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Abstract Background Serum levels of stratifin (SFN), a member of the 14-3-3 protein family, increase in patients with drug-induced lung injury associated with diffuse alveolar damage. Therefore, we hypothesised that SFN levels would be higher in those experiencing acute exacerbation of interstitial lung disease (AE-ILD). A secondary analysis was also planned to determine whether SFN levels could discriminate survival in those with AE. Methods Thirty-two patients with clinically stable ILD (CS-ILD) and 22 patients with AE-ILD were examined to assess whether high serum SFN levels were associated with AE-ILD and whether SFN levels reflected disease severity or prognosis in patients with AE-ILD. Results Serum SFN levels were higher in the AE-ILD group than in the CS-ILD group (8.4 ± 7.6 vs. 1.3 ± 1.2 ng/mL, p

Radiation-induced organizing pneumonia is a rare complication of radiation therapy for thoracic cancer. Carbon-ion radiotherapy, an emerging treatment modality for early-stage lung cancer treatment, can also cause lung injuries. However, as cases of radiation-induced organizing pneumonia caused by carbon-ion radiotherapy for lung cancer have not been reported, its clinical features remain unclear. A 69-year-old woman was referred to our hospital 11 months after being diagnosed with early lung cancer due to refractory pneumonitis induced by carbon-ion radiotherapy. She had developed fever and dyspnea 4 months after undergoing carbon-ion radiotherapy and was subsequently diagnosed with radiation pneumonitis. The administration of oral prednisolone resulted in improvement. However, she relapsed each time the dose of prednisolone was tapered. She was diagnosed with radiation-induced organizing pneumonia caused by carbon-ion radiotherapy for lung cancer based on the clinical course and the results of the examination performed at our hospital. An improvement was observed after administering methylprednisolone (1000 mg/d) for 3 days. The dose of oral prednisolone was slowly tapered over a period of ≥6 months with no relapse. Organizing pneumonia caused by carbon-ion radiotherapy for lung cancer is treatable with corticosteroids; however, tapering the dose of corticosteroids may lead to relapse.

Abstract Background Drug-induced interstitial lung disease (DILD) is a lung injury caused by various types of drugs and is a serious problem in both clinical practice and drug development. Clinical management of the condition would be improved if there were DILD-specific biomarkers available; this study aimed to meet that need. Methods Biomarker candidates were identified by non-targeted metabolomics focusing on hydrophilic molecules, and further validated by targeted approaches using the serum of acute DILD patients, DILD recovery patients, DILD-tolerant patients, patients with other related lung diseases, and healthy controls. Results Serum levels of kynurenine and quinolinic acid (and kynurenine/tryptophan ratio) were elevated significantly and specifically in acute DILD patients. The diagnostic potentials of these biomarkers were superior to those of conventional lung injury biomarkers, Krebs von den Lungen-6 and surfactant protein-D, in discriminating between acute DILD patients and patients with other lung diseases, including idiopathic interstitial pneumonia and lung diseases associated with connective tissue diseases. In addition to identifying and evaluating the biomarkers, our data showed that kynurenine/tryptophan ratios (an indicator of kynurenine pathway activation) were positively correlated with serum C-reactive protein concentrations in patients with DILD, suggesting the potential association between the generation of these biomarkers and inflammation. Our in vitro experiments demonstrated that macrophage differentiation and inflammatory stimulations typified by interferon gamma could activate the kynurenine pathway, resulting in enhanced kynurenine levels in the extracellular space in macrophage-like cell lines or lung endothelial cells. Extracellular quinolinic acid levels were elevated only in macrophage-like cells but not endothelial cells owing to the lower expression levels of metabolic enzymes converting kynurenine to quinolinic acid. These findings provide clues about the molecular mechanisms behind their specific elevation in the serum of acute DILD patients. Conclusions The serum concentrations of kynurenine and quinolinic acid as well as kynurenine/tryptophan ratios are promising and specific biomarkers for detecting and monitoring DILD and its recovery, which could facilitate accurate decisions for appropriate clinical management of patients with DILD.

