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A 58-year-old man who had inhaled acetylene while welding 2 and 4 days previously and subsequently developed cough, dyspnea, and fever was referred by his general practitioner. A computed tomography scan showed diffuse ground-glass opacities in both lungs, and bronchoalveolar lavage fluid showed an increased proportion of eosinophils (25 %). Acute eosinophilic pneumonia (AEP) was diagnosed. Inhalation of acetylene was considered to be the most likely cause of AEP. Respiratory symptoms improved rapidly with intravenous corticosteroids. This is a rare case of AEP caused by inhalation of acetylene., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Acetaminophen (APAP)-induced liver injury is the most common cause of acute liver failure. Macrophages are key players in liver restoration following APAP-induced liver injury. Thromboxane A 2 (TXA 2 ) and its receptor, thromboxane prostanoid (TP) receptor, have been shown to be involved in tissue repair. However, whether TP signaling plays a role in liver repair after APAP hepatotoxicity by affecting macrophage function remains unclear., Methods: Male TP knockout (TP -/- ) and C57BL/6 wild-type (WT) mice were treated with APAP (300 mg/kg). In addition, macrophage-specific TP-knockout (TP △mac ) and control WT mice were treated with APAP. We explored changes in liver inflammation, liver repair, and macrophage accumulation in mice treated with APAP., Results: Compared with WT mice, TP -/- mice showed aggravated liver injury as indicated by increased levels of alanine transaminase (ALT) and necrotic area as well as delayed liver repair as indicated by decreased expression of proliferating cell nuclear antigen (PCNA). Macrophage deletion exacerbated APAP-induced liver injury and impaired liver repair. Transplantation of TP-deficient bone marrow (BM) cells to WT or TP -/- mice aggravated APAP hepatotoxicity with suppressed accumulation of macrophages, while transplantation of WT-BM cells to WT or TP -/- mice attenuated APAP-induced liver injury with accumulation of macrophages in the injured regions. Macrophage-specific TP -/- mice exacerbated liver injury and delayed liver repair, which was associated with increased pro-inflammatory macrophages and decreased reparative macrophages and hepatocyte growth factor (HGF) expression. In vitro, TP signaling facilitated macrophage polarization to a reparative phenotype. Transfer of cultured BM-derived macrophages from control mice to macrophage-specific TP -/- mice attenuated APAP-induced liver injury and promoted liver repair. HGF treatment mitigated APAP-induced inflammation and promoted liver repair after APAP-induced liver injury., Conclusions: Deletion of TP signaling in macrophages delays liver repair following APAP-induced liver injury, which is associated with reduced accumulation of reparative macrophages and the hepatotrophic factor HGF. Specific activation of TP signaling in macrophages may be a potential therapeutic target for liver repair and regeneration after APAP hepatotoxicity., (© 2024. The Author(s).)

Angiogenesis, the formation of new blood vessels from the preexistent microvasculature, is an essential component of wound repair and tumor growth. Nonsteroidal anti-inflammatory drugs that suppress prostanoid biosynthesis are known to suppress the incidence and progression of malignancies including colorectal cancers, and also to delay the wound healing. However, the precise mechanisms are not fully elucidated. Accumulated results obtained from prostanoid receptor knockout mice indicate that a prostaglandin E-type receptor signaling EP 3 in the host microenvironment is critical in tumor angiogenesis inducing vascular endothelial growth factor A (VEGF-A). Further, lymphangiogenesis was also enhanced by EP signaling via VEGF-C/D inductions in pathological settings. These indicate the importance of EP receptor to facilitate angiogenesis and lymphangiogenesis in vivo. Prostanoids act beyond their commonly understood activities in smooth muscle contraction and vasoactivity, both of which are quick responses elicited within several seconds on stimulations. Prostanoid receptor signaling will be a potential therapeutic target for disease conditions related to angiogenesis and lymphangiogenesis., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

Background/aim: Intestinal lymphatic vessels (lacteals) play a critical role in the absorption and transport of dietary lipids into the circulation. Calcitonin gene-related peptide and receptor activity-modifying protein 1 (RAMP1) are involved in lymphatic vessel growth. This study aimed to examine the role of RAMP1 signaling in lacteal morphology and function in response to a high-fat diet (HFD)., Materials and Methods: RAMP1 deficient (RAMP1 -/- ) or wild-type (WT) mice were fed a normal diet (ND) or HFD for 8 weeks., Results: RAMP1 -/- mice fed a HFD had increased body weights compared to WT mice fed a HFD, which was associated with high levels of total cholesterol, triglycerides, and glucose. HFD-fed RAMP1 -/- mice had shorter and wider lacteals than HFD-fed WT mice. HFD-fed RAMP1 -/- mice had lower levels of lymphatic endothelial cell gene markers including vascular endothelial growth factor receptor 3 (VEGFR3) and lymphatic vascular growth factor VEGF-C than HFD-fed WT mice. The concentration of an absorbed lipid tracer in HFD-fed RAMP1 -/- mice was higher than that in HFD-fed WT mice. The zipper-like continuous junctions were predominant in HFD-fed WT mice, while the button-like discontinuous junctions were predominant in HFD-fed RAMP1 -/- mice., Conclusion: Deletion of RAMP1 signaling suppressed lacteal growth and VEGF-C/VEGFR3 expression but accelerated the uptake and transport of dietary fats through discontinuous junctions of lacteals, leading to excessive obesity. Specific activation of RAMP1 signaling may represent a target for the therapeutic management of diet-induced obesity., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: The aim of this article is to evaluate the effectiveness and safety of rituximab (RTX) for microscopic polyangiitis and granulomatosis with polyangiitis in Japan., Methods: In this prospective observational study, all patients with microscopic polyangiitis and granulomatosis with polyangiitis administered RTX were enrolled at each institution. During the observation period of 2 years, data up to 6 months were analysed. Cox proportional hazards analysis was used to assess the factors associated with an outcome., Results: Of the 75 patients who received RTX for remission induction therapy, 53 achieved remission by the sixth month and 50 were in remission at the sixth month. During therapy, 38 serious adverse events were observed in 24 patients, 21 serious infections in 16 patients, and 9 patients died. No factors were associated with remission; however, there was a significant difference between patients with and without remission in serious adverse events (22.6% vs. 54.5%), serious infections (11.3% vs. 45.4%), and death (1.9% vs. 36.4%). The hazard ratio (95% confidence interval) for serious infection was 3.49 (1.29-9.74) for patients aged ≥ 75 years and 3.53 (1.31-9.53) for pulmonary complications. Four patients maintained remission for 6 months., Conclusions: The effectiveness and safety of RTX for microscopic polyangiitis and granulomatosis with polyangiitis for up to 6 months was demonstrated., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Endometriosis is highly dependent on angiogenesis and lymphangiogenesis. Prostaglandin E2, an arachidonic acid metabolite, has been shown to promote the formation of new blood and lymphatic vessels. However, the role of another arachidonic acid metabolite, thromboxane A 2 (TXA 2 ) in angiogenesis and lymphangiogenesis during endometriosis remains largely unexplored. Using a murine model of ectopic endometrial transplantation, fragments from the endometrium of WT donor mice were transplanted into the peritoneal walls of recipient WT mice (WT→WT), resulting in an increase in both the area and density of blood and lymphatic vessels. Upon transplantation of endometrial tissue from thromboxane prostanoid (TP) receptor (TXA 2 receptor)‑deficient (TP ‑/‑ ) mice into TP ‑/‑ mice (TP ‑/‑ →TP ‑/‑ ), an increase in implant growth, angiogenesis, and lymphangiogenesis were observed along with upregulation of pro‑angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs). Similar results were obtained using a thromboxane synthase (TXS) inhibitor in WT→WT mice. Furthermore, TP ‑/‑ →TP ‑/‑ mice had a higher number of F4/80 + cells than that of WT→WT mice, with increased expression of genes related to the anti‑inflammatory macrophage phenotype in endometrial lesions. In cultured bone marrow (BM)‑derived macrophages, the levels of VEGF‑A, VEGF‑C, and VEGF‑D decreased in a TP‑dependent manner. Furthermore, TP signaling affected the polarization of cultured BM‑derived macrophages to the anti‑inflammatory phenotype. These findings imply that inhibition of TP signaling promotes endometrial implant growth and neovascularization.

