. Functional enrichment revealed the 20 shared genes mostly enriched in extracellular region, which is critical in the organization of extracellular matrix. The protein-protein networks unrevealed the interaction of the 11 shared genes involving in collagen deposition and the connection between PYCR1 with PSAT1. PSAT1, PYCR1, COL10A1 and KIAA1683 were screened by the LASSO regression. ROC curves comprising area under the curve (AUC) verified the potential diagnostic value of PSAT1 and COL10A1 in both IPF and NSCLC. CONCLUSIONS: We revealed dysregulated extracellular matrix through aberrant expression of the relevant genes, which provided further understanding for the common molecular mechanisms predisposing the occurrence of both IPF and NSCLC.

Pretreatment mortality risk prediction model in patients with polymyositis/dermatomyositis-associated interstitial lung disease.

OBJECTIVES: Risk prediction for patients with polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD) is challenging due to heterogeneity in the disease course. We aimed to develop a mortality risk prediction model for PM/DM-ILD. METHODS: This prognostic study analysed patients with PM/DM-ILD admitted to Nanjing Drum Hospital from 2016 to 2021. The primary outcome was mortality within 1 year. We used a least absolute shrinkage and selection operator (LASSO) logistic regression model to identify predictive laboratory indicators. These indicators were used to create a laboratory risk score, and we developed a mortality risk prediction model by incorporating clinical factors. The evaluation of model performance encompassed discrimination, calibration, clinical utility and practical application for risk prediction and prognosis. RESULTS: Overall, 418 patients with PM/DM-ILD were enrolled and randomly divided into development (n=282) and validation (n=136) cohorts. LASSO logistic regression identified four optimal features in the development cohort, forming a laboratory risk score: C reactive protein, lactate dehydrogenase, CD3+CD4+ T cell counts and PO2/FiO2. The final prediction model integrated age, arthralgia, anti-melanoma differentiation-associated gene 5 antibody status, high-resolution CT pattern and the laboratory risk score. The prediction model exhibited robust discrimination (area under the receiver operating characteristic: 0.869, 95% CI 0.811 to 0.910), excellent calibration and valuable clinical utility. Patients were categorised into three risk groups with distinct mortality rates. The internal validation, sensitivity analyses and comparative assessments against previous models further confirmed the robustness of the prediction model. CONCLUSIONS: We developed and validated an evidence-based mortality risk prediction model with simple, readily accessible clinical variables in patients with PM/DM-ILD, which may inform clinical decision-making.

Prognostic factors of fungal infection in anti-melanoma differentiation-associated gene 5 antibody-positive associated interstitial lung disease.

OBJECTIVE: To investigate the potential risk factors for mortality in fungal infection in anti-melanoma differentiation-associated gene 5 antibody-positive associated interstitial lung disease (MDA5-ILD). METHODS: Patients diagnosed with MDA5-ILD from April 2017 to November 2022 were included. The demographic data, laboratory examinations, therapeutic and follow-up information were recorded. Fungal infection diagnosis was established based on a combinations of host factors, clinical features and mycologic evidences. High-dose corticosteroid therapy was defined as the initial corticosteroid doses > 240mg/d. The primary endpoint was mortality. Potential factors for fungal infection occurrence and prognostic factors were analyzed using logistic regression analysis and Cox proportional hazards regression. RESULTS: In total, 121 patients with MDA5-ILD were included. During follow-up, 41 (33.9%) patients had suffered fungal infection and 39.0% (16/41) of whom had ever received high-dose corticosteroid therapy. The median interval from corticosteroid use to the occurrence of fungal infection was 29 (10-48) days. The mean survival time of patients with fungal infection was 234.32 ± 464.76 days. The mortality in MDA5-ILD with fungal infection was 85.4% (35/41), which was significantly higher than those without (85.4% VS 56.3%, P < 0.001). High-dose corticosteroid therapy (P = 0.049) was independent risk factor for fungal infection occurrence. Decreased serum albumin level (P = 0.024) and high-dose corticosteroid therapy (P = 0.008) were both associated with increased mortality in MDA5-ILD patients with fungal infection. CONCLUSION: Fungal infection is associated with an increased mortality in MDA5-ILD. The serum albumin level and corticosteroid dose should be taken into consideration when treating MDA5-ILD. Key Points • This study showed fungal infection is associated with an increased mortality in MDA5-ILD. In MDA5-ILD patients with fungal infection, the presence of decreased serum albumin level and high-dose corticosteroid therapy were identified as predictors for mortality.

