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Background Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with few effective therapeutic options. Recently, drug repositioning, which involves identifying novel therapeutic potentials for existing drugs, has been popularized as a new approach for the development of novel therapeutic reagents. However, this approach has not yet been fully utilized in the field of pulmonary fibrosis. Methods The present study identified novel therapeutic options for pulmonary fibrosis using a systematic computational approach for drug repositioning based on integration of public gene expression signatures of drug and diseases (in silico screening approach). Results Among the top compounds predicted to be therapeutic for IPF by the in silico approach, we selected BI2536, a polo-like kinase (PLK) 1/2 inhibitor, as a candidate for treating pulmonary fibrosis using an in silico analysis. However, BI2536 accelerated mortality and weight loss rate in an experimental mouse model of pulmonary fibrosis. Because immunofluorescence staining revealed that PLK1 expression was dominant in myofibroblasts while PLK2 expression was dominant in lung epithelial cells, we next focused on the anti-fibrotic effect of the selective PLK1 inhibitor GSK461364. Consequently, GSK461364 attenuated pulmonary fibrosis with acceptable mortality and weight loss in mice. Conclusions These findings suggest that targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis by inhibiting lung fibroblast proliferation without affecting lung epithelial cells. In addition, while in silico screening is useful, it is essential to fully determine the biological activities of candidates by wet-lab validation studies.

A 36-year-old woman who had been diagnosed with systemic lupus erythematosus (SLE) was admitted to our hospital due to increasing disease SLE activity. Despite the intensification of immunosuppressive treatment, headache newly developed and worsened. Magnetic resonance imaging (MRI) revealed spreading of a high-intensity area along the sulci of the bilateral cerebellar hemispheres. She was diagnosed with neuropsychiatric SLE and methylprednisolone (mPSL) pulse therapy was started. However, consciousness disorder due to cerebellar oedema with obstructive hydrocephalus appeared and required decompressive craniectomy. The histological findings of the biopsy specimens from cerebellar vermis were compatible with features of vasculitis. She was successfully treated adding intravenous cyclophosphamide therapy.

Lenvatinib is a multi-targeted tyrosine kinase inhibitor available for the treatment of unresectable hepatocellular carcinoma (HCC). We herein report an 84-year-old-man with interstitial pneumonia caused by lenvatinib. Four months after the start of lenvatinib administration for HCC, chest computed tomography revealed bilateral ground-glass opacity. However, he continued to take lenvatinib for four more months until he complained of dyspnea on exertion. This is a case of lenvatinib-induced interstitial pneumonia that progressed relatively slowly with a long asymptomatic period despite the appearance of pneumonia on image findings.

Background Systemic lupus erythematosus (SLE) commonly affects the lungs. However, the incidence of interstitial pneumonia (IP) related to SLE was reported to be about 10%, less than in the case of other connective tissue diseases, and the mechanism via which IP is related to SLE remains to be elucidated. Methods We retrospectively reviewed the medical records and high-resolution computed tomography (HRCT) images of 69 SLE patients who were admitted to our hospital between January 2011 and December 2015. Results Fifty-five of the patients were female (80%), and the mean age at the onset of SLE was 42.4 years. IP developed in 20 patients (29%), 14 of whom were female (70%), and the mean age at SLE onset was 53.4 years, significantly older than those without IP (38.0 years) ( p = 0.003). Half of the patients were found to have IP during the initial diagnosis of SLE. The IP pattern on the HRCT images was consistent with that of usual interstitial pneumonia (UIP) in 25% of the patients and of nonspecific interstitial pneumonia (NSIP) in 55%. One patient exhibited acute exacerbation but survived. The radiological findings revealed that the disease progressed slowly in most of the patients; however, pulmonary function was retained. No significant differences were observed in the survival rates between patients with and without IP. Conclusion In SLE cases, IP primarily occurred in male and elderly patients. In addition to the NSIP pattern, the UIP pattern was evident on HRCT scans of IP-related SLE. The survival of SLE patients was unrelated to IP.