Background: Accumulating evidence suggests that prostaglandin E 2 , an arachidonic acid (AA) metabolite, enhances lymphangiogenesis in response to inflammation. However, thromboxane A 2 (TXA 2 ), another AA metabolite, is not well known. Thus, this study aimed to determine the role of thromboxane prostanoid (TP) signaling in lymphangiogenesis in secondary lymphedema., Methods and Results: Lymphedema was induced by the ablation of lymphatic vessels in mouse tails. Compared with wild-type mice, tail lymphedema in Tp-deficient mice was enhanced, which was associated with suppressed lymphangiogenesis as indicated by decreased lymphatic vessel area and pro-lymphangiogenesis-stimulating factors. Numerous macrophages were found in the tail tissues of Tp-deficient mice. Furthermore, the deletion of TP in macrophages increased tail edema and decreased lymphangiogenesis and pro-lymphangiogenic cytokines, which was accompanied by increased numbers of macrophages and gene expression related to a pro-inflammatory macrophage phenotype in tail tissues. In vivo microscopic studies revealed fluorescent dye leakage in the lymphatic vessels in the wounded tissues., Conclusions: The results suggest that TP signaling in macrophages promotes lymphangiogenesis and prevents tail lymphedema. TP signaling may be a therapeutic target for improving lymphedema-related symptoms by enhancing lymphangiogenesis., (© 2023. The Author(s).)

Thromboxane (TX) and prostaglandins are metabolites of arachidonic acid, a twenty-carbon unsaturated fatty acid, and have a variety of actions that are exerted via specific receptors. Angiogenesis is defined as the formation of new blood vessels from pre-existing vascular beds and is a critical component of pathological conditions, including inflammation and cancer. Lymphatic vessels play crucial roles in the regulation of interstitial fluid, immune surveillance, and the absorption of dietary fat from the intestine; and they are also involved in the pathogenesis of various diseases. Similar to angiogenesis, lymphangiogenesis, the formation of new lymphatic vessels, is a critical component of pathological conditions. The TP-dependent accumulation of platelets in microvessels has been reported to enhance angiogenesis under pathological conditions. Although the roles of some growth factors and cytokines in angiogenesis and lymphangiogenesis have been well characterized, accumulating evidence suggests that TX induces the production of proangiogenic and prolymphangiogenic factors through the activation of adenylate cyclase, and upregulates angiogenesis and lymphangiogenesis under disease conditions. In this review, we discuss the role of TX as a regulator of angiogenesis and lymphangiogenesis, and its emerging importance as a therapeutic target., Competing Interests: Declaration of Competing Interest All the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier Masson SAS.)

Aims: Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) induces angiogenesis through the prostaglandin E2 receptor (EP1-4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE2 is known to modulate the function and differentiation of Tregs. We hypothesized that mPGES-1/PGE2-EP signalling could contribute to recovery from ischaemic conditions by promoting the accumulation of Tregs., Methods and Results: Wild-type (WT), mPGES-1-deficient (mPges-1-/-), and EP4 receptor-deficient (Ep4-/-) male mice, 6-8 weeks old, were used. Hindlimb ischaemia was induced by femoral artery ligation. Recovery from ischaemia was suppressed in mPges-1-/- mice and compared with WT mice. The number of accumulated forkhead box protein P3 (FoxP3)+ cells in ischaemic muscle tissue was decreased in mPges-1-/- mice compared with that in WT mice. Expression levels of transforming growth factor-β (TGF-β) and stromal cell derived factor-1 (SDF-1) in ischaemic tissue were also suppressed in mPges-1-/- mice. The number of accumulated FoxP3+ cells and blood flow recovery were suppressed when Tregs were depleted by injecting antibody against folate receptor 4 in WT mice but not in mPges-1-/- mice. Recovery from ischaemia was significantly suppressed in Ep4-/- mice compared with that in WT mice. Furthermore, mRNA levels of Foxp3 and Tgf-β were suppressed in Ep4-/- mice. Moreover, the number of accumulated FoxP3+ cells in ischaemic tissue was diminished in Ep4-/- mice compared with that in Ep4+/+ mice., Conclusion: These findings suggested that mPGES-1/PGE2 induced neovascularization from ischaemia via EP4 by promoting the accumulation of Tregs. Highly selective EP4 agonists could be useful for the treatment of peripheral artery disease., Competing Interests: Conflict of interest: The authors declare no conflicts of interest associated with this manuscript., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Takayasu arteritis (TAK) is a rare, large-vessel vasculitis, frequently presenting at approximately 20 years of age. Patients with TAK without characteristic clinical findings are sometimes left undiagnosed and are followed by a fever of unknown origin; delayed diagnosis may lead to irreversible ischaemia and organ damage. Here, we report a case of an 18-year-old woman with TAK complicated by acute pericarditis at initial presentation. She was diagnosed with idiopathic acute pericarditis and treated with non-steroidal anti-inflammatory drugs (NSAIDs). However, the patient's fever and pain in the chest and upper back persisted. On admission to our hospital, magnetic resonance angiography and ultrasonography revealed wall thickening in the common carotid artery, subclavian artery, and aorta, along with vascular narrowing in the celiac, superior mesenteric, and bilateral renal arteries. The patient was diagnosed with TAK and treated with glucocorticoids, including methylprednisolone pulse therapy, and azathioprine. The treatment improved the patient's signs and symptoms, and pericardial effusion decreased. Acute pericarditis is a rare manifestation of TAK, but it is important to differentiate diseases, including TAK in patients with acute pericarditis who fail to respond to 2-3 weeks of conventional therapy with NSAIDs., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background/aim: Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme, which catalyzes the final step of prostaglandin E 2 (PGE 2 ) synthesis. PGE 2 in involved in wound-induced angiogenesis. Regulatory T cells (Tregs) regulate not only immune tolerance but also tissue repair and angiogenesis. We examined whether the mPGES-1/PGE 2 axis contributes to wound-induced angiogenesis and granulation tissue formation through Treg accumulation., Materials and Methods: The dorsal subcutaneous tissues of male mPGES-1-deficient (mPGES-1 -/- ) and C57BL/6 wild-type (WT) mice were implanted with polyurethane sponge disks. Angiogenesis was estimated by determining the wet weight of sponge tissues and the expression of proangiogenic factors including CD31, vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β) in granulation tissues., Results: Angiogenesis was suppressed in mPGES-1 -/- mice compared with WT mice, which was associated with attenuated forkhead box P3 (Foxp3) expression and Foxp3 + Treg accumulation. The number of cells double-positive for Foxp3/TGFβ and Foxp3/VEGF were lower in mPGES-1 -/- mice than in WT mice. Neutralizing Tregs with antibodies (Abs) against CD25 or folate receptor 4 (FR4) inhibited the Foxp3+ Treg angiogenesis and accumulation in WT mice, but not in mPGES-1 -/- mice. The topical application of PGE 2 into the implanted sponge enhanced angiogenesis and accumulation of Tregs expressing TGFβ and VEGF in WT and mPGES-1 -/- mice., Conclusion: Tregs producing TGFβ and VEGF accumulate in wounds and contribute to angiogenesis through mPGES-1-derived PGE 2 mPGES-1 induction may control angiogenesis in skin wounds by recruiting Tregs., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To describe the operation of an outpatient rehabilitation practice at a Japanese hospital severely affected by the coronavirus disease 2019 (COVID-19) pandemic., Design: Analytical observational study., Setting: Outpatient rehabilitation department in Saitama, Japan., Participants: Number (N=953) of outpatients from January 2019 to July 2021., Interventions: Not applicable., Main Outcome Measures: This paper begins with a review of the infection control measures that were initiated after declaration of a state of emergency in April 2020. The effects of the pandemic were then examined by comparing the daily average number of outpatients from January 2020 to July 2021 with that noted for the same duration during 2019., Results: In April 2020, the average daily number of patients decreased by 77.1% compared with the number in 2019 and was further decreased by 65.7% and 63.7% in May and June 2020, respectively. The time limitations on rehabilitation were lifted in June, and the number of patients increased by 82.3% in July 2020. Thereafter, it remained at approximately 80% throughout the rest of the year compared with that noted in 2019. From January 2021 to July 2021, the number of patients approached the number noted during normal practice or was even higher., Conclusions: The implementation of infection control measures, adjustments to procedures, and widespread vaccination permitted the continuation of our outpatient practice., (© 2022 The Authors.)