Abstract Pleuroparenchymal fibroelastosis (PPFE) progresses slowly but sometimes relatively quickly, leading to decreased activities of daily living (ADL) and muscle weakness. Skeletal muscle atrophy and muscle weakness in chronic obstructive pulmonary disease (COPD) patients may be caused by cachexia and are associated with reduced ADLs and increased risk of death. However, the association between skeletal muscle mass and the prognosis of PPFE patients remains unknown. We retrospectively analysed the clinical significance of the cross-sectional area of the erector spinae muscle (ESMCSA), a skeletal muscle index, and predictors of mortality within 3 years in PPFE 51 patients, idiopathic pulmonary fibrosis (IPF) 52 patients and COPD 62 patients. PPFE patients had significantly lower ESMCSA than IPF or COPD patients, and lower ESMCSA (

Abstract Introduction Secondary spontaneous pneumothorax (SSP) occurs as one of the complications associated with interstitial pneumonia (IP). Chest drainage is performed when there is a large volume of air in the pleural space. Notably, SSP with IP (SSP‐IP) is frequently not curable by chest drainage only. A digital drainage system (DDS) provides an objective evaluation of air leakage and maintains a pre‐determined negative pressure, compared to an analog drainage system (ADS). Few studies have reported the effectiveness of DDS in the treatment of SSP‐IP. This study aimed to assess the usefulness of DDS for SSP‐IP. Methods This retrospective study included patients with SSP‐IP who had undergone chest drainage. We reviewed the included patients' medical records, laboratory data, computed tomography findings, and pulmonary function data. Results DDS was used in 24 patients and ADS in 49 patients. The mean duration of chest drainage was 11.4 ± 1.9 days in the DDS group and 14.2 ± 1.3 days in the ADS group, which was not significantly different (p = 0.218). Surgery, pleurodesis, and/or factor XIII administration were performed in 40 patients. Additionally, five (20.8%) patients in the DDS group and nine (18.4%) in the ADS group had a recurrence of pneumothorax within 4 weeks (p = 1.000). One patient (14%) in the DDS group and six (12.2%) in the ADS group (p = 0.414) were cured of pneumothorax but later died. Conclusion DDS did not demonstrate a significant difference in the shortening of chest drainage duration. Further study is needed to validate the results of this study.

Two anti-fibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells (PBMCs) are immunocompetent cells that could orchestrate cell–cell interactions associated with IPF pathogenesis. We employed RNA sequencing to examine the transcriptome signature in the bulk PBMCs of patients with IPF and the effects of anti-fibrotic drugs on these signatures. Differentially expressed genes (DEGs) between “patients with IPF and healthy controls” and “before and after anti-fibrotic treatment” were analyzed. Enrichment analysis suggested that fatty acid elongation interferes with TGF-β/Smad signaling and the production of oxidative stress since treatment with NTD upregulates the fatty acid elongation enzymes ELOVL6. Treatment with PFD downregulates COL1A1, which produces wound-healing collagens because activated monocyte-derived macrophages participate in the production of collagen, type I, and alpha 1 during tissue damage. Plasminogen activator inhibitor-1 (PAI-1) regulates wound healing by inhibiting plasmin-mediated matrix metalloproteinase activation, and the inhibition of PAI-1 activity attenuates lung fibrosis. DEG analysis suggested that both the PFD and NTD upregulate SERPINE1, which regulates PAI-1 activity. This study embraces a novel approach by using RNA sequencing to examine PBMCs in IPF, potentially revealing systemic biomarkers or pathways that could be targeted for therapy.