Effect of high-dose intravenous methylprednisolone pulse (IVMP) therapy in the survival of patients with anti-melanoma differentiation-associated gene 5-related rapidly progressive interstitial lung disease: a retrospective analysis.

OBJECTIVES: To assess the impacts of high-dose intravenous methylprednisolone pulse (IVMP) therapy in survival and the occurrences of treatment-related infection of patients with anti-melanoma differentiation-associated gene 5 antibody-related rapidly progressive interstitial lung disease (MDA5-RPILD). METHODS: Patients with MDA5-RPILD from June 2017 to August 2022 in our hospital were retrospectively reviewed. IVMP therapy was defined as intravenous methylprednisolone (mPSL) 0.5g/day for 3 consecutive days during hospitalization or 7 days prior to admission and patients were divided into IVMP group and non-IVMP group based on who had ever received IVMP therapy. All-cause mortality and the incidence of adverse events during treatment were compared between the two groups. RESULTS: Sixty-four patients with MDA5-RPILD were enrolled. Among them, twenty-three (35.9%) patients had ever received IVMP therapy. The overall mortality was comparable between IVMP and non-IVMP group (IVMP group: 22/23, 95.7% vs. non-IVMP group: 38/41, 92.7%, p=0.11). And the incidence of treatment-related infections was also close (IVMP group: 21/23, 91.3% vs. non-IVMP group: 32/41, 78.0%, p=0.30). After adjustment for gender, age, smoking history, duration from symptom onset to diagnosis, and combination with steroid-sparing agent treatment, the Cox proportional hazards model showed that IVMP therapy was not associated with an improved survival (adjusted HR 1.10; 95% CI 0.57-2.13; p=0.77). CONCLUSION: Our study showed that the survival benefits and adverse events were comparable between IVMP-treated and untreated MDA5-RPILD patients. Future prospective trials are needed to investigate the optimal treatment regimen in MDA5-RPILD. Key Points • This observational study found that IVMP therapy may be not associated with an improved outcome in patients with MDA5-RPILD. • Treatment-related infections are common; however, the incidence of treatment-related infections had no difference between IVMP and non-IVMP group.

ZLN005 improves the protective effect of mitochondrial function on alveolar epithelial cell aging by upregulating PGC-1α.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal pulmonary interstitial disease that usually occurs in the elderly. The senescence of alveolar epithelial cells (AECs) is an important mechanism of IPF. The AECs of patients with IPF have lower expression of peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α), which has been shown to play an important role in maintaining mitochondrial morphology and energy metabolism. This study sought to explore the mechanism by which ZLN005 improves mitochondrial function by upregulating PGC-1α to protect AECs from aging. Methods: Western blot was used to detect the expression of PGC-1α, mitochondrial synthesis protein nuclear respiratory factor-1 (NRF-1), and p21WAF1 in the lung tissue of the IPF patients and the mice with bleomycin (BLM)-induced pulmonary fibrosis. A549 cells and mice AEC2 cells were treated with hydrogen peroxide (H2O2) to construct cell senescence models. Cell senescence was detected by senescence-associated beta-galactosidase staining. The mitochondrial respiratory function was measured, including the adenosine triphosphate (ATP) generation, reactive oxygen species (ROS) level, changes in cell membrane potential, and energy metabolism. Using lentivirus as a vector and using gene editing technology to over express (upPGC-1α) and knockdown PGC-1α (shPGC-1α) in the A549 cells. The PGC-1α agonist ZLN005 was used to pretreat the A549 and shPGC-1α A549 cells, and cell aging and mitochondrial respiratory function were observed. Results: The Western blot and immunofluorescence assays showed that the expression of PGC-1α and NRF-1 was decreased in the lung tissues of the IPF patients and BLM-induced mice pulmonary fibrosis model, while the expression of p21WAF1 was increased. The results of the immunofluorescence and mitochondrial function experiments also indicated that the expression of PGC-1α and mitochondrial synthesis protein NRF-1 were decreased in the senescent cells. Further, the mitochondrial morphology was abnormal and the mitochondrial function was impaired. PGC-1α was involved in the AEC senescence by regulating mitochondrial morphology and function. Treatment with the agonist of PGC-1α (i.e., ZLN005) blocked the H2O2-induced cell senescence by enhancing the expression of PGC-1α. Conclusions: These results provide preliminary insights into the potential clinical application of ZLN005 as a novel therapeutic agent for the treatment of IPF.