Background: Infection is one of the primary concerns during treatment for rheumatoid arthritis (RA) in elderly patients. However, infection risk of patients with RA receiving targeted therapy (TT) including biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKIs) in elderly patients are scarce. The aim of this study was to compare the risk of hospitalized infection (HI) with TT versus methotrexate (MTX) therapy among young, elderly, and older elderly patients with RA., Methods: Using Japanese claims data, patients satisfying the following criteria were enrolled: (1) ≥ one ICD10 code for RA; (2) ≥ one prescription of MTX or TT (bDMARDs and JAKIs) between April 2008 and September 2018; and (3) ≥16 years old. We calculated the incidence rate (IR) of HI per 100 patient-years in the young, elderly, and older elderly groups (those aged 16-64, 65-74, and ≥75 years, respectively) and the IR ratio (TT vs. MTX) of HI. A logistic regression model was used to estimate the associations between HI and TT versus MTX in each group., Results: The overall IR of HI per 100 patient-years (95% confidence interval) was 3.2 [2.9-3.5], 5.0 [4.6-5.4], and 10.1 [9.5-10.9] in the young, elderly, and older elderly groups, respectively. Concomitant use of MTX or immunosuppressive DMARDs with TT was less frequent in the elderly and older elderly groups. The adjusted odds ratio of TT vs. MTX for HI was 1.3 (1.0-1.7; p = 0.021), 0.79 (0.61-1.0; p = 0.084), and 0.73 (0.56-0.94; p = 0.015) in the young, elderly, and older elderly groups, respectively., Conclusion: The overall IR of HI was increased with age. The risk of HI under TT compared to MTX was not elevated in elderly and older elderly patients after adjusting for patients' characteristics and concomitant treatments., (© 2022. The Author(s).)

Obesity is accompanied by and accelerated with chronic inflammation in adipose tissue, especially visceral adipose tissue (VAT). This low-level inflammation predisposes the host to the development of metabolic disease, most notably type 2 diabetes. We have focused on the capacity of glycolipid-reactive, CD1d-restricted natural killer T (NKT) cells to modulate obesity and its associated metabolic sequelae. We previously reported that CD1d knockout (KO) mice are partially protected against the development of obesity-associated insulin resistance, and these findings were recapitulated in mice with an adipocyte-specific CD1d deficiency, suggesting that NKT cell-adipocyte interactions play a critical role in exacerbating disease. However, many other CD1d-expressing cells contribute to the in vivo responses of NKT cells to lipid antigens. In the present study, we examined the role of CD1d expression by macrophages (Mϕ) in the development of obesity-associated metabolic inflammation using LysMcre-cd1d1 f / f mice where the CD1d1 gene is disrupted in a Mϕ-specific manner. Unexpectedly, these animals contained a higher frequency of T-bet + CD4 + T cells in VAT with increased production of Th1 cytokines that aggravated VAT inflammation. Mϕ from mutant mice displayed increased production of IL-12p40, suggesting M1 polarization. These findings indicate that interactions of CD1d on Mϕ with NKT cells play a beneficial role in obesity-associated VAT inflammation and insulin resistance with a sharp contrast to an aggravating role of CD1d in another type of antigen-presenting cell, dendritic cells., (© 2022 John Wiley & Sons Ltd.)

Lymphatic vessels have crucial roles in the regulation of interstitial fluids, immune surveillance, and the absorption of dietary fat in the intestine. Lymphatic function is also closely related to the pathogenesis of various disease states such as inflammation, lymphedema, endometriosis, liver dysfunction, and tumor metastasis. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing lymphatic vessels, is a critical determinant in the above conditions. Although the effect of growth factors on lymphangiogenesis is well-characterized, and biologically active lipids are known to affect smooth muscle contractility and vasoaction, there is accumulating evidence that biologically active lipids are also important inducers of growth factors and cytokines that regulate lymphangiogenesis. This review discusses recent advances in our understanding of biologically active lipids, including arachidonic acid metabolites, sphingosine 1-phosphate, and lysophosphatidic acid, as regulators of lymphangiogenesis, and the emerging importance of the lymphangiogenesis as a therapeutic target., Competing Interests: Declaration of Competing Interest All authors declare that there are no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The process of gastric ulcer healing includes cell migration, proliferation, angiogenesis and re-epithelialization. Platelets contain angiogenesis stimulating factors that induce angiogenesis. Thromboxane A 2 (TXA 2 ) not only induces platelet activity but also angiogenesis. This study investigated the role of TXA 2 in gastric ulcer healing using TXA 2 receptor knockout (TPKO) mice. Gastric ulcer healing was suppressed by treatment with the TXA 2 synthase inhibitor OKY-046 and the TXA 2 receptor antagonist S-1452 compared with vehicle-treated mice. TPKO showed delayed gastric ulcer healing compared with wild-type mice (WT). The number of microvessels and CD31 expression were lower in TPKO than in WT mice, and TPKO suppressed the expression of transforming growth factor beta (TGF-β) and vascular endothelial growth factor A (VEGF-A) in areas around gastric ulcers. Immunofluorescence assays showed that TGF-β and VEGF-A co-localized with platelets. Gastric ulcer healing was significantly reduced in WT mice transplanted with TPKO compared with WT bone marrow. These results suggested that TP signalling on platelets facilitates gastric ulcer healing through TGF-β and VEGF-A., (© 2021 The Authors. International Journal of Experimental Pathology published by John Wiley & Sons Ltd on behalf of Company of the International Journal of Experimental Pathology (CIJEP).)

Objectives: To investigate the risk factors and clinical characteristics of lymphoproliferative disorder (LPD) in Japanese patients with rheumatoid arthritis (RA)., Methods: We enrolled patients with RA aged ≥20 years who visited the participating hospitals between April 2011 and July 2011. We investigated the risk factors for LPD using a Cox proportional hazard model and described pathological features and vital prognosis of LPD in patients with RA., Results: We enrolled 9815 patients with the following characteristics at baseline: female 79.4%, median age 63 years; median disease duration 7 years; median DAS28-CRP (3) 3.1; prevalence of MTX use 60.0%. Sixty-eight patients (0.69%) developed LPD in 3-year observation period. Multivariable analysis showed that age by decade (hazard ratio [95% confidence interval], 1.47 [1.18-1.85]) and MTX use at baseline (2.35 [1.25-4.42] for ≤8 mg/week, 4.39 [2.07-9.32] for >8 mg/week versus non-use) were significant risk factors of LPD. Of 55 patients with pathological diagnosis, diffuse large B cell lymphoma was the most frequent (54%). The 5-year mortality of LPD was 24%. The major cause of death was lymphoma (81%)., Conclusion: This nationwide study revealed risk factors, clinical characteristics, and prognosis of LPD in the largest number of Japanese patients with RA., (© 2021 Japan College of Rheumatology.)

Background/aim: Although the pathology of sinusoidal obstruction syndrome (SOS) is characterized by damage to liver sinusoidal endothelial cells (LSECs), the processes underlying LSEC repair are incompletely understood. The angiopoietin (Ang)/Tie system contributes to angiogenesis. The present study aimed to examine the processes of LSEC repair and the involvement of the Ang/Tie pathway in LSEC recovery., Materials and Methods: Experimentally, SOS was induced by intraperitoneal injection of monocrotaline (MCT) to C57/BL6 mice., Results: Levels of LSEC markers were up-regulated during the repair phase of MCT-induced hepatotoxicity. The damaged LSECs recovered from the injury by expanding LSECs expressing lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in the peri-central area of MCT-injured livers, while LSECs in the same area of uninjured livers lacked LYVE-1 expression. Bone marrow (BM)-derived cells did not incorporate into the restored LSECs. Tie2 expression was related to LSEC recovery in MCT-injured liver tissue., Conclusion: The resident LSECs neighboring uninjured tissue replace damaged LSECs in MCT-injured livers. Tie2 is involved in LSEC recovery from MCT-induced hepatotoxicity., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Monocrotaline (MCT) administration induces liver injury in rodents that mimics the pathology of human sinusoidal obstruction syndrome. MCT-induced SOS models are used to investigate the mechanism of injury and optimize treatment strategies. However, the processes underlying liver repair are largely unknown. Specifically, the role of macrophages, the key drivers of liver repair, has not been elucidated. The current study aimed to examine the role of macrophages in the repair of MCT-induced liver injury in male C57/BL6 mice. Maximal liver injury occurred at 48 h post-MCT treatment, followed by repair at 120 h post-treatment. Immunofluorescence analysis revealed that CD68 + macrophages were recruited to the injured regions after MCT treatment. This was associated with the decreased expression of genes related to a pro-inflammatory macrophage phenotype and the increased expression of those associated with a reparative macrophage phenotype during the repair phase. The results also revealed that stromal cell-derived factor-1 (SDF-1) and its receptor C-X-C chemokine receptor-4 (CXCR4) were upregulated, and CD68 + macrophages were co-localized with CXCR4 expression. Treatment of mice with AMD3100, a CXCR4 antagonist, delayed liver repair and increased the expression of genes related to a pro-inflammatory macrophage phenotype. In contrast, SDF-1 treatment stimulated liver repair and increased the expression of genes related to a reparative macrophage phenotype. The results suggested that macrophages accumulate in the liver and repair damaged tissue after MCT treatment, and that the SDF-1-CXCR4 axis is involved in this process., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Otaka et al.)

