Therapeutic strategies to target connective tissue growth factor in fibrotic lung diseases.

The treatment of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), remains challenging as current available antifibrotic agents are not effective in halting disease progression. Connective tissue growth factor (CTGF), also known as cellular communication factor 2 (CCN2), is a member of the CCN family of proteins that regulates cell signaling through cell surface receptors such as integrins, the activity of cytokines/growth factors, and the turnover of extracellular matrix (ECM) proteins. Accumulating evidence indicates that CTGF plays a crucial role in promoting lung fibrosis through multiple processes, including inducing transdifferentiation of fibroblasts to myofibroblasts, epithelial-mesenchymal transition (EMT), and cooperating with other fibrotic mediators such as TGF-ß. Increased expression of CTGF has been observed in fibrotic lungs and inhibiting CTGF signaling has been shown to suppress lung fibrosis in several animal models. Thus, the CTGF signaling pathway is emerging as a potential therapeutic target in IPF and other pulmonary fibrotic conditions. This review provides a comprehensive overview of the current evidence on the pathogenic role of CTGF in pulmonary fibrosis and discusses the current therapeutic agents targeting CTGF using a systematic review approach.

Outcomes and prognosis of progressive pulmonary fibrosis in patients with antineutrophil cytoplasmic antibody-positive interstitial lung disease.

Approximately one-third of fibrosing interstitial lung diseases exhibit progressive pulmonary fibrosis (PPF), a clinicopathological condition distinct yet resembling idiopathic pulmonary fibrosis (IPF). PPF in ANCA-positive ILD (ANCA-ILD) is poorly documented. To clarify incidence, predictors of PPF in ANCA-ILD, and their prognostic impact, 56 patients with ANCA-ILD were followed for ≥ 1 year (April 2004 to April 2021). PPF was defined per ATS/ERS/JRS/ALAT PPF 2022 guideline. We compared PPF and non-PPF in 38 patients with pulmonary function tests and ≥ 1 year follow up. ANCA-ILD (19 male, 19 female; mean age 72 years) comprised 21 patients with microscopic polyangiitis ILD (MPA-ILD) and 17 with ANCA-positive IP without systemic vasculitis (ANCA-IP). PPF occurred in 15/38 (39.5%) overall, and 27% of patients with MPA-ILD and 53% with ANCA-IP. Patient characteristics did not differ between PPF and non-PPF, however, the survival was significantly worse in patients with PPF than those with non-PPF. On multivariate regression analysis, higher age, higher serum SP-D level, and lower baseline %FVC were associated with PPF. In ANCA-ILD, 39.5% of patients demonstrated PPF, which is associated with increased mortality. Predictors of PPF were older age, higher SP-D, and lower baseline %FVC.

ATS/JRS/ALAT Hypersensitivity Pneumonitis Guidelines for Diagnosis of humidifier lung and summer-type hypersensitivity pneumonitis.

BACKGROUND: The ATS/JRS/ALAT Guidelines for the Diagnosis of Hypersensitivity Pneumonitis (GL for HP) were published in 2020. Humidifier lung and summer-type HP are forms of HP, but it is unclear whether they can be diagnosed using GL for HP. This study examined the level of confidence where humidifier lung and summer-type HP can be diagnosed with GL for HP. METHODS: Data from 23 patients with humidifier lung and 20 patients with summer-type HP (mean age, 67.3 and 57.4 years, respectively) diagnosed between October 2012 and January 2022 were retrospectively reviewed. We evaluated high resolution computed tomography (HRCT) patterns, bronchoalveolar lavage fluid (BALF) findings, exposures, and histopathological findings to determine the level of confidence where a diagnosis of HP could be made using the GL for HP. RESULTS: HRCT pattern was classified as typical HP in 5 (22%) and compatible with HP in 18 (78%) patients with humidifier lung and considered as typical HP in 17 (85%) and compatible with HP in 3 (15%) patients with summer-type. The confidence level for diagnosis of HP was definite in 2 (8.7%), moderate in 14 (60.9%), and low in 7 (30.4%) patients with humidifier lung. It was definite in 12 (60%), high in 3 (15%), and moderate in 5 (25%) patients with summer-type HP. CONCLUSIONS: GL for HP showed utility in diagnosing humidifier lung in many patients with a moderate to low confidence. However, there was a definite to high confidence for patients with summer-type HP.