Elevated serum mitochondrial DNA levels were associated with the progression and mortality in idiopathic pulmonary fibrosis.

Circulating mitochondrial DNA (mtDNA) was implicated in idiopathic pulmonary fibrosis (IPF), but the association between circulating mtDNA levels with clinical parameters in IPF was unclear. In this study, we investigate the relationship between serum mtDNA levels with the progression and mortality of IPF. Eighty-three patients with clinical diagnoses of IPF and fifty-three healthy controls were enrolled. Clinical data were collected and IPF patients were classified as stable disease (SD) and progressive disease (PD) based on the diagnostic criteria. Serum mtDNA levels were measured by real-time quantitative PCR and were compared between the two groups. Associations of the mtDNA levels with pulmonary function data and clinical parameters were assessed. Cox regression was performed to access the association between serum mtDNA levels with mortality in IPF. The serum mtDNA levels were significantly higher in IPF patients compared to those in healthy controls (P < 0.001), and further higher in patients with PD than those with SD (P < 0.001). Serum mtDNA levels were significantly inverse correlated with carbon monoxide diffusing capacity percent predicted (DLCO% predicted) (P = 0.030) and serum albumin levels (P = 0.008). During follow-up, 36 patients (43.4 %) died with a median survival of 46.00 (IQR: 25.00-69.75) months. Multivariate analysis showed that higher serum mtDNA levels were a significant predictor of mortality in IPF. In conclusion, elevated serum mtDNA levels were associated with the progression and mortality of IPF, which provided new insights that mitochondrial metabolism might have a potential role in the pathogenesis of IPF.

Lipid metabolism in idiopathic pulmonary fibrosis: From pathogenesis to therapy.

Idiopathic pulmonary fibrosis (IPF) is a chronic irreversible interstitial lung disease characterized by a progressive decline in lung function. The etiology of IPF is unknown, which poses a significant challenge to the treatment of IPF. Recent studies have identified a strong association between lipid metabolism and the development of IPF. Qualitative and quantitative analysis of small molecule metabolites using lipidomics reveals that lipid metabolic reprogramming plays a role in the pathogenesis of IPF. Lipids such as fatty acids, cholesterol, arachidonic acid metabolites, and phospholipids are involved in the onset and progression of IPF by inducing endoplasmic reticulum stress, promoting cell apoptosis, and enhancing the expression of pro-fibrotic biomarkers. Therefore, targeting lipid metabolism can provide a promising therapeutic strategy for pulmonary fibrosis. This review focuses on lipid metabolism in the pathogenesis of pulmonary fibrosis.

Prediction model for the pretreatment evaluation of mortality risk in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease.