[Figure: see text].

Y-doped BaZrO 3 , BaCeO 3 and BaZr 1-x Ce x O 3 show high proton conductivity at intermediate temperature and are promising electrolyte candidates in electrochemical devices. However, in most cases, the present cell fabrication process seems to be unavailable to avoid the addition of NiO, which is either added to improve the sinterability of these electrolyte or diffuses from the electrode substrate during co-sintering. In this work, a systematic investigation was performed to study the effect of NiO on BaZr 0.8-x Ce x Y 0.2 O 3-δ (BZCY20) covering the full Ce range from 0 to 0.8. The results revealed that regardless of the composition of BZCY20, both the dehydration temperature and proton concentration decreased by adding NiO, which further greatly decreased the ionic conductivity and the transport number. And it is found that the redox cycles in Ce-rich samples containing Ni makes the grain boundary conductivity worse and the electrolyte brittle. The conclusion is that NiO is detrimental to the performance of the electrochemical cells using these materials as the electrolyte, although compromise might be achieved in certain degree by tuning the Ce content. However, it should be noted that to further improve the cell performance, a new sintering additive or new processing for cell fabrication is essential., (© 2020 Wiley-VCH GmbH.)

Destruction of liver sinusoidal endothelial cells (LSECs) is an initial event in sinusoidal obstruction syndrome (SOS) that leads to accumulation of platelets in the liver. Herein, we explored the role of platelets during progression of experimental SOS induced by monocrotaline (MCT) in mice. Depletion of platelets using an anti-CD41 antibody or anti-thrombocyte serum exacerbated MCT-induced liver injury in C57BL/6 mice, as indicated by an increase in the alanine transaminase (ALT) level, which was associated with hemorrhagic necrosis. Thrombocytosis induced by thrombopoietin (TPO) or the TPO receptor agonist romiplostim (ROM) attenuated MCT-induced liver injury, as evidenced by lower levels of ALT and mRNA encoding matrix metalloproteinase (MMP) 9, and higher levels of mRNA encoding vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR3. The level of activated hepatic platelets was higher in TPO- and ROM-treated mice than in saline-treated mice. Co-culture with a high number of platelets increased the viability of LSECs and their mRNA levels of CD31, VEGFR2, and VEGFR3, and decreased their mRNA level of MMP9. The level of VEGF-A was increased in the culture medium of LSECs co-cultured with platelets. These results indicate that platelets attenuate MCT-induced liver injury by minimizing damage to LSECs., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To compare the risk of hospitalized infection (HI) between users and non-users of hydroxychloroquine (HCQ) in systemic lupus erythematosus (SLE)., Methods: Using claims data, patients were defined as SLE cases by the following criteria: 1) they had at least one SLE diagnostic code; 2) they had a prescription for specific drugs, including corticosteroids, steroid pulse therapy, and immunosuppressive drugs; and 3) they were at least 16 years old between September 2015 and July 2017 (n = 17,483). The SLE cases with at least one prescription for HCQ were defined as the HCQ group (n = 1,431), while the others were defined as the non-HCQ group. Among the SLE cases, propensity score-matched cases were observed for 1 year (n = 1,095 in each group)., Results: The median age and proportion of female patients in both groups were about 42 years and 88%, respectively. The proportions of cases with HIs were similar (HCQ group, 4.5%; non-HCQ group, 5.6%; p = 0.240, McNemar test). The hazard ratio of the HCQ group for HIs after adjusting for patients' characteristics was not significant at 0.9 (0.6-1.3)., Conclusion: The use of HCQ was not associated with a risk of HIs in patients with SLE.

Neuroimmune interactions are involved in the development of endometriosis. Here, we examined the role of a neuropeptide, calcitonin gene-related peptide (CGRP), and its receptor, receptor activity-modifying protein (RAMP) 1, in growth of endometrial tissues and the formation of blood and lymphatic vessels in a mouse ectopic endometrial transplantation model. Endometrial fragments from donor wild-type (WT) mice transplanted into the peritoneal wall of recipient WT mice grew with increased density of blood and lymphatic vessels. When tissues from RAMP1-deficient (RAMP1 -/- ) mice were transplanted into RAMP1 -/- mice, implant growth and angiogenesis/lymphangiogenesis were decreased. CGRP was up-regulated in dorsal root ganglia, and CGRP + nerve fibres were distributed into the implants from the peritoneum. RAMP1 was co-expressed with CD11b (macrophages) and S100A4 (fibroblasts), but did not co-localize with blood vessel endothelial cell marker CD31 or lymphatic vessel endothelial hyaluronan receptor (LYVE)-1. Cultured with CGRP, macrophages up-regulated vascular endothelial growth factor (VEGF)-A, VEGF-C and VEGF-D, whereas fibroblasts up-regulated VEGF-C, but not VEGF-A or VEGF-D, in a RAMP1-dependent manner. CGRP receptor antagonist CGRP8-37 inhibited growth of and angiogenesis/lymphangiogenesis within endometrial tissue implants. These results suggest that RAMP1 signalling is crucial for growth and angiogenesis/lymphangiogenesis in endometrial tissue. Blockade of RAMP1 is a potential tool for the treatment of endometriosis., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objective: To compare 3 fat suppression methods-water excitation (WE), chemical shift selective (CHESS), and short T1 inversion recovery (STIR)-for optimal image quality and apparent diffusion coefficient (ADC) values with magnetic resonance imaging (MRI) using diffusion-weighted imaging (DWI) of the oral and maxillofacial region., Study Design: In total, 53 patients with 73 lesions were enrolled in this study. MRI using DWI protocols with the 3 fat suppression methods were performed in addition to a conventional MRI protocol. The diagnostic image quality of lesions, image uniformity, degree of image artifacts, and ADC values of the lesions were evaluated. Average visual scores and ADC values were compared, and post hoc pairwise comparisons were performed, with the level of significance set at P < .0167., Results: Diagnostic image quality was not significantly different among the fat suppression methods (P ≥ .042). Image uniformity was significantly higher (P < .001), and the degree of image artifacts was significantly lower (P < .001), in images using the STIR method. Mean ADC values did not differ significantly among the 3 methods., Conclusions: The STIR method was the most useful fat suppression method for DWI of the oral and maxillofacial region because of its high level of image uniformity and few image artifacts., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Hepatic tissue repair plays a critical role in determining the outcome of hepatic ischemia-reperfusion (I/R) injury. Hepatic lymphatics participate in the clearance of dead tissues and contribute to the reparative process after acute hepatic injury; however, it remains unknown whether lymphangiogenesis in response to hepatic inflammation is involved in liver repair. Herein, we determined if hepatic lymphangiogenesis improves liver repair after hepatic I/R injury. Using a mouse model of hepatic I/R injury, we investigated hepatic lymphatic structure, growth, and function in injured murine livers. Hepatic I/R injury enhanced lymphangiogenesis around the portal tract and this was associated with increased expression of pro-lymphangiogenic growth factors including vascular endothelial growth factor (VEGF)-C and VEGF-D. Recombinant VEGF-D treatment facilitated liver repair in association with the expansion of lymphatic vessels and increased expression of genes related to the reparative macrophage phenotype. Treatment with a VEGF receptor 3 (VEGFR3) inhibitor suppressed liver repair, lymphangiogenesis, drainage function, and accumulation of VEGFR3-expressing reparative macrophages. VEGF-C and VEGF-D upregulated expression of genes related to lymphangiogenic factors and the reparative macrophage phenotype in cultured macrophages. These results suggest that activation of VEGFR3 signaling increases lymphangiogenesis and the number of reparative macrophages, both of which play roles in liver repair. Expanded lymphatics and induction of reparative macrophage accumulation may be therapeutic targets to enhance liver repair after hepatic injury.

