Role of surfactant protein A in non-infectious lung diseases

Surfactant protein A (SP-A) is a large multimeric protein found in the airways and alveoli of the lungs. SP-A is a member of the collectin family of proteins, characterized by NH2-terminal collagen-like regions and COOH-terminal lectin domains. Although other surfactant proteins such as SP-B function to reduce surface tension in the lungs, SP-A as well as SP-D regulates the pulmonary immune response. To date, a number of studies have shown the immunoregulatory function of SP-A, mainly in the field of infectious diseases. By binding to a wide variety of pathogens, SP-A opsonizes and enhances pathogen uptake by phagocytes. In addition to the effect on pathogens, recent studies have shown that SP-A also modulates lung immune system in the area of non-infectious lung diseases. In this review, the potential role of SP-A in the multiple aspects of pulmonary host defense will be discussed, focusing mainly on non-infectious lung diseases such as acute and chronic pulmonary fibrosis and lung cancer

A mutation in SFTPA1 and pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by scattered fibrotic lesions in the lungs. The pathogenesis and genetic basis of IPF remain poorly understood. Here, we show that a homozygous missense mutation in SFTPA1 caused IPF in a consanguineous Japanese family. The mutation in SFTPA1 disturbed the secretion of SFTPA1 protein. Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as patients spontaneously developed pulmonary fibrosis that was accelerated by influenza virus infection. Sftpa1-KI mice showed increased necroptosis of alveolar epithelial type II (AEII) cells with phosphorylation of IRE1α leading to JNK-mediated up-regulation of Ripk3. The inhibition of JNK ameliorated pulmonary fibrosis in Sftpa1-KI mice, and overexpression of Ripk3 in Sftpa1-KI mice treated with a JNK inhibitor worsened pulmonary fibrosis. These findings provide new insight into the mechanisms of IPF in which a mutation in SFTPA1 promotes necroptosis of AEII cells through JNK-mediated up-regulation of Ripk3, highlighting the necroptosis pathway as a therapeutic target for IPF

COPD・肺がんの予防

Chronic obstructive pulmonary disease (COPD) is a long-standing, crippling disease characterized by the accelerated decline of lung function, commonly brought by aging and long-time inhalation of toxic chemicals such as tobacco smoking. Consequently, most COPD patients suffer from chronic cough, sputum and dyspnea on exertion. Moreover, in addition to the decline of lung function due to the destruction of the alveolar structure, COPD is closely related to other diseases such as osteoporosis, cardiovascular diseases, diabetes, muscle dysfuncion, and lung cancer. Therefore, COPD is currently recognized as a systemic disease that the comprehensive management and care are necessary. Although COPD represents an increasing burden throughout the world and is one of the major causes of death word-wide, the issue has been arisen that the recognition of COPD in the general society is still low, especially in Japan. On the other hand, lung cancer is a life-threatening disease with the leading cause of malignancy-related death world-wide, the etiology of which is also closely related to tobacco smoking. Because the pathogenesis and the mortality of COPD and lung cancer are closely related each other, the action to prevent these diseases could be made simultaneously, primarily by the smoking cessation and the detection survey. In this article, we describe the present situation of COPD and lung cancer, the importance of smoking cessation, and the effort of Tokushima City Medical Association to manage COPD in Tokushima

Development of improved method to identify and analyze lung fibrocytes with flow cytometry in a reporter mouse strain

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

A case of pulmonary pleomorphic carcinoma with malignant phenotypes induced by ZEB1-associated epithelial-mesenchymal transition

A 60-year-old man was admitted to our hospital with non-small cell lung cancer (NSCLC). Imaging and pathological studies revealed NSCLC, not otherwise specified (NOS), at clinical stage T3N1M0 stage IIIA. We started radiotherapy alone because of obstructive pneumonia and end-stage renal disease, but the tumors progressed rapidly and resulted in death due to air obstruction by pharyngeal metastasis. The cancer was diagnosed as pleomorphic carcinoma in an autopsy. Viable lung tumor cells, which were resistant to radiotherapy, and the pharyngeal metastasis had mesenchymal phenotypes and expressed ZEB1 but not SNAI1. These observations indicated that ZEB1-associated epithelial-mesenchymal transition has malignant features including resistance to radiotherapy and aggressive metastatic potential. ZEB1-associated EMT may be an important mechanism to understand the pathophysiology of pleomorphic carcinoma

Pregnancy-associated plasma protein Aを悪性胸膜中皮腫細胞の遊走能を促進する遺伝子として同定 : 治療標的としての可能性

Despite recent advances in treatment, malignant pleural mesothelioma (MPM) remains a deadly disease. Targeted therapy generated broad interests and is highly expected for the treatment of MPM, yet promising preclinical results have not been translated into substantial clinical benefits for the patients. In this study, we tried to identify the genes which play functional roles in cell migration as well as to test whether they can be used as novel targets for molecular targeted therapy for MPM in preclinical model. In our study, pregnancy-associated plasma protein A (PAPPA) was identified as a gene whose expression level is correlated with MPM cell migration by correlation analysis combining MPM cell migration ability and their gene expression profiles. Highly migratory cells were selected from MPM cell lines, MSTO-211H, NCI-H290 and EHMES-1 in vitro and up-regulation of PAPPA in these cells were confirmed. In vitro, PAPPA was demonstrated to stimulate the MPM cell migration via cleavage of insulin-like growth factor-binding protein-4 and subsequent release of IGF-1. Gene silencing of PAPPA in MPM cells led to reduced migration, invasion and proliferation. Furthermore, PAPPA shRNA transfected NCI-H290 when orthotopically inoculated into pleural cavity of severe combined immunodeficiency recipient mice, failed to develop tumors and produce bloody pleural effusion as control shRNA transfected cells did. Our study suggests that PAPPA plays a functional role in promoting MPM cell migration and it might serve as a potential therapeutic target for the treatment of MPM