Abstract Drug-induced interstitial lung disease (DILD) occurs when drug exposure causes inflammation of the lung interstitium. DILD can be caused by different types of drugs, and some DILD patterns results in a high mortality rate; hence, DILD poses a serious problem in clinical practice as well as drug development, and strategies to diagnose and distinguish DILD from other lung diseases are necessary. We aimed to identify novel biomarkers for DILD by performing lipidomics analysis on plasma samples from patients with acute and recovery phase DILD. Having identified lysophosphatidylcholines (LPCs) as candidate biomarkers for DILD, we determined their concentrations using validated liquid chromatography/mass spectrometry biomarker assays. In addition, we evaluated the ability of LPCs to discriminate patients with acute phase DILD from those with recovery phase DILD, DILD-tolerant, or other lung diseases, and characterized their association with clinical characteristics. Lipidomics analysis revealed a clear decrease in LPC concentrations in the plasma of patients with acute phase DILD. In particular, LPC(14:0) had the highest discriminative index against recovery phase and DILD-tolerant patients. LPC(14:0) displayed no clear association with causal drugs, or subjects’ backgrounds, but was associated with disease severity. Furthermore, LPC(14:0) was able to discriminate between patients with DILD and other lung diseases, including idiopathic interstitial pneumonia and lung disease associated with connective tissue disease. LPC(14:0) is a promising biomarker for DILD that could improve the diagnosis of DILD and help to differentiate DILD from other lung diseases, such as idiopathic interstitial pneumonia and connective tissue disease.

No reliable serum biomarker for diffuse alveolar damage, a poor prognosis subtype of drug-induced interstitial lung disease, is currently available. Here, the authors show stratifin/14-3-3σ in serum is a promising biomarker for diagnosis of this type of disease.

Abstract Background Cellular patterns in bronchoalveolar lavage fluid (BALF) are used to distinguish or rule out particular diseases in patients with acute respiratory failure (ARF). However, whether BALF cellular patterns can predict mortality or not is unknown. We test the hypothesis that BALF cellular patterns have predictive value for mortality in patients with ARF. Methods This was a retrospective single-center observational study conducted in a Japanese University Hospital. Consecutive patients (n = 78) with both pulmonary infiltrates and ARF who were examined by bronchoalveolar lavage (BAL) between April 2015 and May 2018 with at least 1 year of follow-up were analyzed. Primary analysis was receiver operating characteristic curve—area under the curve (ROC-AUC) analysis for 1-year mortality. Results Among the final sample size of 78 patients, survivors (n = 56) had significantly increased lymphocyte and eosinophil counts and decreased neutrophil counts in BALF compared with non-survivors (n = 22). Among the fractions, lymphocyte count was the most significantly different (30 [12-50] vs. 7.0 [2.9-13]%, P

Abstract Background If anaplastic lymphoma kinase (ALK) gene rearrangement in lung cancer is identified, ALK‐tyrosine kinase inhibitors (ALK‐TKIs) can be an effective treatment. However, the details of drug‐induced lung injury (DILI) caused by ALK‐TKI, which can be a serious side effect of ALK‐TKIs, remains unclear. This study aimed to investigate the clinical features and the onset risk factors of DILI by ALK‐TKIs in clinical practice. Methods The clinical features of 56 consecutive patients who received crizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were retrospectively examined. Among these, patients diagnosed with DILI due to ALK‐TKIs were evaluated in terms of clinical features and parameters. Each clinical parameter before the administration of ALK‐TKIs was compared between the DILI onset group and the non‐onset group. Results A total of seven cases were diagnosed with DILI due to ALK‐TKIs; no DILI‐related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance

BackgroundSarcoidosis is a granulomatous systemic disease of unknown etiology. Mononuclear cells such as macrophages or lymphocytes in lung tissue and hilar or mediastinal lymph nodes have been recognized to play an essential role in granuloma formation in pulmonary sarcoidosis. Peripheral blood mononuclear cells (PBMCs) consist of several immunocompetent cells and have been shown to play a mechanistic role in the pathogenesis of sarcoidosis. However, the genetic modifications that occur in bulk PBMCs of sarcoidosis remain to be elucidated.PurposeThis study aimed to explore the pathobiological markers of sarcoidosis in PBMCs by comparing the transcriptional signature of PBMCs from patients with pulmonary sarcoidosis with those of healthy controls by RNA sequencing.MethodsPBMC samples were collected from subjects with pulmonary sarcoidosis with no steroid/immunosuppressant drugs (n = 8) and healthy controls (n = 11) from August 2020 to April 2021, and RNA sequencing was performed with the PBMC samples.ResultsPrincipal component analysis using RNA sequencing datasets comparing pulmonary sarcoidosis with healthy controls revealed that the two groups appeared to be differentiated, in which 270 differentially expressed genes were found in PBMCs between sarcoidosis and healthy controls. Enrichment analysis for gene ontology suggested that some biological processes related to the pathobiology of sarcoidosis, such as cellular response to interleukin (IL)-1 and IFN-γ, regulation of IL-6 production, IL-8 secretion, regulation of mononuclear cell migration, and response to lipopolysaccharide, were involved. Enrichment analysis of the KEGG pathway indicated the involvement of tumor necrosis factor (TNF), toll-like receptor signaling, IL-17 signaling pathways, phagosomes, and ribosomes. Most of the genes involved in TNF and IL-17 signaling pathways and phagosomes were upregulated, while most of the ribosome-related genes were downregulated.ConclusionThe present study demonstrated that bulk gene expression patterns in PBMCs were different between patients with pulmonary sarcoidosis and healthy controls. The changes in the gene expression pattern of PBMCs could reflect the existence of sarcoidosis lesions and influence granuloma formation in sarcoidosis. These new findings are important to strengthen our understanding of the etiology and pathobiology of sarcoidosis and indicate a potential therapeutic target for sarcoidosis.

Primary racemose hemangioma of the bronchial artery (RHBA) is one of the causes of massive hemoptysis. A 72-year-old woman was admitted to our hospital with recurrent hemoptysis. Bronchoscopy showed an endobronchial lesion, and the angiography of the right bronchial arteries indicated RHBA. Bronchial arterial embolization (BAE) was performed to prevent hemoptysis. Although the endobronchial lesion shrank after the first BAE, the lesion re-increased and caused massive hemoptysis. A thoracoscopic right upper lobectomy was performed, and hemoptysis did not recur. Therefore, in cases of RHBA where there is recurrent hemoptysis and the endobronchial lesions that remain after BAE, additional treatments should be considered.

Pneumocystis pneumonia (PCP) typically occurs in immunocompromised individuals and rarely presents in immunocompetent individuals. A 55-year-old man was referred to our hospital with cough and anorexia that persisted for 2 months. Chest computed tomography revealed bilateral central consolidation. He was diagnosed with PCP via bronchoscopy. His symptoms and imaging findings improved with the administration of only trimethoprim and sulfamethoxazole. Although he had non-alcoholic fatty liver disease, there were no other complications that could potentially cause immunodeficiency. It should be noted that PCP in immunocompetent individuals can have a subacute disease course presenting with bilateral central consolidation.

Herein, we present the case of a 63-year-old man with autoimmune pulmonary alveolar proteinosis (APAP) complicated by Mycobacterium avium complex (MAC) infection. APAP was diagnosed based on serum anti-granulocyte-macrophage colony-stimulating factor antibody, bronchoalveolar lavage fluid (BALF) findings, and transbronchial lung biopsy. Nodular shadows with cavities were visible on chest CT images, and Mycobacterium intracellulare was identified by BALF culture. Rifampicin, ethambutol, and clarithromycin were administered, and 4 months later, the nodular shadows of MAC had disappeared, and APAP was remarkably improved. Thus, in cases of APAP exacerbation complicated with infections, such as MAC, control of the infections may improve APAP.