Lymphangiogenesis is related to the growth of endometriosis. Here, we examined whether vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) signaling plays a role in lymphangiogenesis during endometriosis. Endometrial fragments from wild-type (WT) mice transplanted into the peritoneal wall of host WT mice (WT→WT) developed well and displayed enhanced lymphangiogenesis associated with increases in mRNA levels of VEGF-C and VEGF-D. Compared with WT mice, the implant size and lymphangiogenesis were reduced, when endometrial fragments from mice lacking the VEGFR1 tyrosine kinase (TK) domain (TK -/- ) were transplanted into host TK -/- mice (TK -/- →TK -/- ). Treatment of WT→WT mice with the VEGFR3 kinase inhibitor suppressed the size of implants and lymphangiogenesis. Immunofluorescence analyses demonstrated that VEGF-C and VEGF-D were expressed in both CD11b + and S100A4 + cells. TK -/- →TK -/- mice had lower numbers of CD11b + and S100A4 + cells than WT→WT mice. When isolated bone marrow (BM)-derived macrophages or culture murine fibroblasts were stimulated with placental growth factor (PlGF), a specific agonist of VEGFR1, the levels of VEGF-C and VEGF-D were increased in a VEGFR1-dependent manner. These results suggest that VEGFR1 signaling in macrophages and fibroblasts contributes to the growth of endometrial implants and lymphangiogenesis., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

In the intestine, the formation of new lymphatic vessels from pre-existing lymphatic vasculature (lymphangiogenesis) is related to the progression of inflammatory bowel disease (IBD). However, it remains unclear whether lymphangiogenesis contributes to mucosal repair after acute colitis. Prostaglandin Ereceptor EP4 suppresses the development of experimental colitis. In this study, we investigated whether EP4 exerts this effect by contributing to lymphangiogenesis, in turn promoting mucosal tissue repair, following acute colitis. We elicited experimental colitis in male C57/BL6 mice by administering dextran sulphate sodium (DSS) via the drinking water for 5 days, followed by normal water for 9 additional days. From Day 5 through Day 13, the experimental mice received a daily dose of EP4-selective agonist, EP4-selective antagonist, or vehicle. On Day 14, mice treated with vehicle had recovered 95 % of body weight and exhibited moderate increases in disease activity and histological score relative to untreated controls. Compared with vehicle, post-treatment with EP4 antagonist increased signs of colitis, colonic tissue destruction, and CD11b + cell infiltration, associated with elevated lymphatic vessel density (LVD) and reduced percentage of lymphatic vessel area (LVA%). By contrast, post-treatment with EP4 agonist improved disease activity, suppressed CD11b + infiltration, and decreased levels of inflammatory cytokines; these changes were associated with upregulation of lymphatic growth factors and lymphangiogenesis, as evidenced by increases in LVA% and lymphatic drainage function. Inhibition of vascular endothelial growth factor receptor 3 (VEGFR3) caused a delay in mucosal repair, accompanied by impaired lymphangiogenesis. These results suggest that EP4 stimulation aids in mucosal repair from DSS-induced acute colitis by promoting lymphangiogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest related to this work., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Calcitonin gene-related peptide (CGRP) regulates inflammation via signaling through receptor activity-modifying protein (RAMP) 1. Here, we investigated the role of RAMP1 signaling in growth of lymphatic vessels during inflammation. Lymphangiogenesis in the diaphragm of RAMP1-deficient ( -/- ) mice or their wild-type (WT) counterparts was induced by repeated intraperitoneal injection of lipopolysaccharide (LPS). Compared with WT mice, LPS-induced lymphangiogenesis in RAMP1 -/- mice was suppressed. This was accompanied by the reduced expression of vascular endothelial growth factor (VEGF)-C and VEGF-D. The number of CD4 + cells in diaphragm tissue from WT mice was greater than RAMP1 -/- mice. Removing CD4 + cells attenuated lymphangiogenesis and expression of VEGF-C and VEGF-D. CD4 + cells isolated from RAMP1 -/- mice exhibited reduced expression of VEGF-C and VEGF-D. The number of CD11b + cells from RAMP1 -/- mice was higher than WT mice and was associated with the upregulated expression of genes related to pro-inflammatory macrophage phenotype and downregulation of reparative macrophage phenotype-related expression. When fluorescein isothiocyanate (FITC)-dextran was injected into the peritoneal cavity, the amount of residual FITC-dextran in WT mice was lower than that in RAMP1 -/- mice. The present results suggest that RAMP1 signaling in immune cells plays a critical role in inflammation-related lymphangiogenesis; therefore, it represents a novel target for controlling lymphangiogenesis.

Macrophage plasticity is essential for liver wound healing; however, the mechanisms underlying macrophage phenotype switching are largely unknown. Dendritic cells (DCs) are critical initiators of innate immune responses; as such, they orchestrate inflammation following hepatic injury. Here, we subjected EP3-deficient (Ptger3 -/- ) and wild-type (WT) mice to hepatic ischemia-reperfusion (I/R) and demonstrate that signaling via the prostaglandin E (PGE) receptor EP3 in DCs regulates macrophage plasticity during liver repair. Compared with WT mice, Ptger3 -/- mice showed delayed liver repair accompanied by reduced expression of hepatic growth factors and accumulation of Ly6C low reparative macrophages and monocyte-derived DCs (moDCs). MoDCs were recruited to the boundary between damaged and undamaged liver tissue in an EP3-dependent manner. Adoptive transfer of moDCs from Ptger3 -/- mice resulted in impaired repair, along with increased numbers of Ly6C high inflammatory macrophages. Bone marrow macrophages (BMMs) up-regulated expression of genes related to a reparative macrophage phenotype when co-cultured with moDCs; this phenomenon was dependent on EP3 signaling. In the presence of an EP3 agonist, interleukin (IL)-13 derived from moDCs drove BMMs to increase expression of genes characteristic of a reparative macrophage phenotype. The results suggest that EP3 signaling in moDCs facilitates liver repair by inducing IL-13-mediated switching of macrophage phenotype from pro-inflammatory to pro-reparative., (© 2020 Federation of American Societies for Experimental Biology.)

Background: Accumulation of myeloid-derived suppressor cells (MDSCs) to tumors is related to cancer prognosis. We investigated the contribution of host stromal microsomal prostaglandin E synthase-1 (mPGES-1) to the accumulation of MDSCs in metastasized lungs of prostate cancer in mice., Material and Methods: Eight-week-old male C57Bl/6 wild type (WT) mice and mPGES-1 knock out mice (mPGES-1KO) were injected with RM9 murine prostate cancer cell line (5 × 10 6 cells/mL). Lung metastasis was evaluated by the number of colonies, the weight of the lung, and the number of MDSCs (CD11b + Gr1 + cells) in the lung., Results: Intravenous injections of RM9, a murine prostate cancer cell line to WT mice revealed that lung metastasis and accumulation of MDCSs were suppressed with treatments with a Gr1 antibody, a COX-2 inhibitor, and an mPGES-1 inhibitor. Lung metastasis and accumulation of CD11b + Gr1 + MDSCs were suppressed in mPGES-1KO mice. The mRNA level of stromal cell-derived factor-1 (SDF-1) in the lung and the number of accumulated SDF-1-expressing CD11b + Gr1 + MDSCs were elevated at an early stage in lung metastasis of C-X-C chemokine receptor type 4 (CXCR4)-expressing RM9 in an mPGES-1-dependent manner. The number of CXCR4-expressing CD11b + Gr1 + MDSCs in WT mice was higher than that in mPGES-1KO mice. RM9 lung metastasis and accumulation of CD11b + Gr1 + MDSCs were suppressed by CXCR4 antibody in WT mice but not in mPGES-1KO. WT mice transplanted with mPGES-1 KO bone marrow (BM) showed a significant reduction in lung metastasis and accumulation of CD11b + Gr1 + MDSCs., Conclusion: These results suggest that mPGES-1 enhances tumor metastasis by inducing accumulation of BM-derived MDSCs. Selective mPGES-1 inhibitors might, therefore, represent valuable therapeutic tools for the suppression of tumor metastasis., (Copyright © 2019. Published by Elsevier Masson SAS.)