Vascular-Parenchymal Cross-Talk Promotes Lung Fibrosis through BMPR2 Signaling.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive lung scarring. IPF-related pulmonary vascular remodeling and pulmonary hypertension (PH) result in a particularly poor prognosis. Objectives: To study the pathogenesis of vascular remodeling in fibrotic lungs and its contribution to progression of fibrosis. Methods: We used an experimental model of lung fibrosis associated with PH by transient overexpression of active TGF-ß1 (transforming growth factor-ß1). Samples from patients with fibrotic lung diseases were analyzed in depth using immunostaining, gene expression, and gene mutations. Measurements and Main Results: We found a reduction in endothelial cells (ECs) and activation of vascular smooth muscle cells (VSMCs) in fibrotic lungs. Coculturing fibroblasts with VSMCs or ECs from fibrotic lungs induced fibrotic phenotypes in fibroblasts. IPF fibroblasts induced EC death and activation of VSMCs in coculture systems. Decreased concentrations of BMPR2 (bone morphogenic protein receptor 2) and its signaling were observed in ECs and VSMCs from fibrotic lungs in both rats and humans. On fibroblasts treated with media from VSMCs, BMPR2 suppression in VSMCs led to fibrogenic effects. Tacrolimus activated BMPR2 signaling and attenuated fibrosis and PH in rodent lungs. Whole-exome sequencing revealed rare mutations in PH-related genes, including BMPR2, in patients with IPF undergoing transplantation. A unique missense BMPR2 mutation (p.Q721R) was discovered to have dysfunctional effects on BMPR2 signaling. Conclusions: Endothelial dysfunction and vascular remodeling in PH secondary to pulmonary fibrosis enhance fibrogenesis through impaired BMPR2 signaling. Tacrolimus may have value as a treatment of advanced IPF and concomitant PH. Genetic abnormalities may determine the development of PH in advanced IPF.

Therapeutic strategies targeting pro-fibrotic macrophages in interstitial lung disease.

Idiopathic pulmonary fibrosis (IPF) is the representative phenotype of interstitial lung disease where severe scarring develops in the lung interstitium. Although antifibrotic treatments are available and have been shown to slow the progression of IPF, improved therapeutic options are still needed. Recent data indicate that macrophages play essential pro-fibrotic roles in the pathogenesis of pulmonary fibrosis. Historically, macrophages have been classified into two functional subtypes, "M1″ and "M2," and it is well described that "M2″ or "alternatively activated" macrophages contribute to fibrosis via the production of fibrotic mediators, such as TGF-ß, CTGF, and CCL18. However, highly plastic macrophages may possess distinct functions and phenotypes in the fibrotic lung environment. Thus, M2-like macrophages in vitro and pro-fibrotic macrophages in vivo are not completely identical cell populations. Recent developments in transcriptome analysis, including single-cell RNA sequencing, have attempted to depict more detailed phenotypic characteristics of pro-fibrotic macrophages. This review will outline the role and characterization of pro-fibrotic macrophages in fibrotic lung diseases and discuss the possibility of treating lung fibrosis by preventing or reprogramming the polarity of macrophages. We also utilized a systematic approach to review the literature and identify novel and promising therapeutic agents that follow this treatment strategy.

Serum autotaxin levels in chronic disease and acute exacerbation of fibrosing interstitial lung disease.

Background: Autotaxin (ATX) is an ecto-enzyme that catalyses the hydrolysis of lysophospholipids to the lipid mediator lysophosphatidic acid (LPA). LPA/ATX signalling has emerged as a new therapeutic target for pulmonary fibrosis; however, the serum levels and dynamics of ATX during the clinical course of fibrosing interstitial lung disease (ILD) remain unknown. This study sought to examine the serum ATX levels in fibrosing ILD in the chronic phase and in acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). We aimed to elucidate the association between serum ATX level and clinical characteristics including disease progression and prognosis. Methods: In total, 119 patients with fibrosing ILD and 38 healthy volunteers as controls were enrolled in the study and their serum ATX activity was analysed. We also included six male patients with AE-IPF in order to analyse the changes in serum ATX at the onset of AE-IPF. Results: Patients with fibrosing ILD showed significantly higher serum ATX levels compared with healthy controls in both sexes. Per cent change in forced vital capacity after 1 year correlated with serum ATX levels in female patients. High serum ATX levels (>0.721 mg·â€ŠL-1) were associated with worse outcome in survival curve and multivariate analysis of male patients. Serum ATX activity decreased after the onset of AE-IPF. Conclusion: Serum ATX levels were significantly higher in patients with fibrosing ILD compared with healthy controls, and this was associated with disease progression and outcome. This suggests the potential of serum ATX as a promising biomarker for the treatment of fibrosing ILD.