Background: Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease (anti-MDA5 DM-ILD) is a disease with high mortality. We sought to develop an effective and convenient prediction tool to estimate mortality risk in patients with anti-MDA5 DM-ILD and inform clinical decision-making early. Methods: This prognostic study included Asian patients with anti-MDA5 DM-ILD hospitalized at the Nanjing Drum Hospital from December 2016 to December 2020. Candidate laboratory indicators were retrospectively collected. Patients hospitalized from 2016 to 2018 were used as the discovery cohort and applied to identify the optimal predictive features using a least absolute shrinkage and selection operator (LASSO) logistic regression model. A risk score was determined based on these features and used to construct the mortality risk prediction model in combination with clinical characteristics. Results were verified in a temporal validation comprising patients treated between 2019 and 2020. The primary outcome was mortality risk within one year. The secondary outcome was overall survival. The prediction model's performance was assessed in terms of discrimination, calibration, and clinical usefulness. Results: This study included 127 patients, (72 men [56.7%]; median age, 54 years [interquartile range, 48-63 years], split into discovery (n = 87, 70%) and temporal validation (n=37, 30%) cohorts. Five optimal features were selected by LASSO logistic regression in the discovery cohort (n = 87) and used to construct a risk score, including lymphocyte counts, CD3+CD4+ T-cell counts, cytokeratin 19 fragment (CYFRA21-1), oxygenation index, and anti-Ro52 antibody. The retained predictive variables in the final prediction model were age, Heliotrope, fever, and risk score, and the most predictive factor was the risk score. The prediction model showed good discrimination (AUC: 0.915, 95% CI: 0.846-0.957), good calibration (Hosmer-Lemeshow test, P = 0.506; Brier score, 0.12), and fair clinical usefulness in the discovery cohort. The results were verified among patients in the temporal validation cohort (n = 38). We successfully divided patients into three risk groups with very different mortality rates according to the predictive score in both the discovery and validation cohorts (Cochran-Armitage test for trend, P < 0.001). Conclusions: We developed and validated a mortality risk prediction tool with good discrimination and calibration for Asian patients with anti-MDA5 DM-ILD. This tool can offer individualized mortality risk estimation and inform clinical decision-making.

Soluble ST2 in serum predicts the prognosis of idiopathic pulmonary fibrosis: a retrospective study.

Background: Idiopathic pulmonary fibrosis (IPF) is a heterogeneous and progressive fibrosing interstitial lung disease with a poor prognosis. However, there are currently no effective biomarker that can reliably predict the prognosis for IPF in clinic. The serum level of soluble suppression of tumorigenicity-2 (sST2), which is involved in the immune response, has proven to be a prognostic predictor for various diseases. Previous studies have confirmed that the immune dysfunction plays an important role in the pathogenesis of IPF and the serum sST2 concentrations in patients with IPF are elevated. However, the relationship between sST2 and the prognosis of IPF remains unknown. Methods: A total of 83 patients with IPF and 20 healthy controls from 2016 to 2021 were enrolled and demographic variables, indices of lung function testing as well as the biomarkers including the sST2 were obtained at baseline. During follow-up, the primary endpoint was defined as all-cause death and clinical deterioration. Cox hazard models and Kaplan-Meier method were used to assess the prognostic value of various indices including sST2. Results: Mean duration of follow-up was 29 months, during which 49 patients had an event, and of them, 35 patients died. The sST2 level was higher in the IPF patients compared with the healthy controls. Although the sST2 level did not directly predict all-cause death in the present study, it was proved to be an independent predictor of event-free survival. Multivariate forward stepwise model which was adjusted by age, sex, and body surface area (BSA) showed that the overexpression of sST2 increased the hazard ratio [1.005, 95% confidence interval (CI): 1.001-1.010]. A higher sST2 serum level heralded more deterioration and the poor outcomes. Moreover, the effect of sST2 on the prognosis of IPF may not necessarily involve the development of IPF-related pulmonary hypertension (PH). Conclusions: In our study, the sST2 serum level was significantly elevated and a higher serum level of sST2 predicted more deterioration and poor outcomes in patients with IPF. Thus, sST2 can serve as a valuable prognostic biomarker for the outcome of IPF. However, further multicenter clinical trials of larger sample size are needed in the future.

A Retrospective Analysis of Outcome in Melanoma Differentiation-Associated Gene 5-Related Interstitial Lung Disease Treated with Tofacitinib or Tacrolimus.