Sinusoidal obstruction syndrome (SOS) is a major complication of chemotherapy and hematopoietic stem cell transplantation. The early stage of SOS is characterized by liver sinusoidal endothelial cell (LSEC) injury accompanied by platelet aggregation. Thromboxane A 2 (TxA 2 ) induces platelet aggregation through the thromboxane prostanoid (TP) receptor. In this study, we explored the role of TP signaling in a monocrotaline (MCT)-induced mouse model of SOS. Relative to wild-type (WT) mice, TP-deficient (TP -/- ) mice exhibited more severe MCT-liver injury, as indicated by elevated levels of alanine aminotransferase (ALT) and coagulative necrosis. Extensive accumulation of platelets in the liver was observed in both WT and TP -/- mice. TP expression co-localized with CD31-positive LSECs. MCT treatment caused LSEC destruction, concomitant with elevated expression of matrix metalloproteinases (MMPs) and adhesion molecules in WT mice, and LSEC damage was further exacerbated in TP -/- mice. Viability of isolated LSECs was lower in cells from TP -/- mice, whereas mRNA levels of MMPs and adhesion molecules were higher; U46619, a TxA 2 agonist, reduced these levels in WT mice. These data suggest that TP signaling has no effect on platelet accumulation during MCT-induced liver injury, but instead prevents injury by suppressing LSEC damage., (Copyright © 2019. Published by Elsevier Inc.)

Dermatan sulfate oligosaccharides having reducing end 2,5-anhydro-d-talose were prepared by partial N-deacetylation of dermatan sulfate polysaccharide with hydrazine followed by deamination with nitrous acid, and the effect of these oligosaccharides on the activity of bovine testicular hyaluronidase was investigated. Hydrolysis activity and transglycosylation activity of this enzyme were assessed in an independent reaction system by analyzing the products by HPLC. Dermatan sulfate oligosaccharides inhibited hyaluronan hydrolysis by bovine testicular hyaluronidase. Kinetic analysis of the hydrolysis reaction revealed that the inhibition mode by dermatan sulfate oligosaccharides was as competitive as that previously shown by chondroitin sulfate oligosaccharides. Transglycosylation of hyaluronan by bovine testicular hyaluronidase, as a reverse reaction of hydrolysis of hyaluronan, was also inhibited. These inhibitory effects were dependent on the dose and sulfation degree of dermatan sulfate., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with a poor prognosis. Fibroblast proliferation amplifies extracellular matrix deposition and increases angiogenesis. Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic factors. VEGF interacts with VEGF receptors (VEGFR1 and VEGFR2). A previous study showed that VEGFR1 tyrosine kinase (TK) signaling induced blood flow recovery mediated by bone marrow (BM)-derived stem cells. We hypothesized that VEGFR1-TK signaling might be related to pulmonary fibrosis., Material and Methods: Six-week-old male C57Bl/6 wild-type (WT) mice and VEGFR1 TK knockout mice (TKKO mice) were treated with a single intratracheal injection of bleomycin (BLM; 0.1 μg in 50 μl saline) or vehicle (saline; 50 μl). Lung fibrosis was evaluated by histology, real-time PCR and ELISA for pro-fibrotic factors, and assessment of lung mechanics., Results: The fibrotic area in the lung and the lung elastance were significantly reduced in TKKO mice (P < 0.01). The expression of the fibrosis-related factors type I collagen, S100A4, and transforming growth factor (TGF)-β was also significantly reduced in TKKO mice on day 21 after BLM injection. TKKO mice also had significantly lower levels of stromal cell-derived factor (SDF)-1 in the lungs and plasma on days 14 and 21 after BLM treatment (P < 0.05). Moreover, the expression of C-X-C chemokine receptor type 7 (CXCR7) and CXCR4, the receptors for SDF-1, was also suppressed in TKKO mice. Immunohistochemical analysis showed that treatment with a CXCR4 antibody decreased the accumulation of VEGFR1 + cells in the lung in WT mice but not in TKKO mice., Conclusion: These results suggest that VEGFR1 TK signaling promotes BLM-induced pulmonary fibrosis by activating the SDF-1/CXCR4 axis in infiltrating VEGFR1 + cells., (Copyright © 2019. Published by Elsevier Masson SAS.)

Angiogenesis is critical in maintenance of endometrial tissues. Here, we examined the role of VEGF receptor 1 (VEGFR1) signaling in angiogenesis and tissue growth in an endometriosis model. Endometrial fragments were implanted into the peritoneal wall of mice, and endometrial tissue growth and microvessel density (MVD) were determined. Endometrial fragments from wild-type (WT) mice grew slowly with increased angiogenesis determined by CD31 + MVD, peaking on Day 14. When tissues from WT mice were transplanted into VEGFR1 tyrosine kinase-knockout mice, implant growth and angiogenesis were suppressed on Day 14 compared with growth of WT implants in a WT host. The blood vessels in the implants were not derived from the host peritoneum. Immunostaining for VEGFR1 suggested that high numbers of VEGFR1 + cells such as macrophages were infiltrated into the endometrial tissues. When macrophages were deleted with Clophosome N, both endometrial tissue growth and angiogenesis were significantly suppressed. Bone marrow chimera experiments revealed that growth and angiogenesis in endometrial implants were promoted by host bone marrow-derived VEGFR1 + /CD11b + macrophages that accumulated in the implants, and secreted basic fibroblast growth factor (bFGF). A FGF receptor kinase inhibitor, PD173047 significantly reduced size of endometrial tissues and angiogenesis. VEGFR1 signaling in host-derived cells is crucial for growth and angiogenesis in endometrial tissue. Thus, VEGFR1 blockade is a potential treatment for endometriosis.

Background: Ulcerative Colitis (UC) is an inflammatory bowel disease that affects the colon. The development of UC is regulated by immune cells. Previously, we showed that vascular endothelial growth factor receptor 1 (VEGFR1) tyrosine kinase (TK) signaling induces healing of mucosal damage by recruiting VEGFR1 + cells appear to be lineage monocyte cells. Recent studies show that development of UC correlates with the number of regulatory T cells (Tregs). Here, we investigated whether VEGFR1-TK signaling induces healing of UC via accumulation of Tregs or not., Method: Acute colitis was induced in C57/Bl6N (wild-type [WT]) and VEGFR1 T K knockout (VEGFR1 T K -/- ) mice by administration of 2.0% dextran sulfate sodium (DSS)., Results: Total colon length in VEGFR1 T K -/- mice was shorter than that in WT mice. The ulcer length and the disease activity index (DAI) score were significantly higher in VEGFR1 T K -/- mice than in WT mice, whereas CD31 mRNA and protein levels were significantly lower. Accumulation of forkhead box P3 + (Foxp3 + ) VEGFR1 + Tregs was lower in VEGFR1 T K -/- mice, as was expression of interleukin (IL)-10 and transforming growth factor (TGF)-β. The survival rate of WT mice treated with an anti-folate receptor 4 (FR4) antibody was 40%, while that of WT mice treated with control IgG was 90%. Moreover, WT mice treated with a neutralizing antibody against C-X-C chemokine receptor type 4 (CXCR4) showed significantly shorter colon length than WT with control antibody. In VEGFR1 T K -/- , infiltration of Foxp3 + Tregs expressing VEGFR1 and CXCR4 into ulcerated areas was lower than that in WT mice., Conclusion: VEGFR1-TK signaling plays a critical role in UC healing and angiogenesis via accumulation of VEGFR1 + CXCR4 + Foxp3 + Tregs in ulcerated tissue. (264 words)., (Copyright © 2018. Published by Elsevier Masson SAS.)

