栗山 祥子

BACKGROUND: The prognosis of pulmonary hypertension (PH) associated with connective tissue diseases related to interstitial pneumonia (CTD-IP PH) is relatively good among patients with PH and lung disease. However, the impact of pulmonary vasodilator treatment on the prognosis of CTD-IP PH compared with that of PH-induced chronic lung disease (group-3 PH) remains unclear. METHODS: From 2012 to 2022, 50 patients with lung parenchymal lesions diagnosed with PH (mean pulmonary arterial pressure >20 mmHg) at Juntendo University Hospital were divided into two groups: CTD-IP PH (30 patients) and group 3-PH (20 patients). The impact of pulmonary vasodilator treatment and the use of long-term oxygen therapy (LTOT) on the prognosis of each group was examined retrospectively. RESULTS: The prognosis of CTD-IP PH was significantly better compared to group-3 PH. While the treatment with pulmonary vasodilators did not affect the prognosis in group 3-PH, the prognosis of the patients treated with vasodilators in the CTD-IP PH group was significantly better than that of the non-treated patients. Treatment with multi-pulmonary vasodilators did not affect the prognosis in CTD-IP PH. Although the prognosis for the patients with LTOT was poor in all registered patients in the present study, treatment with pulmonary vasodilators improved the prognosis even under the use of LTOT in CTD-IP PH (P = 0.002). In a multivariate analysis of the CTD-IP PH group, pulmonary vasodilator treatment was an independent factor for better prognosis. CONCLUSION: Treatment with a pulmonary vasodilator for CTD-IP PH may improve the prognosis, even in patients requiring LTOT.

The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1-expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)-containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.

BACKGROUND AND OBJECTIVE: Remodelling of pulmonary arteries (PA) contributes to the progression of pulmonary hypertension (PH). Periostin, a matricellular protein, has been reported to be involved in the development of PH. We examined the role of periostin in the pathogenesis of PH using different types of experimental PH. METHODS: PH was induced by vascular endothelial growth factor receptor antagonist (Sugen5416) plus hypoxic exposure (SuHx) and venous injection of monocrotaline-pyrrole (MCT-P) in wild-type (WT) and periostin-/- mice. Pulmonary haemodynamics, PA remodelling, expression of chemokines and fibroblast growth factor (FGF)-2, accumulation of macrophages to small PA and the right ventricle (RV) were examined in PH-induced WT and periostin-/- mice. Additionally, the role of periostin in the migration of macrophages, human PA smooth muscle (HPASMCs) and endothelial cells (HPMVECs) was investigated. RESULTS: In PH induced by SuHx and MCT-P, PH and accumulation of M2 macrophage to small PA were attenuated in periostin-/- mice. PA remodelling post-SuHx treatment was also mild in periostin-/- mice compared to WT mice. Expression of macrophage-associated chemokines and FGF-2 in lung tissue, and accumulation of CD68-positive cells in the RV were less in SuHx periostin-/- than in SuHx WT mice. Periostin secretion in HPASMCs and HPMVECs was enhanced by transforming growth factor-β. Periostin also augmented macrophage, HPASMCs and HPMVECs migration. Separately, serum periostin levels were significantly elevated in patients with PH compared to healthy controls. CONCLUSION: Periostin is involved in the development of different types of experimental PH, and may also contribute to the pathogenesis of human PH.

Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. We evaluated the inhibitory effects of nintedanib both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and we evaluated pulmonary hemodynamics and PAs pathology. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.

BACKGROUND: Loxoprofen is a nonsteroidal anti-inflammatory drug used in the treatment of many diseases. However, there are no case reports about loxoprofen-induced pneumonia. We have encountered a rare case of loxoprofen-induced pneumonia. CASE PRESENTATION: We report the case of a 71-year-old Japanese woman who was initially treated with loxoprofen for fever. She was admitted to our hospital because of worsening of her symptoms, including fever and dyspnea. Her symptoms improved after treatment with ceftriaxone. Seven days after admission, she again developed high fever. She was again treated with loxoprofen and levofloxacin. However, acute respiratory failure developed after initiation of loxoprofen treatment. Chest computed tomography showed peribronchovascular consolidation. She was diagnosed with loxoprofen-induced pneumonia for which she was administered steroids. After treatment, her dyspnea and radiological findings improved. CONCLUSIONS: The findings in this case report reveal an association between treatment with a nonsteroidal anti-inflammatory drug and pneumonia. This rare case was diagnosed after accidental retreatment with loxoprofen. This is the first report of loxoprofen-induced pneumonia.