Background : Pirfenidone (PFD), an anti-fibrosis drug for idiopathic pulmonary fibrosis (IPF), suppresses disease progression and delays decline of forced vital capacity. However, this drug rarely makes marked improvement of pulmonary function, chest high-resolution computed tomography (HRCT) findings and hypoxia. Case presentation : A 59 year-old-man, who was a former smoker and had a history of alcoholic liver cirrhosis, developed exertional dyspnea and was referred to our hospital. HRCT showed honeycomb changes with surrounding ground-glass opacity (GGO) in a predominantly basal and subpleural distribution. He was diagnosed with IPF and the treatment with PFD was started. At 16 months after the start of treatment, the predicted forced vital capacity value markedly improved from 82.9% to 98.6%. His resting-state partial pressure of arterial oxygen while breathing room air increased from a minimum of 54.7 mmHg (at 2 months treatment) to 72.5 mmHg. The GGO observed at diagnosis disappeared in HRCT. But after 32 months of treatment, his general condition got worse gradually, and he died from chronic progression of IPF after 48 months of treatment. Conclusion : Our case suggests that a complication of chronic liver disease and the existence of GGO may be characteristics of super-responder to PFD treatment for IPF patients. J. Med. Invest. 67 : 358-361, August, 2020.

Rationale: The in vivo pharmacokinetics analysis provides the valuable information about not only the pharmacological mechanism but also toxicity evaluation. Although nintedanib, one of the approved antifibrotic drug, is widely used to the treatment for idiopathic pulmonary fibrosis, no previous reports have focused on the localization of nintedanib in lung tissue. In this study, we investigated the localization of nintedanib in pulmonary fibrosis using Mass Spectrometry Imaging (MSI) and compared with those of cyclophosphamide. Methods: Pulmonary fibrosis was induced in mice by subcutaneously administration of bleomycin-A5. Lung tissues were collected 2-48 hours after oral administration of nintedanib or cyclophosphamide. The lung tissues were histologically examined and analyzed using an imaging mass spectrometer (iMScope TRIO). Results: The detection intensities of nintedanib were highest in lung tissues collected 4-6 hours after administration of nintedanib. The detectable period of nintedanib was longer than 24 hours. Those of cyclophosphamide diminished earlier than nintedanib. This tendency was same in both fibrotic region and normal region. Conclusions: Nintedanib is distributed in lung tissues regardless of the structural changes by pulmonary fibrosis, and the duration was estimated to be longer than cyclophosphamide. These results also indicate that MSI is a useful technique for evaluating the distribution of antifibrotic drugs in pulmonary fibrosis.

Rationale: Nintedanib is one of two drugs approved for the treatment of idiopathic pulmonary fibrosis. It targets fibroblast growth factor receptors, platelet-derived growth factor receptors and vascular endothelial growth factor receptors shown to be involved in the lung fibrosis pathology, but also Src family kinases including lymphocyte-specific protein tyrosine kinase (Lck) with a low IC50 value. Nevertheless, the significance of Lck inhibition in lung fibrosis is not fully elucidated yet. Aim: To explore the effect of Lck inhibition on experimental lung fibrosis in mice with focus on lymphocytes. Methods: Murine lymphocytes were isolated from spleen by CD4+ T Cell Isolation Kit (Miltenyi Biotec). The inhibitory effect of the Lck inhibitor A-770041 on the phosphorylation of Lck in murine lymphocytes was examined using immunoblot. Lung fibrosis was induced in mice by intratracheal administration of bleomycin. A-770041 was administrated daily by gavage. Bronchoalveolar lavage (BAL) was performed on day 7. Lung tissues were analyzed on day 21 using the Ashcroft score and hydroxyproline assay. Results: A-770041 inhibited the phosphorylation of Lck in murine lymphocytes in a concentration-dependent manner. In the mouse model, A-770041 significantly mitigated lung fibrosis induced by bleomycin. The treatment with A-770041 significantly decreased the total cell number in the BAL fluid, suggesting that the inflammation leading to fibrosis was alleviated by A-770041. Conclusions: These results support the role of lymphocytes in the early stage of lung fibrosis, and suggest that A-770041 might be useful to ameliorate lung inflammation induced by fibrotic injury and subsequent fibrogenesis.

