A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic 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.

[Patient-Reported Outcome(PRO)to Measure Health-Related QOL in Lung Cancer Patients].

Lung cancer as progressive disease is often associated with a poor quality of life(QOL)which is related to a poor prognosis. We review the impact of patient-reported outcome(PRO)as an indicator of health-related QOL on the management of lung cancer patients. Cancer-specific PRO measures, which are primarily applied in scientific research for the past 30 years to compare the therapy outcomes and in drug development with adverse events. Among several PRO measures developed, the EORTC QLQ-C30 and its lung cancer-specific module QLQ-LC13 are the most frequently used instruments in clinical trials with lung cancer patients. Interestingly, cancer-specific PRO measures have been also increasingly used as daily practice, which may provide positive effects on the communication with the patient, mutual decision making and the monitoring and managing of the patient. Moreover, PRO measures have an independent prognostic value to predict survival in lung cancer patients. PRO measures have also the potential to improve the quality of care. Electronic platforms are expected to simplify the implementation of PRO measure in the daily clinic. Nevertheless, the PRO measures have not been properly implemented in Japan.

Role of platelet-derived growth factor/platelet-derived growth factor receptor axis in the trafficking of circulating fibrocytes in pulmonary fibrosis.

Circulating fibrocytes have been reported to migrate into the injured lungs, and contribute to fibrogenesis via CXCL12-CXCR4 axis. In contrast, we report that imatinib mesylate prevented bleomycin (BLM)-induced pulmonary fibrosis in mice by inhibiting platelet-derived growth factor receptor (PDGFR), even when it was administered only in the early phase. The goal of this study was to test the hypothesis that platelet-derived growth factor (PDGF) might directly contribute to the migration of fibrocytes to the injured lungs. PDGFR expression in fibrocytes was examined by flow cytometry and RT-PCR. The migration of fibrocytes was evaluated by using a chemotaxis assay for human fibrocytes isolated from peripheral blood. The numbers of fibrocytes triple-stained for CD45, collagen-1, and CXCR4 were also examined in lung digests of BLM-treated mice. PDGFR mRNA levels in fibrocytes isolated from patients with idiopathic pulmonary fibrosis were investigated by real-time PCR. Fibrocytes expressed both PDGFR-α and -ß, and migrated in response to PDGFs. PDGFR inhibitors (imatinib, PDGFR-blocking antibodies) suppressed fibrocyte migration in vitro, and reduced the number of fibrocytes in the lungs of BLM-treated mice. PDGF-BB was a stronger chemoattractant than the other PDGFs in vitro, and anti-PDGFR-ß-blocking antibody decreased the numbers of fibrocytes in the lungs compared with anti-PDGFR-α antibody in vivo. Marked expression of PDGFR-ß was observed in fibrocytes from patients with idiopathic pulmonary fibrosis compared with healthy subjects. These results suggest that PDGF directly functions as a strong chemoattractant for fibrocytes. In particular, the PDGF-BB-PDGFR-ß biological axis might play a critical role in fibrocyte migration into the fibrotic lungs.

Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice.

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in various biological functions, including cell survival, proliferation, migration, and adhesion. FAK is an essential factor for transforming growth factor ß to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors, including platelet-derived growth factor and insulin-like growth factor I, in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of α-smooth muscle actin induced by transforming growth factor ß, indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis and that it can become a promising target for therapeutic approaches to pulmonary fibrosis.

Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice.

