Size and surface modification of silica nanoparticles affect the severity of lung toxicity by modulating endosomal ROS generation in macrophages.

BACKGROUND: As the application of silica nanomaterials continues to expand, increasing chances of its exposure to the human body and potential harm are anticipated. Although the toxicity of silica nanomaterials is assumed to be affected by their physio-chemical properties, including size and surface functionalization, its molecular mechanisms remain unclear. We hypothesized that analysis of intracellular localization of the particles and subsequent intracellular signaling could reveal a novel determinant of inflammatory response against silica particles with different physico-chemical properties. RESULTS: We employed a murine intratracheal instillation model of amorphous silica nanoparticles (NPs) exposure to compare their in vivo toxicities in the respiratory system. Pristine silica-NPs of 50 nm diameters (50 nm-plain) induced airway-centered lung injury with marked neutrophilic infiltration. By contrast, instillation of pristine silica particles of a larger diameter (3 µm; 3 µm-plain) significantly reduced the severity of lung injury and neutrophilic infiltration, possibly through attenuated induction of neutrophil chemotactic chemokines including MIP2. Ex vivo analysis of alveolar macrophages as well as in vitro assessment using RAW264.7 cells revealed a remarkably lower cellular uptake of 3 µm-plain particles compared with 50 nm-plain, which is assumed to be the underlying mechanism of attenuated immune response. The severity of lung injury and neutrophilic infiltration was also significantly reduced after intratracheal instillation of silica NPs with an amine surface modification (50 nm-NH2) when compared with 50 nm-plain. Despite unchanged efficacy in cellular uptake, treatment with 50 nm-NH2 induced a significantly attenuated immune response in RAW264.7 cells. Assessment of intracellular redox signaling revealed increased reactive oxygen species (ROS) in endosomal compartments of RAW264.7 cells treated with 50 nm-plain when compared with vehicle-treated control. In contrast, augmentation of endosomal ROS signals in cells treated with 50 nm-NH2 was significantly lower. Moreover, selective inhibition of NADPH oxidase 2 (NOX2) was sufficient to inhibit endosomal ROS bursts and induction of chemokine expressions in cells treated with silica NPs, suggesting the central role of endosomal ROS generated by NOX2 in the regulation of the inflammatory response in macrophages that endocytosed silica NPs. CONCLUSIONS: Our murine model suggested that the pulmonary toxicity of silica NPs depended on their physico-chemical properties through distinct mechanisms. Cellular uptake of larger particles by macrophages decreased, while surface amine modification modulated endosomal ROS signaling via NOX2, both of which are assumed to be involved in mitigating immune response in macrophages and resulting lung injury.

Fibroblasts positive for meflin have anti-fibrotic properties in pulmonary fibrosis.

The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine the pathogenesis of IPF, identification of functional fibroblasts is warranted. The aim of this study was to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis.We characterised meflin-positive cells in a single-cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis.scRNA-seq combined with in situ RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic properties to prevent pulmonary fibrosis. Although transforming growth factor-ß-induced fibrogenesis and cell senescence with the senescence-associated secretory phenotype were exacerbated in fibroblasts via the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution.These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.

Birt-Hogg-Dubé syndrome in the elderly.

We present the case of a 73-year-old woman who developed pneumothorax for the first time that was a clinical clue to the diagnosis of Birt-Hogg-Dubé (BHD) syndrome. Although younger onset of pneumothorax is more common in BHD syndrome, the characteristic chest CT findings may contribute to the diagnosis of this disorder in spontaneous pneumothorax of the elderly.