Leukotriene B4 (LTB4) is a lipid mediator that acts as a potent chemoattractant for inflammatory leukocytes. Kidney fibrosis is caused by migrating inflammatory cells and kidney-resident cells. Here, we examined the role of the high-affinity LTB4 receptor BLT1 during development of kidney fibrosis induced by unilateral ureteral obstruction (UUO) in wild-type (WT) mice and BLT1 knockout (BLT1-/-) mice. We found elevated expression of 5-lipoxygenase (5-LOX), which generates LTB4, in the renal tubules of UUO kidneys from WT mice and BLT1-/- mice. Accumulation of immunoreactive type I collagen in WT UUO kidneys increased over time; however, the increase was less prominent in BLT1-/- UUO kidneys. Accumulation of S100A4-positive fibroblasts increased temporally in WT UUO kidneys, but was again less pronounced in-BLT1-/- UUO kidneys. The same was true of mRNA encoding transforming growth factor-β (TGF)-β and fibroblast growth factor (FGF)-2. Finally, accumulation of F4/80-positive macrophages, which secrete TGF-β, increased temporally in WT UUO and BLT1-/- UUO kidneys, but to a lesser extent in the latter. Following LTB4 stimulation in vitro, macrophages showed increased expression of mRNA encoding TGF-β/FGF-2 and Col1a1, whereas L929 fibroblasts showed increased expression of mRNA encoding α smooth muscle actin (SMA). Bone marrow (BM) transplantation studies revealed that the area positive for type I collagen was significantly smaller in BLT1-/-BM→WT than in WT-BM→WT. Thus, LTB4-BLT1 signaling plays a critical role in fibrosis in UUO kidneys by increasing accumulation of macrophages and fibroblasts. Therefore, blocking BLT1 may prevent renal fibrosis., Competing Interests: The authors have declared that no competing interests exist.

Migraine is a severe neurological disorder in which calcitonin gene-related peptide (CGRP) is a key molecule in pathophysiology. Neuronal system-derived CGRP enhances neovascularization in several important pathological conditions and sends a cue to the vascular system. In 2018, the FDA approved erenumab and fremanezumab, antibodies against CGRP receptor and CGRP, as the first new class of drugs for migraine. Treatment of migraine with these antibodies requires great care because neovascularization-related adverse effects may be induced in some patients. Here, we focus on enhancement of neovascularization by CGRP and discuss possible adverse effects resulting from blocking neovascularization. We also suggest that CGRP antibodies may also be used as novel antitumor agents by suppressing tumor-associated angiogenesis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Y-doped BaZrO 3 (BZY) is currently the most promising proton-conductive ceramic-type electrolyte for application in electrochemical devices, including fuel cells and electrolyzer cells. However, owing to its refractory nature, sintering additives, such as NiO, CuO, or ZnO are commonly added to reduce its high sintering temperature from 1600 °C to approximately 1400 °C. Even without deliberately adding a sintering additive, the NiO anode substrate provides another source of the sintering additive; during the co-sintering process, NiO diffuses from the anode into the BZY electrolyte layer. In this work, a systematic study of the effect of NiO, CuO, and ZnO on the electroconductive properties of BaZr 0.8 Y 0.2 O 3-δ (BZY20) is conducted. The results revealed that the addition of NiO, CuO, or ZnO into BZY20 not only degraded the electrical conductivity but also resulted in enhancement of the hole conduction. Removal of these sintering additives can be realized by post-annealing in hydrogen at a mild temperature of 700 °C, but it is kinetically very slow. Therefore, the addition of NiO, CuO, and ZnO is detrimental to the electroconductive properties of BZY20, and significantly restrict its application as an electrolyte. The development of new sintering additives, new anode catalysts, or new methods for preparing BZY electrolyte-based cells is urgently needed., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: To compare a fat-suppressed T2-weighted periodically rotated overlapping parallel lines with enhanced reconstruction (T2W-PROPELLER) sequence with a fat-suppressed T2-weighted fast spin-echo (T2W-FSE) sequence in the oral and maxillofacial regions for the evaluation of the presence of motion artifacts caused by mandibular movements., Methods: Fifty-six healthy adult volunteers were examined in a closed mouth position and then with three different rhythmical mandibular movements throughout MR scanning: open-close movement (movement 1), lateral movement (movement 2) and open-close and lateral movement (movement 3). All subjects were scanned first with fat-suppressed T2W-FSE and then with fat-suppressed T2W-PROPELLER while performing the same movements. Motion artifacts, including ghosting or pulsation artifacts, streak artifacts, susceptibility artifacts and the overall image quality were independently evaluated by two oral and maxillofacial radiologists using a five-point scale. The score graded by the two observers was averaged., Results: The inter-observer agreement was almost perfect for all evaluated items (κ ≥ 0.81). The T2W-PROPELLER images showed significantly fewer ghosting artifacts than T2W-FSE images in subjects performing the mandibular movements throughout MR scanning (P < .001). T2W-PROPELLER images also showed significantly fewer pulsation artifacts than T2W-FSE images, regardless of the performance of a movement, throughout MR scanning (P < .001). Finally, the T2W-PROPELLER images showed a significantly better overall image quality than T2W-FSE images in subjects performing movements 2 or 3 throughout MR scanning (P < .001)., Conclusion: The PROPELLER technique was found to be effective in reducing the motion artifacts caused by mandibular movements on fat-suppressed T2W MR images in the oral and maxillofacial regions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The significance of the relationship between the nervous and immune systems with respect to disease course is increasingly apparent. Immune cells in the liver and spleen are responsible for the development of acute liver injury, yet the regulatory mechanisms of the interactions remain elusive. Calcitonin gene-related peptide (CGRP), which is released from the sensory nervous system, regulates innate immune activation via receptor activity-modifying protein 1 (RAMP1), a subunit of the CGRP receptor. Here, we show that RAMP1 in Kupffer cells (KCs) plays a critical role in the etiology of immune-mediated hepatitis. RAMP1-deficient mice with concanavalin A (ConA)-mediated hepatitis, characterized by severe liver injury accompanied by infiltration of immune cells and increased secretion of pro-inflammatory cytokines by KCs and splenic T cells, showed poor survival. Removing KCs ameliorated liver damage, while depleting T cells or splenectomy led to partial amelioration. Adoptive transfer of splenic T cells from RAMP1-deficient mice led to a modest increase in liver injury. Co-culture of KCs with splenic T cells led to increased cytokine expression by both cells in a RAMP1-dependent manner. Thus, immune-mediated hepatitis develops via crosstalk between immune cells. RAMP1 in KCs is a key regulator of immune responses., Competing Interests: The authors have declared that no competing interests exist.