クリゾチニブ ガ ソウコウ シタ Performance Status フリョウ anaplastic lymphoma kinase イデンシ テンザ ヨウセイ ハイセンガン ノ 1レイ

A ２７-year-old female was referred to our hospital for further examination of hoarseness, cough, and hemoptysis. Positron emission tomography-computed tomography revealed FDG accumulation in a huge mass in the left lower lobe, lymph nodes in the hilum, mediastinum and right cervical lesion left scapula and vertebral body. Further examination yielded the diagnosis of primary lung adenocarcinoma （cT２aN３M１b : Stage IV） harboring the anaplastic lymphoma kinase （ALK） fusion oncogene. Although her general condition was getting worse due to rapid increase of the pleural effusion, crizotinib promptly diminish the pleural effusion and ameliorated the patient’s condition. The adverse events of crizotinib, such as nausea, vomiting and visual disturbance, were generally mild and well tolerable during treatment. These findings suggest that crizotinib is a promising candidate for ALK-positive non-small cell lung cancer patients even with poor performances

Fibrocytes : A Novel Stromal Cells to Regulate Resistance to Anti-Angiogenic Therapy and Cancer Progression

An adequate blood supply is essential for cancer cells to survive and grow; thus, the concept of inhibiting tumor angiogenesis has been applied to cancer therapy, and several drugs are already in clinical use. It has been shown that treatment with those anti-angiogenic drugs improved the response rate and prolonged the survival of patients with various types of cancer; however, it is also true that the effect was mostly limited. Currently, the disappointing clinical results are explained by the existence of intrinsic or acquired resistance to the therapy mediated by both tumor cells and stromal cells. This article reviews the mechanisms of resistance mediated by stromal cells such as endothelial cells, pericytes, fibroblasts and myeloid cells, with an emphasis on fibrocytes, which were recently identified as the cell type responsible for regulating acquired resistance to anti-angiogenic therapy. In addition, the other emerging role of fibrocytes as mediator-producing cells in tumor progression is discussed

Dual effects of FGFR inhibition in lung fibrosis

[Rationale] Fibroblast growth factors (FGF) are major factors associated with the pathogenesis of pulmonary fibrosis. Nintedanib, a tyrosine kinase inhibitor targeting several growth factor receptors including the FGF receptor (FGFR), has been approved for the treatment of idiopathic pulmonary fibrosis (IPF). On the other hand, recent reports suggest that FGF are required for epithelial recovery. In this study, we focused on FGF signaling to both fibroblasts and alveolar epithelial cells (AECs), and examined the effect of a pan-FGFR blocker on experimental pulmonary fibrosis in mice. [Methods] The effects of BGJ398, a pan-FGFR inhibitor, on the migration and proliferation of fibroblasts and AECs were assessed using transwell migration or 3H-thymidine incorporation assays. The expression of FGFR was analyzed using immunoblot or flow cytometry. We also investigated the effect of BGJ398 on the pulmonary fibrosis induced by bleomycin in mice. [Results] Both lung fibroblasts and AECs expressed FGFRs. BGJ398 significantly inhibited the proliferation and migration of lung fibroblasts stimulated with FGF2. BGJ398 also reduced the proliferation of AECs in response to FGF2. Although the administration of BGJ398 ameliorated pulmonary fibrosis in bleomycin-treated mice, it increased mortality due to alveolar injury and inhibition of AEC regeneration. [Conclusions] These data suggest that the total inhibition of FGFR signaling can suppress lung fibrosis by inhibiting fibroblast activities, although alveolar injury is simultaneously caused

Prevention of Pemetrexed-Induced Rash Using Low-Dose Corticosteroids : A Phase II Study

Background: Rash eruptions are a common side-effect of pemetrexed, for which the administration of 8 mg/day of dexamethasone for 3 days from the day preceding pemetrexed administration is recommended. This study aimed to prospectively assess the effectiveness of prophylactic administration of low-dose dexamethasone for pemetrexed-induced rashes. Methods: This single-arm, phase II study recruited patients with non-squamous non–small cell lung cancer and malignant pleural mesothelioma scheduled to receive chemotherapy including pemetrexed. Patients received 2 mg of dexamethasone daily from days 2 to 6 after chemotherapy with pemetrexed. The primary endpoint was the 3-week incidence of rash eruptions. Results: Twenty-five patients were enrolled between September 2017 and May 2019. The incidence of rash after 3 weeks was 16.7%. Rashes erupted mainly on the upper half of the body, such as the chest and neck, and were of grades 1 and 2 in 2 patients each. No rashes of grade 3 or higher were observed, and there were no adverse events associated with additional corticosteroids. Conclusion: Prophylactic administration of low-dose dexamethasone for 5 days from the day after pemetrexed administration resulted in a milder incidence and severity of rash. These findings may provide a standard preventative strategy for pemetrexed-induced rashes. (Trial identifier: UMIN000025666)