Pulmonary tumor thrombotic microangiopathy successfully treated with corticosteroids: a case report.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy is a special type of tumor thromboembolism. We report the case of a patient who developed pulmonary tumor thrombotic microangiopathy with alveolar hemorrhage. Almost all patients with pulmonary tumor thrombotic microangiopathy die within 1 week of the onset of dyspnea; however, the prognosis in this case was better, with 10 weeks of survival from presentation. CASE PRESENTATION: A 62-year-old Japanese man was referred to our hospital with a 4-week history of dyspnea on exertion and severe pulmonary hypertension. Five years previously, he had undergone distal gastrectomy for gastric cancer. He was afebrile, normotensive, and hypoxemic. A physical examination was unremarkable except for purpura on his upper extremities and trunk. Blood tests showed anemia and disseminated intravascular coagulation. Chest computed tomography revealed diffuse ground-glass opacities with emphysema in his upper lungs, moderate pleural effusions, mediastinal lymphadenopathy, and enlargement of the right ventricle and main pulmonary artery. A computed tomography pulmonary angiogram showed no evidence of pulmonary embolism. Lung perfusion scintigraphy showed multiple segmental defects. Although recurrence of gastric cancer was confirmed from the results of bone marrow biopsy, bronchoscopy was not performed due to bleeding diathesis. He was treated with corticosteroids, antibiotics, and platelet transfusion, following which resolution of the abnormal lung shadows and right ventricular pressure overload along with partial alleviation of respiratory failure was observed. Because of his poor performance status, he was eventually transited to palliative care and died 6 weeks after admission. Necropsy of the lung confirmed the diagnosis of pulmonary tumor thrombotic microangiopathy with alveolar hemorrhage. CONCLUSIONS: Pulmonary tumor thrombotic microangiopathy should be considered in the differential diagnosis of patients with cancer who present with severe pulmonary hypertension. In pulmonary tumor thrombotic microangiopathy, local inflammation in pulmonary microvasculature may contribute to pulmonary hypertension, and regulation of inflammation using corticosteroids may help improve the prognosis.

Torque ratio as a predictable factor on primary stability of orthodontic miniscrew implants.

OBJECTIVE: To evaluate the torque ratio (TR) as a predictable factor on primary stability of orthodontic miniscrews. DESIGN: Fifty-eight orthodontic patients (17 men, 41 women; mean age, 21.9 years) with a total of 112 titanium miniscrews of 3 different diameters were subjected. Maximum insertion torque (MIT) and maximum removal torque (MRT) were measured by a digital torque checker at the screw placement. Four weeks after the placement, the stable screw was recorded as a success. Multiple logistic regression analysis was performed to estimate the influence of each clinical variable on success. RESULTS: Success rates were 82.1% to 89.5%, and there were no significant differences in the 3 types of miniscrews. MIT and MRT showed a positive correlation but did not affect the success rates of miniscrews directly. On the contrary, TR was significantly higher in the success group than in the failure group. In multiple regression analysis, age, TR, and screw proximity had a significant influence on the miniscrew success. CONCLUSIONS: TR might be related with the miniscrew success rates, and it can be used as a predictable factor on primary stability of orthodontic miniscrew implants. Miniscrew implants should be replaced if MRT is significantly lower than MIT at placement surgery.

Clinical analysis of isolated zygomatic arch fractures.

PURPOSE: The purpose of this study is to analyze the characteristics of isolated zygomatic arch fractures and to evaluate the functional and radiological outcomes of the treatment. PATIENTS AND METHODS: Forty patients with isolated zygomatic arch fractures were analyzed clinically. RESULTS: The patients were 25 males and 15 females with an average age of 42 years. The cause of injury was traffic accident in 26, followed by fall in 8, sports in 3, and assault in 3. The left side was involved in 25 cases. Fractures were classified into 5 types according to the degree of displacement and loss of bone contact. Reduction was performed in 31 patients, 26 treated by the Gillies temporal approach. Conservative treatment was chosen in 9 patients. The reduction status was excellent in 12 cases, good in 17 cases, and fair in 2 cases. There was no difference in the reduction status in terms of the fracture types or the interval between reduction and injury. Interincisal distance (IID) at maximal mouth opening recovered from 33.4 to 43.8 mm by excellent reduction, from 26.2 to 42.2 mm by good reduction, from 27.5 to 40 mm by fair reduction, and from 41 to 46.6 mm by conservative treatment. CONCLUSIONS: Good functional and radiological outcomes were obtained in isolated zygomatic arch fractures. Reduction status was not influenced by either the fracture type or the interval between reduction and injury, and recovery of IID was similarly achieved by excellent, good, and fair reduction.