Circulating fibrocytes had been reported to migrate into the injured lungs, and contribute to fibrogenesis via chemokine-chemokine receptor systems including CXCL12-CXCR4 axis. Here we hypothesized that blockade of CXCR4 might inhibit the migration of fibrocytes to the injured lungs and the subsequent pulmonary fibrosis. To explore the antifibrotic effects of blockade of CXCR4, we used a specific antagonist for CXCR4, AMD3100, in bleomycin-induced pulmonary fibrosis model in mice. Administration of AMD3100 significantly improved the loss of body weight of mice treated with bleomycin, and inhibited the fibrotic lesion in subpleural areas of the lungs. The quantitative analysis demonstrated that treatment with AMD3100 reduced the collagen content and fibrotic score (Aschcroft score) in the lungs. Although AMD3100 did not affect cell classification in bronchoalveolar lavage fluid on day 7, the percentage of lymphocytes was reduced by AMD3100 on day 14. AMD3100 directly inhibited the migration of human fibrocytes in response to CXCL12 in vitro, and reduced the trafficking of fibrocytes into the lungs treated with bleocmycin in vivo. These results suggest that the blockade of CXCR4 might be useful strategy for therapy of patients with pulmonary fibrosis via inhibiting the migration of circulating fibrocytes.

CCN6 as a profibrotic mediator that stimulates the proliferation of lung fibroblasts via the integrin ß1/focal adhesion kinase pathway.

Idiopathic pulmonary fibrosis is a progressive and lethal disease of the lung that is characterized by the proliferation of fibroblasts and increased deposition of the extracellular matrix. The CCN6/WISP-3 is a member of the CCN family of matricellular proteins, which consists of six members that are involved in many vital biological functions. However, the regulation of lung fibroblasts mediated by CCN6 protein has not been fully elucidated. Here, we demonstrated that CCN6 induced the proliferation of lung fibroblasts by binding to integrin ß1, leading to the phosphorylation of FAK(Y397). Furthermore, CCN6 showed a weak, but significant, ability to stimulate the expression of fibronectin. CCN6 was highly expressed in the lung tissues of mice treated with bleomycin. Our results suggest that CCN6 plays a role in the fibrogenesis of the lungs mainly by stimulating the growth of lung fibroblasts and is a potential target for the treatment of pulmonary fibrosis.

[An autopsy case of gastric cancer presenting as acute respiratory failure due to pulmonary tumor thrombotic microangiopathy with concomitant high serum level of vascular endothelial growth factor-D].

A 49-year-old man consulted our hospital several days after the onset of dyspnea and was admitted because it rapidly exacerbated 9 days after presentation. Diffuse centrilobular micronodular shadows and diffuse opacities in all lung fields were noted on high-resolution computed tomography of the chest. Severe pulmonary hypertension and dilatation of the right ventricle was observed on echocardiography. Although there was no evidence of thrombus in the central portion of the pulmonary artery or deep veins of the lower limbs, the patient's respiratory insufficiency rapidly progressed and he died about 14 hours after admission. A postmortem examination revealed widespread gastric cancer and tumor emboli in the pulmonary arterioles, complicated with intraluminal organization, which is consistent with pulmonary-tumor thrombotic microangiopathy (PTTM). His serum level of vascular endothelial growth factor-D (VEGF-D) was elevated, but VEGF-D was not detected by immunohistological staining. A possible pathophysiological association with PTTM and VEGF-D should be examined in future studies.

[A case of adult onset idiopathic pulmonary hemosiderosis markedly improved by steroid therapy].

A case of adult onset idiopathic pulmonary haemosiderosis (IPH) was reported. A 53-year-old man was admitted to our hospital because of repeated bloody sputum on June 2, 2006. Chest radiograph on admission disclosed diffuse infiltrative shadows in both lung fields, and one month later these shadows became more marked. The chest CT on July 5, 2006 showed patchy areas of ground-glass opacity and consolidation, exhibiting a distinctly peripheral distribution. Bronchoscopic findings revealed oozing bleeding from the orifice of B5 in the right lung and B9 in the left lung. We employed video-assisted thoracoscopic surgery for lung biopsy and he as primary IPH was diagnosed clinicopathologically. His symptoms and radiographic findings were markedly improved after steroid therapy, followed by no signs of recurrence. It may be important to establish a definitive diagnosis early, even in IPH, using VATS, for further effective therapy.