Upregulation of the erythropoietin (EPO)/EPO receptor (EPOR) system plays a protective role against chronic hypoxia-induced pulmonary hypertension (hypoxic PH) through enhancement of endothelial nitric oxide (NO)-mediated signaling. Genistein (Gen), a phytoestrogen, is considered to ameliorate NO-mediated signaling. We hypothesized that Gen attenuates and prevents hypoxic PH. In vivo, Sprague-Dawley rats raised in a hypobaric chamber were treated with Gen (60 mkg/kg) for 21 days. Pulmonary hemodynamics and vascular remodeling were ameliorated in Gen-treated hypoxic PH rats. Gen also restored cGMP levels and phosphorylated endothelial NO synthase (p-eNOS) at Ser(1177) and p-Akt at Ser(473) expression in the lungs. Additionally, Gen potentiated plasma EPO concentration and EPOR-positive endothelial cell counts. In experiments with hypoxic PH rats' isolated perfused lungs, Gen caused NO- and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent vasodilation that reversed abnormal vasoconstriction. In vitro, a combination of EPO and Gen increased the p-eNOS and the EPOR expression in human umbilical vein endothelial cells under a hypoxic environment. Moreover, Gen potentiated the hypoxic increase in EPO production from human hepatoma cells. We conclude that Gen may be effective for the prevention of hypoxic PH through the improvement of PI3K/Akt-dependent, NO-mediated signaling in association with enhancement of the EPO/EPOR system.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease predominantly affecting young women. Some of these patients develop lymphedema of the lower extremities and buttocks; however, neither the exact frequency of LAM-associated lymphedema nor the clinical features of such patients is well delineated. OBJECTIVES: To document the frequency, features, and treatment of LAM-associated lymphedema. METHODS: We reviewed all medical records of patients listed in the Juntendo University LAM registry for the 30 years preceding August 2010. RESULTS: Of 228 patients registered with a diagnosis of LAM, eight (3.5%) had LAM-associated lymphedema of the lower extremities. All were females with sporadic LAM, and their mean age when diagnosed was 32.5 years (range 23-44). Lymphedema of the lower extremities was the chief or a prominent presenting feature in five of these LAM patients. CT scans showed that all eight patients had enlarged lymph nodes (lymphangioleiomyomas) in the retroperitoneum and/or pelvic cavity. Yet, cystic destruction of the lungs was mild in four patients, moderate in two and severe only in two. Seven of these patients were treated by administering a fat-restricted diet and complex decongestive physiotherapy, and four received a gonadotropin-releasing hormone analog. With this combined protocol, all eight patients benefitted from complete relief or good control of the lymphedema. CONCLUSIONS: Lymphedema is a rare complication of LAM and may be associated with axial lymphatic involvement or dysfunction rather than severe cystic lung destruction. The combined multimodal treatments used here effectively resolved or controlled LAM-associated lymphedema.

Background. Pseudomembranous Aspergillus tracheobronchitis, which shows striking findings in the bronchi, is a rare form of pulmonary aspergillosis. Case. We describe a case of pseudomembranous Aspergillus tracheobronchitis in an asthma patient who was receiving inhaled fluticasone propionate therapy. Bronchofibroscopy revealed a characteristic white mucus layer throughout the trachea and bronchi. Histological examination of a biopsy specimen showed numerous branched hyphae suggestive of Aspergillus in the mucosa. Pseudomembranous Aspergillus tracheobronchitis is a rare disease that usually occurs in immunocompromised patients. Conclusion. We believe that both asthmatic inflammation in the airway and inhaled corticosteroid therapy might have contributed to the development of pseudomembranous Aspergillus tracheobronchitis.

We reviewed the clinicopathological characteristics of lung abscesses retrospectively. We analyzed 89 patients hospitalized from July 1984 to May 2009. Most were men (76/89). There were large proportions with alcohol consumption (29.2%) and dental caries or gingivitis (60.7%). Furthermore, those without other diseases accounted for only 13.5%. Predominant infectious species were clear in 43 cases (48.3%) including identification of bacteria. The identification rate of predominant bacteria improved from 38.5% to 56.0% after initiation of the introduction of expectoration culture, bronchoscopic specimen collection and gingival culture in 2003, facilitating clarification of the predominant bacteria. The Streptococcus anginosus group with predominant bacteria being slightly aerobic streptococci, anaerobic bacterium, and aerobic bacterium was detected in 10, 12, and 31 cases, respectively. The improvement in the identification rate of predominant bacteria was achieved by carrying out examination with close liaison with the staff of our inspection room. In selecting antimicrobials based on diagnostic significance, we should focus on positive identification of predominant bacteria, a factor which appears to have major clinical significance.

Thymic carcinoma is comparatively rare and no standard treatment has been established for advanced stage cases. We reviewed our therapeutic experience in 12 cases of thymic carcinoma. They consisted of 9 men and 3 women, ranging from 38 to 69 years of age, with a mean age of 56.5. According to Masaoka's classification, 5 cases were stage III and 7 were preoperative stage IVb. Nine cases were squamous cell carcinoma and 3 were adenocarcinoma. Four cases of preoperative clinical stage III underwent extended thymectomy, but none were completely resected and were classified as stage IV postoperatively. Chemotherapy combined with radiation therapy was given in 1 case, chemotherapy (monotherapy) was given in 4 cases, radiation therapy was given in 1 case, and 2 cases received best supportive care. The median survival time (MST) of patients who had undergone combined modality treatments including surgery was 1971 days, which was longer than the MST of 567 days of patients who were not able to undergo surgery. The prognosis outcome of advanced thymic carcinoma is poor, but combined modality therapies such as surgery, chemotherapy and radiation can be effective for some advanced thymic carcinoma cases.