New risk scoring system for predicting 3-month mortality after acute exacerbation of idiopathic pulmonary fibrosis.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is often fatal. A straightforward staging system for AE-IPF would improve prognostication, guide patient management, and facilitate research. The aim of study is to develop a multidimensional prognostic AE-IPF staging system that uses commonly measured clinical variables. This retrospective study analyzed data from 353 consecutive patients with IPF admitted to our hospital during the period from January 2008 through January 2018. Multivariate analysis of information from a database of 103 recorded AE-IPF cases was used to identify factors associated with 3-month mortality. A clinical prediction model for AE-IPF was developed by using these retrospective data. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of this model. Logistic regression analysis showed that PaO2/FiO2 ratio, diffuse HRCT pattern, and serum C-reactive protein (CRP) were significantly associated with 3-month mortality; thus, PaO2/FiO2 ratio < 250 (P), CRP ≥ 5.5 (C), and diffuse HRCT pattern (radiological) (R) were included in the final model. A model using continuous predictors and a simple point-scoring system (PCR index) was developed. For the PCR index, the area under the ROC curve was 0.7686 (P < 0.0001). The sensitivity of the scoring system was 78.6% and specificity was 67.8%. The PCR index identified four severity grades (0, 1, 2, and 3), which were associated with a 3-month mortality of 7.7%, 29.4%, 54.8%, and 80%, respectively. The present PCR models using commonly measured clinical and radiologic variables predicted 3-month mortality in patients with AE-IPF.

The Role for miR-146b-5p in the Attenuation of Dermal Fibrosis and Angiogenesis by Targeting PDGFRα in Skin Wounds.

As a candidate microRNA antifibrotic effector in skin wounds, miR-146b-5p was upregulated by basic FGF, and PDGFRα was identified as a direct target of miR-146b-5p in fibroblasts. The treatment of fibroblasts with a miR-146b-5p mimic markedly downregulated the expression of PDGFRα and collagen type I. miR-146b-5p mimic transfection in wounds markedly attenuated cutaneous fibrosis, whereas a miR-146b-5p inhibitor strongly promoted fibrosis, with increases in PDGFRα and collagen I levels. These results indicate the positive effects of miR-146b-5p for the suppression of fibrosis, possibly through the inhibition of PDGFRα. The miR-146b-5p inhibitor markedly increased CD34+ vessel numbers and CD34 expression in wounds. We found miR-146b-5p+ cells in close contact with S100+ adipocytes. Moreover, we discovered the specific colocalization of the exosome marker CD81 and miR-146b-5p in the adipose tissue cells of mimic-transfected wounds, with miR-146b-5p signals being detected in the FSP1+ fibroblastic cells of adipose tissues. Therefore, fibroblastic cells of adipose tissues, which may specifically pick up and contain miR-146b-5p by exosome after transfection, may play an important role in the suppression of fibrosis. In this process, the inhibition of PDGFRα in adipose tissue cells by miR-146b-5p may lead to the loss of their PDGFRα-induced profibrotic activities, thereby suppressing fibrosis.

Immunohistochemical Detection of Propionibacterium acnes in Granulomas for Differentiating Sarcoidosis from Other Granulomatous Diseases Utilizing an Automated System with a Commercially Available PAB Antibody.