OBJECTIVE: The efficacy of tofacitinib (TOF) in the early diagnosis of melanoma differentiation-associated gene 5 (MDA5)-related interstitial lung disease (ILD) has been described. However, whether TOF exposure is associated with a reduced 1-year mortality rate remains undetermined. METHODS: Patients diagnosed with MDA5-ILD receiving TOF or tacrolimus (TAC) treatment were included. A Cox proportional hazards model, which was adjusted for age, sex, smoking history, anti-MDA5 antibody titers, and concurrent use of other steroid-sparing agents, was performed to compare all-cause mortality and to investigate the risk factors predicting 1-year mortality rates in the 2 treatment groups. RESULTS: During the study period, 26 patients were treated with TOF and 35 were treated with TAC. The 6-month (38.5% vs 62.9%; P = 0.03) and 1-year (44.0% vs 65.7%; P = 0.03) mortality rates in the TOF group were significantly lower than those in the TAC group. There were 13 patients diagnosed with rapidly progressive ILD (RP-ILD) in the TOF group and 22 in the TAC group. The majority of deaths occurred in patients with RP-ILD. The 6-month (76.9% vs 95.5%; P = 0.02) and 1-year (84.6% vs 100.0%; P = 0.02) mortality rates of patients with RP-ILD in the TOF group were also lower than those in the TAC group, respectively. The adjusted model showed that TOF exposure was associated with a lower risk for 1-year mortality (hazard ratio 0.44, 95% CI 0.20-0.96; P = 0.04). However, the incidence of adverse events (73.1% vs 74.3%; P > 0.99) and medication discontinuation rates (23.1% vs 14.3%; P = 0.50) in the TOF and TAC groups were similar, respectively. CONCLUSION: Our observational study showed that TOF use might have a potential effect on improving the outcomes of MDA5-ILD. Future clinical trials are needed to assess the long-term efficacy and tolerability of TOF.

KLF4 regulates TERT expression in alveolar epithelial cells in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) was considered as a telomere-mediated disease. TERT and TERC correlated with telomere length. Although telomerase gene mutations were associated with IPF, majority patients did not carry mutations. The mechanism by which telomerase expression was regulated in IPF are still unclear. In this study, we aimed to delineate the mechanisms that how TERT protein expression were regulated in alveolar epithelial cells (AECs) in pulmonary fibrosis. Here, we found that P16, P21 and fibrosis markers (αSMA and Collagen-I) were prominently increased in lung tissues of IPF patients and bleomycin-induced mouse models, while the expression of KLF4 and TERT were decreased in AECs. In vivo experiments, AAV-6 vectors mediated KLF4 over-expression with specific SP-C promoter was constructed. Over-expression of KLF4 in AECs could protect TERT expression and suppress the development of pulmonary fibrosis in bleomycin-induced mouse models. In the mechanism exploration of TERT regulation, KLF4 and TERT were both down-regulated in bleomycin-induced senescent MLE-12 and BEAS-2B cells. Compared with control group, small-interfering RNA targeting KLF4 significantly reduced the TERT expression and telomerase activity, while overexpression of KLF4 can increased the expression of TERT and telomerase activity in senescent AECs. Furthermore, ChIP showed that KLF4 protein could bind to the TERT promoter region in MLE-12 cells, suggesting that KLF4 could implicate in pathogenesis of lung fibrosis through regulating TERT transcription in AECs. Taken together, this study identified that KLF4 might be a promising potential target for further understanding the mechanism and developing novel strategy for the treatment of lung fibrosis in IPF.

Anti-Ro52 antibodies are associated with the prognosis of adult idiopathic inflammatory myopathy-associated interstitial lung disease.

OBJECTIVES: In the present study, we aimed to assess the prevalence and clinical significance of anti-Ro52 antibodies in a cohort of patients with idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) with different myositis-specific autoantibodies (MSAs). METHODS: A cohort of 267 IIM-ILD patients, including 62 patients with PM, 126 patients with DM and 79 patients with clinically amyopathic DM (CADM) were retrospectively analysed in this study. Clinical and laboratory findings, pulmonary function tests (PFTs), HRCT patterns and treatment information were compared between patients with and without anti-Ro52 antibodies. The association between prognosis and anti-Ro52 antibodies was also evaluated based on different MSA subgroups. RESULTS: Anti-Ro52 antibodies were more frequent in patients with anti-MDA5 (62.1%, P < 0.01) and anti-Jo1 (64.9%, P < 0.01) antibodies than in those with other MSAs. The proportion of patients with anti-Jo1 antibodies was higher in the anti-Ro52 antibody-positive group than in the anti-Ro52 antibody-negative group. Patients with anti-Ro52 antibodies were more likely to exhibit the Gottron sign than the anti-Ro52 antibody-negative group (P < 0.001). Furthermore, it was a predictive factor for rapid progression interstitial lung disease (RP-ILD) (P = 0.001) and was also associated with a higher mortality rate (log-rank test, P = 0.001). Furthermore, RP-ILD was more frequently exhibited in anti-MDA5- and anti-Ro52-positive patients. Moreover, anti-Ro52 antibody positivity was closely associated with a higher mortality rate in anti-MDA5-ILD patients (log-rank test, P < 0.05). CONCLUSIONS: Anti-Ro52 antibodies were highly prevalent in patients with anti-MDA5 and anti-Jo1 antibodies. Within all patients with IIM-ILD, those with anti-Ro52 autoantibodies had a higher frequency of RP-ILD and a poorer prognosis, especially in the anti-MDA5 antibody subgroup.