Introduction Fibrocytes are emerging myeloid‐derived circulating cells that can migrate into damaged tissues and usually contribute to their repair. Key features of fibrocytes include the expression myeloid markers, production of extracellular matrix proteins, and secretion of various humoral factors that activate resident fibroblasts; they also have the potential to differentiate into fibroblasts. However, no specific surface markers have been identified to identify fibrocytes in vivo. One reason could be that the method used to detect fibrocytes requires intracellular collagen staining. Methods In the present study, to establish an improved method for the detection of lung fibrocytes and to analyze viable fibrocytes, we used collagen I(α)2‐green fluorescent protein (Col‐GFP) reporter mice, which had undergone the intratracheal instillation of bleomycin (BLM). Results Using flow cytometry to gate out cells with autofluorescence, we clearly found that CD45+ GFP+ cells resided in the lungs of Col‐GFP mice at a steady state and these cells increased after BLM injury, peaking at Day 14. These cells expressed not only known cell surface markers of fibrocytes, but also some novel markers, in addition to a low level of collagen I in comparison to CD45− GFP+ cells. Conclusion Our findings suggest that the improved method can be a useful for the detection of pure lung fibrocytes and allows us to further analyze the characteristics of viable fibrocytes., In this report, we established improved method for detection of lung fibrocytes. Using flow cytometry to gate out cells with autofluorescence and combine expression pattern of CD11b, CD11c, Gr‐1, we clearly found fibrocytes resided in lungs.

Background Mycobacterium xenopi-infected patients have a high prevalence of pulmonary cavities and nodules. However, the clinical course for patients with miliary nodules due to M. xenopi has not yet been reported. Case presentation We encountered a case of miliary nodules with gradually worsening coughing and sputum production in a 44-year-old male who had renal dysfunction due to glomerulosclerosis with a decade-long history of steroid therapy. Although we started anti-tuberculosis treatment on clinical suspicion of miliary tuberculosis, cultures of sputum and bronchial lavage were both positive for M. xenopi. The patient was successfully treated with rifampin, ethambutol and clarithromycin, without fibrosis. It was unclear whether the miliary pattern was induced by hematogenous or endobronchial spread of the M. xenopi infection. Conclusion Even when clinical and radiological disease manifestations are similar to those of miliary tuberculosis, M. xenopi infection should be considered in the differential diagnosis of miliary nodules.

A case of primary gingival tuberculosis in a 71-year-old Japanese woman is herein presented. A serous saliva culture was positive for tuberculosis, and we recognized that the origin of the tuberculosis infection was the gingiva based on the genetic identification in gingival biopsy tissue. The definitive diagnosis was facilitated by the genetic identification, a useful modern tool for diagnosing infectious diseases. The location and clinical presentation of this lesion were unusual, which underlines the importance of considering tuberculosis in the differential diagnosis of oral lesions that affect the gingiva.

Introduction Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare entity of unknown etiology in young adults that is typically characterized by cervical lymphadenopathy and persistent fever. The pathogenesis of KFD has been suggested to be an abnormal immune response, and infections or autoimmune diseases are considered to be involved in KFD. However, KFD associated with community acquired pneumonia (CAP) has not been reported. Case description A 35-year-old male was admitted due to high fever, diffuse air-space consolidation in the right lung with ipsilateral pleural effusion and massive mediastinal and hilar lymphadenopathy without cervical lesions. On clinical suspicion of malignant lymphoma complicated with pneumonia, we performed a video-assisted thoracoscopic lymph node biopsy, and the diagnosis of KFD was established. Complete cure of the intrathoratic lesions was observed by administration of β-lactam antibiotics alone without steroid therapy. Discussion and evaluation Previous large case series have identified no pathogenic relationship between KFD and pneumonia. The hilar adenopathy could have caused airway compression leading to pneumonia. Conclusions KFD should be considered in the differential diagnosis of massive mediastinal and hilar lymphadenopathy, even when there are no superficial lesions. In addition, we need to bear in mind that unexpected disorders occasionally coexist with common diseases.