Propionibacterium acnes is implicated in the pathogenesis of sarcoidosis. We investigated the usefulness of immunohistochemistry (IHC) with a commercially available P. acnes-specific monoclonal antibody (PAB antibody) for differentiating sarcoidosis from other granulomatous diseases. Formalin-fixed paraffin-embedded tissue samples from 94 sarcoidosis patients and 30 control patients with other granulomatous diseases were examined by the original manual IHC method. We also compared the detection frequency of P. acnes in sarcoid granulomas between manual and automated IHC methods. P. acnes was detected in sarcoid granulomas of samples obtained by transbronchial lung biopsy (64%), video-associated thoracic surgery (67%), endobronchial-ultrasound-guided transbronchial-needle aspiration (32%), lymph node biopsy (80%), and skin biopsy (80%) from sarcoidosis patients, but not in any non-sarcoid granulomas of the samples obtained from control patients. P. acnes outside granulomas, however, was frequently detected in both groups. The detection status of P. acnes in granulomas did not correlate with the clinical characteristics of sarcoidosis patients. The automated Leica system exhibited the best detection sensitivity (72%) and almost an identical localization for P. acnes in sarcoid granulomas compared with the manual method. IHC with a PAB antibody is useful for differentiating sarcoidosis from other granulomatous diseases by detecting P. acnes in granulomas. An automated method by the Leica system can be used in pathology laboratories for differential diagnosis of granulomas by IHC with the PAB antibody.

Incidence of acute exacerbation of idiopathic pulmonary fibrosis in patients receiving antifibrotic agents: Real-world experience.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a fatal event that can occur during the clinical course of idiopathic pulmonary fibrosis (IPF). Although data from clinical trials suggest that the antifibrotic agents pirfenidone and nintedanib might reduce the risk of AE-IPF, the incidence of AE-IPF in patients receiving antifibrotic agents in clinical settings is unclear. OBJECTIVES: To determine the incidence of AE-IPF in patients receiving antifibrotic agents and compare AE-IPF frequency in patients receiving pirfenidone and nintedanib. METHODS: We retrospectively reviewed the clinical records of 199 patients with IPF who were started on pirfenidone or nintedanib at our institution during the period from 2009 through 2018. Baseline characteristics, incidence of AE-IPF, and outcome after AE-IPF onset were analyzed. RESULTS: During the observation period, the 1-, 2-, and 3-year cumulative incidences of AE-IPF were 9.3 %, 22.1 %, and 25.0 %, respectively. The 1-, 2-, and 3-year cumulative incidence rates for AE-IPF in the pirfenidone group and nintedanib group were 5.1 % vs. 18.6 %, 20.4 % vs. 25.2 %, and 22.6 % vs. 29.6 %, respectively. AE-IPF incidence was significantly lower in patients treated with pirfenidone than in those treated with nintedanib (log rank test, P = 0.035). The 3-month survival rate after AE-IPF onset was 61.1 % in the pirfenidone group and 61.5 % in the nintedanib group; thus, outcomes after AE-IPF onset were similar in the 2 groups. CONCLUSION: The reduction in AE-IPF risk might be greater for pirfenidone than for nintedanib.

Association of rs3750920 polymorphism in TOLLIP with clinical characteristics of fibrosing interstitial lung diseases in Japanese.

TOLLIP polymorphism has been implicated in the development and prognosis of idiopathic pulmonary fibrosis (IPF), mainly in whites. However, ethnic differences in the characteristics of other interstitial pneumonia (non-IPF) subtypes are unclear. We evaluated the association between the rs3750920 genotype and the clinical characteristics of Japanese patients with fibrosing interstitial lung diseases (ILD). We genotyped 102 patients with fibrosing ILD (75 IPF and 27 non-IPF patients) and analyzed the interaction between the rs3750920 genotype distribution and their clinical characteristics. The overall frequencies of the C/C, C/T, and T/T genotypes were 69%, 25%, and 6%, respectively. The proportion of minor T allele carriers was larger in IPF patients than in non-IPF patients (37% vs. 15%, P = 0.031). In addition, survival at 3 years was significantly better for carriers than for non-carriers of the T allele. There was no significant association between genotype distribution and change in pulmonary function after introduction of antifibrotic agents. The frequency of the minor T allele of rs3750920 was low in Japanese patients with fibrosing ILD, particularly in non-IPF patients. Carriers of the minor T allele had better survival than non-carriers. Presence of the T allele might thus be an indicator of better outcomes for fibrosing ILD.

Association of serum monomeric periostin level with outcomes of acute exacerbation of idiopathic pulmonary fibrosis and fibrosing nonspecific interstitial pneumonia.