BackgroundCombined pulmonary fibrosis with emphysema (CPFE) is a clinically meaningful syndrome characterized by coexisting upper-lobe emphysema and lower-lobe interstitial fibrosis. However, ambiguous diagnostic criteria and, particularly, the absence of objective methods to quantify emphysematous/fibrotic lesions in patients with CPFE confound the interpretation of the pathophysiology of this syndrome. We analyzed the relationship between objectively quantified computed tomography (CT) measurements and the results of pulmonary function testing (PFT) and clinical events in CPFE patients.Materials and methodsWe enrolled 46 CPFE patients who underwent CT and PFT. The extent of emphysematous lesions was obtained by calculating the percent of low attenuation area (%LAA). The extent of fibrotic lesions was calculated as the percent of high attenuation area (%HAA). %LAA and %HAA values were combined to yield the percent of abnormal area (%AA). We assessed the relationships between CT parameters and other clinical indices, including PFT results. Multivariate analysis was performed to examine the association between the CT parameters and clinical events.ResultsA greater negative correlation with percent predicted diffusing capacity of the lung for carbon monoxide (DLCO %predicted) existed for %AA (r = -0.73, p < 0.001) than for %LAA or %HAA alone. The %HAA value was inversely correlated with percent predicted forced vital capacity (r = -0.48, p < 0.001), percent predicted total lung capacity (r = -0.48, p < 0.01), and DLCO %predicted (r = -0.47, p < 0.01). Multivariate logistic regression analysis found that %AA showed the strongest association with hospitalization events (odds ratio = 1.20, 95% confidence interval = 1.01-1.54, p = 0.029).ConclusionQuantitative CT measurements reflected deterioration in pulmonary function and were associated with hospitalization in patients with CPFE. This approach could serve as a useful method to determine the extent of lung morphology, pathophysiology, and the clinical course of patients with CPFE.

Very recently, a modest but significant efficacy of granulocyte–macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported. As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use. As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL−1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP. The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases.

A 67-year-old woman with fever and cough was diagnosed with eosinophilic pneumonia because of eosinophilia and increased eosinophil levels in the bronchoalveolar lavage fluid and transbronchial biopsy lung specimens. However, prednisolone therapy at a previous hospital was ineffective. Histological findings from thoracoscopic lung and lymph node biopsies were consistent with multicentric Castleman's disease (MCD). Since specimens also showed prominent eosinophil and IgG4-positive plasma cell infiltration, it was difficult to distinguish IgG4-related disease (IgG4-RD) from MCD. Administration of prednisolone plus tocilizumab improved the symptoms and lung lesions, and prednisolone administration was successfully reduced and then terminated. The present case highlights the difficulty in diagnosing MCD and IgG4-RD, and suggests that combined administration of tocilizumab and prednisolone might be effective in such a case.

TRPV1 and TRPV4, members of the transient receptor potential vanilloid family, are multimodal ion channels activated by various stimuli, including temperature and chemicals. It has been demonstrated that TRPV channels function as tetramers; however, the dynamics of the diffusion, oligomerization, and endocytosis of these channels in living cells are unclear. Here we undertook single-molecule time-lapse imaging of TRPV1 and TRPV4 in HEK 293 cells. Differences were observed between TRPV1 and TRPV4 before and after agonist stimulation. In the resting state, TRPV4 was more likely to form higher-order oligomers within immobile membrane domains than TRPV1. TRPV1 became immobile after capsaicin stimulation, followed by its gradual endocytosis. In contrast, TRPV4 was rapidly internalized upon stimulation with GSK1016790A. The selective loss of immobile higher-order oligomers from the cell surface through endocytosis increased the proportion of the fast-diffusing state for both subtypes. With the increase in the fast state, the association rate constants of TRPV1 and TRPV4 increased, regenerating the higher-order oligomers. Our results provide a possible mechanism for the different rates of endocytosis of TRPV1 and TRPV4 based on the spatial organization of the higher-order structures of the two TRPV channels.