Inhibition of DNA methylation de-represses peroxisome proliferator-activated receptor-γ and attenuates pulmonary fibrosis.

BACKGROUND AND PURPOSE: Development of pulmonary fibrosis is associated with altered DNA methylation modifications of fibrogenic gene expression. However, their causal relationships and the underlying mechanisms remain unclear. This study investigates the critical role of DNA methylation aberration-associated suppression of peroxisome proliferator-activated receptor-γ (PPARγ) in pulmonary fibrosis. EXPERIMENTAL APPROACH: Expression of PPARγ and bioactive DNA methyltransferases (DNMTs) and PPARγ promoter methylation status were examined in fibrotic lungs of idiopathic pulmonary fibrosis (IPF) patients and bleomycin (Blm)-treated mice. DNA demethylating agent 5-aza-2'-deoxycytidine (5aza) and glycyrrhizic acid (GA) derived from medicinal plant were assessed for their PPARγ de-repression and anti-pulmonary fibrosis activities. PPARγ knockout mice were created to determine the critical role of PPARγ in this protection. KEY RESULTS: Lung PPARγ expression was markedly suppressed in IPF patients and Blm mice, accompanied by increased DNMT 1/DNMT3a and PPARγ promoter hypermethylation. Administration of 5-aza and GA similarly demethylated PPARγ promoter, restored PPARγ loss and alleviated fibrotic lung pathologies, including structural alterations and adverse expression of fibrotic mediators and inflammatory cytokines. In cultured lung fibroblasts and alveolar epithelial cells, GA alleviated PPARγ-mediated suppression of fibrosis in a gain of DNMT-sensitive manner, and in PPARγ knockout mice, the anti-fibrotic effects of 5aza and GA were significantly reduced, suggesting that PPARγ is a critical mediator of epigenetic pulmonary fibrogenesis. CONCLUSION AND IMPLICATIONS: Aberrant DNMT1/3a elevations and the resultant PPARγ suppression contribute significantly to the development of pulmonary fibrosis, and strategies targeting DNMT/PPARγ axis with synthetic or natural compounds might benefit patients with pulmonary fibrotic disorders.

Correlation of Lipid Ratios With the Severity of Pulmonary Alveolar Proteinosis: A Cross-Sectional Study.

Background: Lipids are known to accumulate abnormally in the alveoli and circulate during pulmonary alveolar proteinosis (PAP). However, the relationship between lipid ratios and PAP is not clear. In this study, we investigated the lipid ratios in PAP patients and explored the relationships between lipid ratios and the severity of PAP. Methods: A total of 122 PAP patients were diagnosed and divided the mild- moderate PAP group (n = 61) and the severe PAP group (n = 61) according to the value of disease severity score (DSS). One hundred thirty healthy volunteers were classified as the control group. Routine blood examination and pulmonary function tests were performed and lipid profile were measured. Results: Compared with the control group, patients with PAP had significantly higher TG, TC/HDL-C, TG/HDL-C, and non-HDL-C, while lower HDL-C (all P < 0.05). Patients with the severe PAP had higher TC, TG, LDL-C, TC/HDL-C, and non-HDL-C, while lower HDL-C than patients with the mild- moderate PAP (all P < 0.05). Binary logistic regression analysis indicated that TC/HDL-C (OR = 2.322, 95% CI 1.621-3.713, P = 0.024) and non-HDL-C (OR = 1.797, 95% CI 1.239-3.109, P = 0.036) were all significantly correlated with the severity of PAP after adjustment for other risk factors. The AUC value of TC/HDL-C for predicting the severity of PAP was larger than that of non-HDL-C. The AUROC for TC/HDL-C was 0.741 (0.654-0.828), and the optimal cut-off point for TC/HDL-C was 5.05 (sensitivity: 73.6%, specificity: 68.1%). Conclusions: Lipid ratios, including TC-HDL-C and non-HDL-C, were independent risk factors for the severity of PAP. TC/HDL-C is a promising biomarker for the severity of PAP.