BACKGROUND: The associations of serum monomeric periostin (M-PN) level and serial change in M-PN with acute exacerbation of chronic fibrosing interstitial pneumonia (AE-FIP) are unclear. METHODS: We prospectively measured serum M-PN level from onset of AE to day 14 in 37 patients with AE-FIP and evaluated its association with outcome. To determine localization of periostin expression, immunohistochemical staining of pathological lung tissue from autopsy cases of AE-IPF was evaluated. RESULTS: Data from 37 AE-FIP patients (28 men; age 73.9±7.8 years) were analyzed. With healthy controls as reference, serum M-PN level was significantly higher in patients with AE-FIP (P=0.02) but not in those with stable idiopathic pulmonary fibrosis (P=1.00). M-PN was significantly lower on day 7 than at AE-FIP onset in survivors [14.6±5.8 vs. 9.3±2.8 ng/mL (onset to day 7: P<0.001)] but not in non-survivors [14.6±5.1 vs. 13.2±5.1 ng/mL (onset to day 7: P=0.07)]. In analysis using a cut-off value for serial change in M-PN (ΔM-PN), 3-month survival was 92.3% in the ΔM-PN decrease group and 36% in the ΔM-PN increase group (P=0.002). In multivariate analysis, 3-month survival tended to be associated with high ΔM-PN (OR: 12.4, 95% CI: 0.82-187.9, P=0.069). CONCLUSIONS: Serial change in serum M-PN level may be a prognostic indicator of AE-FIP.

Quantification of BIM mRNA in circulating tumor cells of osimertinib-treated patients with EGFR mutation-positive lung cancer.

BACKGROUND: The response rate for osimertinib is high among patients with untreated epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, there exist no biomarkers to predict the efficacy of the same. This study investigated whether BIM-γ mRNA expression in circulating tumor cells (CTCs) predicts poor outcomes for osimertinib treatment in patients with EGFR mutation-positive NSCLC. METHODS: Patients with advanced EGFR-tyrosine kinase inhibitor-untreated NSCLC or post-operative recurrence with EGFR-sensitive mutations (exon 19 deletion or L858R mutation) were included. Informed consent was obtained from all participants. The candidate biomarker BIM-γ was measured in CTCs after blood collection (10 mL of whole blood) at baseline. CTCs were collected with the ClearCell FX system, and quantitative real-time PCR was performed. Relative expression of BIM-γ mRNA from CTCs, as normalized to the reference gene (GAPDH mRNA), was calculated using the KCL22 cell line for calibration. RESULTS: We enrolled 30 EGFR mutation-positive NSCLC patients treated with osimertinib during the period from April 2018 through December 2019. All the patients had an EGFR mutation at the primary site: exon 19 deletion in 15 cases and L858R in 15 cases. Median CTC count at baseline was 12 (range 3-127)/7.5 mL, and median BIM-γ mRNA expression was 0.073 (range 0-1.37). Furthermore, the response rate to osimertinib was worse in patients with high than in those with low BIM-γ mRNA expression (n = 15 each) (26.6% vs. 73.3%, respectively; p = 0.011). Progression-free survival did not significantly differ between groups (p = 0.13). CONCLUSIONS: BIM-γ mRNA overexpression in CTCs from EGFR mutation-positive NSCLC patients is a potential a biomarker for poor response to osimertinib. CLINICAL TRIAL REGISTRATION NUMBER: UMIN:00032055.

Effectiveness of pirfenidone for idiopathic pulmonary fibrosis associated with pleuroparenchymal fibroelastosis-like lesions and nonspecific interstitial pneumonia.

BACKGROUND: Pirfenidone treatment can slow decline in forced vital capacity (FVC) in idiopathic pulmonary fibrosis (IPF). However, its effects for usual interstitial pneumonia (UIP) with pleuroparenchymal fibroelastosis-like lesions (UIP+PPFELL) and UIP with nonspecific interstitial pneumonia (UIP+NSIP) are unclear. OBJECTIVES: The aim of study is to assess pirfenidone effectiveness for UIP+PPFELL and UIP+NSIP. METHODS: We retrospectively analysed data from 58 IPF patients treated with pirfenidone more than 6 months. The outcomes of interest were 6-month follow-up pulmonary function test results, progression-free survival (PFS) and overall survival (OS). Treatment was considered effective if FVC decline was <5% during the 6-month period. We compared clinical characteristics, effectiveness, PFS and OS between patients with typical IPF (n = 32), UIP+PPFELL (n = 12) and UIP+NSIP (n = 14). RESULTS: Data from 58 IPF patients were analysed. At the 6-month follow-up examination, treatment was deemed effective for 9 of 14 (64%) UIP+NSIP patients, 6 of 12 (50%) UIP+PPFELL patients and 14 of 32 (44%) patients with typical IPF. The 6-month decline in FVC before treatment was greater than that after starting treatment in the UIP+NSIP (-210 vs. -57 mL; P = 0.09), UIP+PPFELL (-370 vs. -89 mL; P = 0.001) and typical IPF (-172 vs. -85 mL; P = 0.37). PFS did not significantly differ between the three groups. OS was significantly shorter for UIP+PPFELL (312 days) than for UIP+NSIP (545 days) and typical IPF (661 days). CONCLUSIONS: Pirfenidone decreased the decline in FVC in patients with UIP+PPFELL and UIP+NSIP, as well as in those with typical IPF. However, outcomes were worse for patients with UIP+PPFELL.