Changes in tongue and hyoid positions, and posterior airway space following mandibular setback surgery.

INTRODUCTION: The postural response of the tongue after mandibular setback is clinically important for maintaining normal respiration. Although the hyoid bone moves progressively to adapt physiologically to the altered orofacial configuration following such surgery, it is not clear whether repositioning of the hyoid has an effect on the pharyngeal airway. In the present study, postoperative changes in hyoid position and pharyngeal airway space were assessed retrospectively in patients who had undergone mandibular setback surgery. MATERIAL AND METHODS: Digitized lateral cephalograms from 30 mandibular setback surgery cases taken preoperatively, and 1 month and more than 1 year postoperatively, were used to examine pharyngeal airway morphology and the position of hyoid bone. RESULTS: A significant downward movement of the hyoid bone was found 1 month after surgery, while the pharyngeal airway dimensions at the tongue were maintained. More than 1 year after surgery, the hyoid position returned to its original position, resulting in a significant decrease in retrolingual airway dimension. CONCLUSION: The results indicate that mandibular setback causes airway narrowing late after surgery, while the early postoperative airway dimension is maintained. Long-term observations should be performed because of the changes of oropharyngeal configuration following mandibular setback.

Clinical conditions for eruption of maxillary canines and mandibular premolars associated with dentigerous cysts.

The aim of this study was to investigate the eruption of teeth associated with dentigerous cysts in the mandibular premolar and maxillary canine regions in preadolescents. Fifty-eight cyst-associated teeth, including 47 mandibular premolars and 11 maxillary canines, were examined retrospectively by using normalized panoramic radiographs and histological materials. The subjects were divided into 2 groups: the erupted group, in which the teeth had erupted successfully after marsupialization, and the nonerupted group, in which the teeth had undergone orthodontic traction or cystectomy with removal of the cyst-associated tooth. Eighty-one percent of the mandibular premolars and 36% of the maxillary canines in the cysts erupted successfully about 100 days after marsupialization without traction. The eruption of a mandibular premolar was significantly related to a shallow position in the alveolar bone, shallow angulation of the tooth, and young age of the patient but not to cyst size and dental space for the eruption. The eruption of the maxillary canine was significantly related to the small size of the cyst and the patient's age. The cyst walls of the erupted group showed severe inflammatory cellular infiltration. These findings present a treatment guideline for dentigerous cysts associated with mandibular premolars and maxillary canines in preadolescents.

Factors associated with the stability of titanium screws placed in the posterior region for orthodontic anchorage.

Recently, implant anchors such as titanium screws have been used for absolute anchorage during edgewise treatment. However, there have been few human studies reporting on the stability of implant anchors placed in the posterior region. The purpose of this study was to examine the success rates and to find the factors associated with the stability of titanium screws placed into the buccal alveolar bone of the posterior region. Fifty-one patients with malocclusions, 134 titanium screws of 3 types, and 17 miniplates were retrospectively examined in relation to clinical characteristics. The 1-year success rate of screws with 1.0-mm diameter was significantly less than that of other screws with 1.5-mm or 2.3-mm diameter or than that of miniplates. Flap surgery was associated with the patient's discomfort. A high mandibular plane angle and inflammation of peri-implant tissue after implantation were risk factors for mobility of screws. However, we could not detect a significant association between the success rate and the following variables: screw length, kind of placement surgery, immediate loading, location of implantation, age, gender, crowding of teeth, anteroposterior jaw base relationship, controlled periodontitis, and temporomandibular disorder symptoms. We concluded that the diameter of a screw of 1.0 mm or less, inflammation of the peri-implant tissue, and a high mandibular plane angle (ie, thin cortical bone), were associated with the mobility (ie, failure) of the titanium screw placed into the buccal alveolar bone of the posterior region for orthodontic anchorage.