Association Between Triglyceride Glucose Index and Non-Small Cell Lung Cancer Risk in Chinese Population.

BACKGROUND: Numerous studies showed that insulin resistance (IR) was associated with cancer risk. However, few studies investigated the relationship between IR and non-small cell lung cancer (NSCLC). The aim of this study is to explore the association of triglyceride glucose (TyG) index, a simple surrogate marker of IR, with NSCLC risk. METHODS: 791 histologically confirmed NSCLC cases and 787 controls were enrolled in the present study. Fasting blood glucose and triglyceride were measured. The TyG index was calculated as ln [fasting triglycerides (mg/dl) ×fasting glucose (mg/dl)/2]. Logistic regression analysis was performed to estimate the relationship between NSCLC risk and the TyG index. RESULTS: The TyG index was significantly higher in patients with NSCLC than that in controls (8.42 ± 0.55 vs 8.00 ± 0.45, P < 0.01). Logistic regression analysis showed that the TyG index (OR = 3.651, 95%CI 2.461-5.417, P < 0.001) was independently associated with NSCLC risk after adjusting for conventional risk factors. In addition, a continuous rise in the incidence of NSCLC was observed along the tertiles of the TyG index (29.4 vs 53.8 vs 67.2%, P < 0.001). However, there were no differences of the TyG index in different pathological or TNM stages. In receiver operating characteristic (ROC) curve analysis, the optimal cut-off level for the TyG index to predict incident NSCLC was 8.18, and the area under the ROC curve (AUROC) was 0.713(95% CI 0.688-0.738). CONCLUSIONS: The TyG index is significantly correlated with NSCLC risk, and it may be suitable as a predictor for NSCLC.

Cytokeratin 19 fragment is associated with severity and poor prognosis of interstitial lung disease in anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVES: In the present study, we aimed to assess the clinical significance of cytokeratin 19 fragment (CYFRA21-1) in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-interstitial lung disease (MDA5-DM-ILD). METHODS: A total of 73 MDA5-DM-ILD patients were retrospectively analysed in this work. Their clinical characteristics, including clinical manifestations, laboratory findings, peripheral blood lymphocyte subsets and lung function, were compared between patients with acute/subacute interstitial pneumonia (A/SIP) and chronic interstitial pneumonia (CIP). The level of serum CYFRA21-1 was also compared between the above-mentioned two groups of patients, and its association with the clinical features and mortality of MDA5-DM-ILD was also evaluated. RESULTS: Of the 73 MDA5-DM-ILD patients, 26 patients exhibited the A/SIP pattern. The level of serum CYFRA21-1 was higher in MDA5-DM patients with A/SIP compared with the CIP group (P = 0.009). Lower oxygenation index (OI), CD3+CD4+ T cell counts and percentage of CD3+CD4+ cells were also observed in MDA5-DM patients with A/SIP compared with the CIP group. Higher serum CYFRA21-1, lower OI, and lower zone consolidation were associated with a higher risk of A/SIP in MDA5-DM-ILD. In addition, 38 decedents with MDA5-DM-ILD exhibited a greater level of CYFRA21-1 compared with 35 survivors (P < 0.001). Furthermore, it was a prognostic factor and also associated with a higher mortality rate (log-rank test, P < 0.001). CONCLUSIONS: CYFRA21-1 could be a useful serum indicator associated with occurrence of A/SIP in MDA5-DM-ILD. Moreover, it was associated with a poor survival in MDA5-DM-ILD patients.

Prognostic evaluation of serum osteopontin in patients with anti-MDA5 antibody-positive dermatomyositis associated interstitial lung disease.