Clinical and radiological characteristics of ultrasonic humidifier lung and summer-type hypersensitivity pneumonitis.

BACKGROUND: Ultrasonic humidifier lung is a rare form of hypersensitivity pneumonitis (HP), and its clinical and radiological features are unclear. This study examined the clinical and radiological characteristics of humidifier lung. METHODS: Data from 18 patients with humidifier lung (mean age, 67.3 years) diagnosed during October 2012 through April 2018 were retrospectively reviewed. We compared clinical, laboratory, and CT findings and bronchoalveolar lavage fluid (BALF) characteristics of these patients with those of 19 patients with summer-type HP (mean age, 57.4 years). RESULTS: Cough and dyspnea were the most common symptoms. White blood cell count and serum C-reactive protein titers were higher for humidifier lung than for summer-type HP. Serum levels of Krebs von den Lungen-6 and surfactant protein D were significantly lower for humidifier lung than for summer-type HP. The most common chest CT findings in humidifier lung were ground-glass opacities (88.9%) and mosaic attenuation (50.0%). Centrilobular ground glass nodules were less common in humidifier lung than in summer-type HP (27.8% vs 63.1%; P = 0.043). Peribronchovascular or subpleural nonsegmental consolidation was more frequent in humidifier lung than in summer-type HP (44.4% vs 5.3%; P = 0.013). Lymphocyte fractions in BALF specimens were significantly lower for humidifier lung than for summer-type HP (37.3% vs 69.0%; P < 0.001). Neutrophil fractions were higher for humidifier lung, but the difference was not significant (22.1% vs 8.1%; P = 0.153). The CD4/8 ratio was higher for humidifier lung than for summer-type HP (1.7 vs 0.8; P = 0.003). CONCLUSIONS: The clinical and radiological characteristics of humidifier lung differ from those of summer-type HP.

Plasma matrix metalloproteinase 7, CC-chemokine ligand 18, and periostin as markers for pulmonary sarcoidosis.

BACKGROUND: Some patients with sarcoidosis experience worsening of pulmonary lesions. However, no biomarker has been identified that reflects pulmonary disease status in sarcoidosis. We investigated the usefulness of potential markers of pulmonary fibrosis in patients with sarcoidosis. METHODS: Plasma matrix metalloproteinase 7 (MMP-7), CC-chemokine ligand 18 (CCL-18), and periostin levels were evaluated in 60 patients with sarcoidosis and 30 healthy controls; bronchoalveolar lavage fluid levels were analyzed in 22 patients with sarcoidosis. To determine the usefulness of these markers, we explored potential correlations between these markers and sarcoidosis clinical characteristics. RESULTS: Plasma MMP-7, CCL-18, and periostin concentrations were significantly higher in patients with sarcoidosis than those in healthy controls. MMP-7 concentrations in plasma and bronchoalveolar lavage fluid were higher in patients with sarcoidosis with parenchymal infiltration than in those without lung lesions. Moreover, MMP-7 concentration was negatively correlated with pulmonary function. CONCLUSION: Among these novel biomarkers, MMP-7 most precisely reflected pulmonary sarcoidosis disease status and thus, might be useful for diagnosing and evaluating sarcoidosis, particularly in patients with pulmonary parenchymal lesions.

Clinical importance of long non­coding RNA LINC00460 expression in EGFR­mutant lung adenocarcinoma.