Abstract Noonan syndrome (NS) is a congenital hereditary disorder associated with developmental and cardiac defects. Some patients with NS carry mutations in SOS, a guanine nucleotide exchange factor (GEF) for the small GTPase RAS. NS mutations have been identified not only in the GEF domain, but also in various domains of SOS, suggesting that multiple mechanisms disrupt SOS function. In this study, we examined three NS mutations in different domains of SOS to clarify the abnormality in its translocation to the plasma membrane, where SOS activates RAS. The association and dissociation kinetics between SOS tagged with a fluorescent protein and the living cell surface were observed in single molecules. All three mutants showed increased affinity for the plasma membrane, inducing excessive RAS signalling. However, the mechanisms by which their affinity was increased were specific to each mutant. Conformational disorder in the resting state, increased probability of a conformational change on the plasma membrane, and an increased association rate constant with the membrane receptor are the suggested mechanisms. These different properties cause the specific phenotypes of the mutants, which should be rescuable with different therapeutic strategies. Therefore, single-molecule kinetic analyses of living cells are useful for the pathological analysis of genetic diseases.

A mixture of sphingomyelin (SM) and cholesterol (Chol) exhibits a characteristic lipid raft domain of the cell membranes that provides a platform to which various signal molecules as well as virus and bacterial proteins are recruited. Several proteins capable of specifically binding either SM or Chol have been reported. However, proteins that selectively bind to SM/Chol mixtures are less well characterized. In our screening for proteins specifically binding to SM/Chol liposomes, we identified a novel ortholog of Pleurotus ostreatus, pleurotolysin (Ply)A, from the extract of edible mushroom Pleurotus eryngii, named PlyA2. Enhanced green fluorescent protein (EGFP)-conjugated PlyA2 bound to SM/Chol but not to phosphatidylcholine/Chol liposomes. Cell surface labeling of PlyA2-EGFP was abolished after sphingomyelinase as well as methyl-β-cyclodextrin treatment, removing SM and Chol, respectively, indicating that PlyA2-EGFP specifically binds cell surface SM/Chol rafts. Tryptophan to alanine point mutation of PlyA2 revealed the importance of C-terminal tryptophan residues for SM/Chol binding. Our results indicate that PlyA2-EGFP is a novel protein probe to label SM/Chol lipid domains both in cell and model membranes.

Objective: Management of emergency care Background: Hemoptysis due to airway hemorrhage is treated with hemostatic agents, bronchial artery embolization (BAE), or surgical resection. We present the case of a 65-year-old man with refractory hemoptysis associated with chronic progressive pulmonary aspergillosis (CPPA) who failed to respond to combined endobronchial occlusion (EBO) with endobronchial Watanabe spigot (EWS) and BAE. Case Report: A 63-year-old man was diagnosed with CPPA in the right upper lung and presented to our hospital 2 years later for hemoptysis at age 65. He developed severe hemoptysis during an outpatient visit, and was urgently admitted, intubated, and ventilated to prevent choking on blood clots. Chest computed tomography showed a large mass in the apical portion of the right lung, constituting apical pleural thickening and an encapsulated pleural effusion, and dilatation in the bronchial artery supplying the right upper lung lobe. Bronchoscopy revealed the right upper lobe B1-B3 as the bleeding source. The patient had recurrent hemoptysis that was not controlled by BAE or 6 EBO+EWS procedures, and he ultimately died of hypoxemia. In the literature review, EBO+EWS can effectively control hemoptysis in appropriate cases, without the need for BAE or surgical lung resection. It is less invasive, is associated with fewer adverse events than BAE or surgery, and can achieve temporary hemostasis for severe hemoptysis. Conclusions: BAE and EBO+EWS were ineffective in controlling recurrent hemoptysis caused by CPPA in this case. However, a multidisciplinary approach such as attempting hemostasis with combined EBO+EWS and BAE may be a viable treatment option in severe cases of hemoptysis. [ABSTRACT FROM AUTHOR]