BACKGROUND: The anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody was significantly associated with dermatomyositis associated with interstitial lung disease (DM-ILD) and poor survival in patients. However, there was no convenient and accurate biomarker can predict the poor prognosis of anti-MDA5 positive DM-ILD. This study aimed to evaluate the clinical significance of osteopontin (OPN) in anti-MDA5 positive DM-ILD patients. METHODS: The subjects were 43 patients diagnosed DM-ILD with anti-MDA5 antibody. The clinical data were obtained through a review of patient medical records. The serum samples were collected at the time of initial admission and detected for OPN concentrations and ferritin. In addition, immunohistochemistry analysis for OPN was performed on the lung sections of two patients with DM-ILD and six patients with early-stage lung cancer as normal control. RESULTS: The median value of serum OPN in patients with anti-MDA5 positive DM-ILD was 1755.65 pg/ml. Immunohistochemical findings for OPN suggested that the expression of OPN in alveolar epithelial cells and macrophages of anti-MDA5-positive ILD patients was more obvious. Significant correlations between serum OPN and ferritin levels were observed (r = 0.317, P = 0.038). Although OPN and ferritin were both associated with mortality in Univariate Cox hazards analysis, OPN was an independent predictor of the prognosis of DM-ILD rather than ferritin in Multivariate Cox hazards analysis. CONCLUSION: OPN can be expressed in lung tissues but also can exist as a secreted form in serum, and serum OPN may be a more valuable prognostic biomarker in DM-ILD patients with anti-MDA5 antibody than the serum ferritin.

Incidence and impact of extra-pulmonary organ failures on hospital mortality in acute exacerbation of idiopathic pulmonary fibrosis.

To evaluate hospital mortality and associated risk factors for acute exacerbations of idiopathic pulmonary fibrosis (AEIPF). Emphases were put on incidence and impact of extra-pulmonary organ failures. Patients diagnosed with AEIPF from July 2014 to September 2018 were enrolled. Clinical data were collected. Acute physiology and chronic health evaluation II (APACHE II) and simplified acute physiological score II (SAPS II) were calculated. Extra-pulmonary organ failures were diagnosed upon criteria of sequential organ failure assessment (SOFA). Forty-five patients with AEIPF were included. Eighteen patients (40.0%) developed extra-pulmonary organ failures, and 25 patients (55.6%) died during hospitalization. Serum C-reactive protein (CRP) (p = 0.001), SAPS II (p = 0.004), SOFA (p = 0.001) were higher, whereas arterial oxygen pressure (PaO2)/ fractional inspired oxygen (FiO2) (p = 0.001) was lower in non-survivors than survivors. More non-survivors developed extra-pulmonary organ failures than survivors (p = 0.002). After adjustment, elevated serum CRP (OR 1.038, p = 0.049) and extra-pulmonary organ failure (OR 13.126, p = 0.016) were independent predictors of hospital mortality in AEIPF. AEIPF had high hospital mortality and occurrence of extra-pulmonary organ failure was common. Elevated serum CRP and extra-pulmonary organ failure had predictive values for mortality.

Association of serum macrophage-mannose receptor CD206 with mortality in idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is attracting considerable attention due to disease acceleration and substantial mortality. Macrophages are known to regulate the fibrotic process in idiopathic pulmonary fibrosis. OBJECTIVE: We investigated if two new macrophage-specific serum biomarkers, soluble mannose receptor (MR, sCD206) and soluble CD163 (sCD163), increased in serum obtained from patients with AE-IPF compared to stable IPF (S-IPF). METHODS: A total of 36 IPF patients with AE status, 54 IPF patients with stable status, and 27 normal controls were enrolled in this study. The levels of serum sCD206 and sCD163 were compared among the three groups and analysed with the clinical features and mortality of IPF. RESULTS: The serum concentrations of both markers were higher in patients with AE-IPF than in those with S-IPF (580.0 ng/ml vs 335 ng/ml for sCD206 and 69.2 ng/ml vs 37.9 ng/ml for sCD163). The level of sCD206 was related to an increased risk of mortality (HR = 1.002, p < 0.001). The best separation between decedents and survivors was obtained by sCD206 (area under the receiver operating characteristic curve [AUC] 0.712 and 95% confidence interval 0.595-0.830). CONCLUSION: Our data demonstrated that the macrophage-related markers sCD206 and sCD163 were significantly higher in patients with IPF, especially sCD206 in AE-IPF patients. The high level of serum sCD206 was associated with mortality in idiopathic pulmonary fibrosis.