Long non­coding RNAs (lncRNAs) have been reported to be involved in the physiological and pathological processes of tumor pathogenesis, including epithelial­mesenchymal transition (EMT). However, epidermal growth factor receptor (EGFR)­tyrosine kinase inhibitor (TKI) resistance is a major challenge in the treatment of advanced and recurrent EGFR­mutant lung adenocarcinoma. An increased understanding of the underlying mechanisms would aid in the development of effective therapeutic strategies against EGFR­TKI resistance, strategies which are urgently required for clinical therapy. In this study, long non­coding RNA LINC00460 was identified as a novel marker of a poor response to EGFR­TKI and prognosis. In lung cancer cells, LINC00460 promoted EGFR­TKI resistance as a competitive decoy for miR­149­5p, thereby facilitating interleukin (IL)­6 expression and inducing EMT­like phenotypes. The knockdown or knockout of LINC00460 in gefitinib­resistant non­small cell lung cancer cells restored the response to EGFR­TKI. In addition, as compared with patients with a low LINC00460 expression in tumors, those with a high LINC00460 expression had a significantly shorter progression­free survival following gefitinib therapy, and a shorter overall survival. Therefore, LINC00460 may be a predictor of and potential therapeutic target for EGFR­TKI resistance.

Activation of mucosal-associated invariant T cells in the lungs of sarcoidosis patients.

Although the pathogenesis of sarcoidosis is not fully understood, immunological characterization has elucidated highly polarized expression of the type 1 T helper cell response. Mucosal-associated invariant T (MAIT) cells are innate T cells that recognize bacterial riboflavin and rapidly produce cytokines such as interferon γ and tumor necrosis factor α. We prospectively evaluated the proportion of MAIT cells and the expression levels of cell surface markers in peripheral blood from 40 sarcoidosis patients and 28 healthy controls. MAIT cells in bronchoalveolar lavage fluid (BALF) were also examined in 12 sarcoidosis patients. In peripheral blood, the proportion of MAIT cells was lower (P = 0.0002), but the expression levels of CD69 and programmed death 1 on MAIT cells were higher in sarcoidosis patients than in healthy controls. Moreover, CD69 expression levels were significantly correlated with clinical biomarkers. Sarcoidosis patients with parenchymal infiltration in the lungs showed a significantly higher proportion and number of MAIT cells in BALF compared to patients without parenchymal infiltration. CD69 expression levels on MAIT cells in BALF were higher than levels in peripheral blood. The activation status of MAIT cells might reflect the disease activity of sarcoidosis. Therefore, it is a potential target for sarcoidosis treatment.

Therapeutic Role of Recombinant Human Soluble Thrombomodulin for Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an acute respiratory worsening of unidentifiable cause that sometimes develops during the clinical course of IPF. Although the incidence of AE-IPF is not high, prognosis is poor. The pathogenesis of AE-IPF is not well understood; however, evidence suggests that coagulation abnormalities and inflammation are involved. Thrombomodulin is a transmembranous glycoprotein found on the cell surface of vascular endothelial cells. Thrombomodulin combines with thrombin, regulates coagulation/fibrinolysis balance, and has a pivotal role in suppressing excess inflammation through its inhibition of high-mobility group box 1 protein and the complement system. Thus, thrombomodulin might be effective in the treatment of AE-IPF, and we and other groups found that recombinant human soluble thrombomodulin improved survival in patients with AE-IPF. This review summarizes the existing evidence and considers the therapeutic role of thrombomodulin in AE-IPF.

Development of Propionibacterium acnes-associated Sarcoidosis During Etanercept Therapy.

Although numerous recent studies have reported the development of sarcoidosis in patients treated with tumor necrosis factor alpha (TNF-α) inhibitors, it is unclear whether the pathogenesis of drug-induced sarcoidosis is identical to that of spontaneous sarcoidosis. We herein present the case of a patient who developed sarcoidosis 6 months after the introduction of etanercept as treatment for rheumatoid arthritis. Typical clinical symptoms with noncaseating epithelioid granulomas detected in a mediastinal lymph node specimen were consistent with the diagnosis of sarcoidosis. Immunohistochemistry revealed Propionibacterium acnes in the noncaseating granulomas. The present findings suggest that Propionibacterium acnes is a cause of sarcoidosis, even when the disease is induced by TNF-α inhibitors.