Background & Aims: Liver repair following hepatic ischemia/reperfusion (I/R) injury is crucial to survival. This study aims to examine the role of endogenous prostaglandin E 2 (PGE 2 ) produced by inducible microsomal PGE synthase-1 (mPGES-1), a terminal enzyme of PGE 2 generation, in liver injury and repair following hepatic I/R., Methods: mPGES-1 deficient (Ptges -/- ) mice or their wild-type (WT) counterparts were subjected to partial hepatic ischemia followed by reperfusion. The role of E prostanoid receptor 4 (EP4) was then studied using a genetic knockout model and a selective antagonist., Results: Compared with WT mice, Ptges -/- mice exhibited reductions in alanine aminotransferase (ALT), necrotic area, neutrophil infiltration, chemokines, and proinflammatory cytokine levels. Ptges -/- mice also showed promoted liver repair and increased Ly6C low macrophages (Ly6C low /CD11b high /F4/80 high -cells) with expression of anti-inflammatory and reparative genes, while WT mice exhibited delayed liver repair and increased Ly6C high macrophages (Ly6C high /CD11b high /F4/80 low -cells) with expression of proinflammatory genes. Bone marrow (BM)-derived mPGES-1-deficient macrophages facilitated liver repair with increases in Ly6C low macrophages. In vitro, mPGES-1 was expressed in macrophages polarized toward the proinflammatory profile. Mice treated with the mPGES-1 inhibitor Compound III displayed increased liver protection and repair. Hepatic I/R enhanced the hepatic expression of PGE receptor subtype, EP4, in WT mice, which was reduced in Ptges -/- mice. A selective EP4 antagonist and genetic deletion of Ptger4, which codes for EP4, accelerated liver repair. The proinflammatory gene expression was upregulated by stimulation of EP4 agonist in WT macrophages but not in EP4-deficient macrophages., Conclusions: These results indicate that mPGES-1 regulates macrophage polarization as well as liver protection and repair through EP4 signaling during hepatic I/R. Inhibition of mPGES-1 could have therapeutic potential by promoting liver repair after acute liver injury., Lay Summary: Hepatic ischemia/reperfusion injury is a serious complication that occurs in liver surgery. Herein, we demonstrated that inducible prostaglandin E 2 synthase (mPGES-1), an enzyme involved in synthesizing prostaglandin E 2 , worsens the injury and delays liver repair through accumulation of proinflammatory macrophages. Inhibition of mPGES-1 offers a potential therapy for both liver protection and repair in hepatic ischemia/reperfusion injury., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Vascular endothelial growth factor (VEGF)-A facilitates wound healing. VEGF-A binds to VEGF receptor 1 (VEGFR1) and VEGFR2 and induces wound healing through the receptor's tyrosine kinase (TK) domain. During blood flow recovery and lung regeneration, expression of VEGFR1 is elevated. However, the precise mechanism of wound healing, especially granulation formation on VEGFR1, is not well understood. We hypothesized that VEGFR1-TK signaling induces wound healing by promoting granulation tissue formation. A surgical sponge implantation model was made by implanting a sponge disk into dorsal subcutaneous tissue of mice. Granulation formation was estimated from the weight of the sponge and the granulation area from the immunohistochemical analysis of collagen I. The expression of fibroblast markers was estimated from the expression of transforming growth factor-beta (TGF-β) and cellular fibroblast growth factor-2 (FGF-2) using real-time PCR (polymerase chain reaction) and from the immunohistochemical analysis of S100A4. VEGFR1 TK knockout (TK -/- ) mice exhibited suppressed granulation tissue formation compared to that in wild-type (WT) mice. Expression of FGF-2, TGF-β, and VEGF-A was significantly suppressed in VEGFR1 TK -/- mice, and the accumulation of VEGFR1 + cells in granulation tissue was reduced in VEGFR1 TK -/- mice compared to that in WT mice. The numbers of VEGFR1 + cells and S100A4 + cells derived from bone marrow (BM) were higher in WT mice transplanted with green fluorescent protein (GFP) transgenic WT BM than in VEGFR1 TK -/- mice transplanted with GFP transgenic VEGFR1 TK -/- BM. These results indicated that VEGFR1-TK signaling induced the accumulation of BM-derived VEGFR1 + cells expressing F4/80 and S100A4 and contributed to granulation formation around the surgically implanted sponge area in a mouse model.

Background: Secondary lymphedema commonly arises as a complication of cancer surgery and radiation treatment; however, the underlying mechanisms are poorly understood. Receptor activity-modifying protein 1 (RAMP1) forms a complex with calcitonin receptor-like receptor to generate the receptor for calcitonin gene-related peptide. The present study examined whether RAMP1 plays a role in increased lymphangiogenesis during secondary lymphedema., Methods: A model of lymphedema was generated by surgical removal of pre-existing lymphatic vessels from the subcutaneous tissue on the tails of RAMP1-deficient (RAMP1-/-) mice and their wild-type (WT) counterparts. The maximum diameter of the tail, lymphangiogenesis, and macrophage recruitment were then examined., Results: Compared with that in WT mice, lymphedema in the tails in RAMP1-/- mice was sustained, with suppressed lymphangiogenesis and reduced expression of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 at the distal edge of the lesions. The newly formed lymphatic vessels in RAMP1-/- mice were dilated, with impaired lymphatic flow. RAMP1 was expressed by macrophages recruited into edematous tail tissues distal to the wound. The number of macrophages in RAMP1-/- mice was higher than that in WT mice. Expression of messenger RNA encoding M1 macrophage-related genes, including tumor necrosis factor-α and interleukin-1, was higher in RAMP1-/- mice than in WT mice, whereas expression of messenger RNA encoding M2 macrophage genes, including interleukin-10, was lower., Conclusions: RAMP1 signaling improves lymphedema and accelerates lymphangiogenesis associated with reduced recruitment of pro-inflammatory macrophages., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Liver metastases from colorectal cancer (CRC) are a clinically significant problem. The renin-angiotensin system is involved in tumor growth and metastases. This study was designed to evaluate the role of angiotensin II subtype receptor 1a (AT1a) in the formation of liver metastasis in CRC. A model of liver metastasis was developed by intrasplenic injection of mouse colon cancer (CMT-93) into AT1a knockout mice (AT1aKO) and wild-type (C57BL/6) mice (WT). Compared with WT mice, the liver weight and liver metastatic rate were significantly lower in AT1aKO. The mRNA levels of CD31, transforming growth factor- β1 (TGF-β1), and F4/80 were suppressed in AT1aKO compared with WT. Double immunofluorescence analysis showed that the number of accumulated F4/80 + cells expressing TGF-β1 in metastatic areas was higher in WT than in AT1aKO. The AT1aKO bone marrow (BM) (AT1aKO-BM)→WT showed suppressed formation of liver metastasis compared with WT-BM→WT. However, the formation of metastasis was further suppressed in WT-BM→AT1aKO compared with AT1aKO-BM→WT. In addition, accumulated F4/80 + cells in the liver metastasis were not BM-derived F4/80 + cells, but mainly resident hepatic F4/80 + cells, and these resident hepatic F4/80 + cells were positive for TGF-β1. Angiotensin II enhanced TGF-β1 expression in Kupffer cells. Treatment of WT with clodronate liposomes suppressed liver metastasis by diminishing TGF-β1 + F4/80 + cells accumulation. The formation of liver metastasis correlated with collagen deposition in the metastatic area, which was dependent on AT1a signaling. These results suggested that resident hepatic macrophages induced liver metastasis formation by induction of TGF-β1 through AT1a signaling., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background and Aims: Calcitonin gene-related peptide (CGRP) is thought to be involved in the modulation of intestinal motility. CGRP receptor is composed of receptor activity-modifying protein (RAMP) 1 combined with calcitonin receptor-like receptor (CRLR) for CGRP. The study investigated the role of CGRP in mice with experimentally induced colitis., Methods: The study used dextran sodium sulfate (DSS) to induce colitis in mice. The study compared the severity of colitis in wild-type (WT) mice, mice treated with a CGRP receptor antagonist (CGRP 8-37 ), and RAMP1 knockout ( -/- ) mice. Pathological changes in the mucosa were assessed, and inflammatory cells and cytokine levels were measured., Results: The severity of inflammation in DSS-induced colitis increased markedly in CGRP 8-37 -treated mice and RAMP1 -/- mice compared with WT mice. RAMP1 -/- mice showed more severe damage compared with CGRP 8-37 -treated mice. The number of periodic acid-Schiff-positive cells decreased in CGRP 8-37 -treated mice compared with WT mice and was even further decreased in RAMP1 -/- mice. RAMP1 was expressed by macrophages, mast cells, and T-cells. RAMP1 -/- mice exhibited excessive accumulation of macrophages and mast cells into the colonic tissue with increased levels of tumor necrosis factor-α and interleukin-1β as compared with WT mice. Infiltration of T-cells into the colonic mucosa, which was associated with the expression of T helper (Th) cytokines including Th1 (interferon gamma) and Th17 (IL-17), was augmented in RAMP1 -/- mice., Conclusions: The findings of this study suggest that RAMP1 exerted mucosal protection in DSS-induced colitis via attenuation of recruitment of inflammatory cells and of pro-inflammatory cytokines., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The vascular endothelial growth factor (VEGF) family has a key role in the formation of blood vessels and lymphatics. Among the members of this family, VEGF-C is one of the most important factors involved in lymphangiogenesis via binding with two receptors (vascular endothelial growth factor receptor-2 and -3: VEGFR-2 and VEGFR-3). Soluble VEGFR-2 (sVEGFR-2) has a role in maintaining the alymphatic state of the cornea associated with binding to VEGF-C, and selectively inhibits lymphangiogenesis but not angiogenesis. In this study, we introduced sVEGFR-2 into lung cancer cells and evaluated the influence on tumor progression and on genes regulating lymphatic formation and metastasis in vivo. A retroviral vector was used to introduce the sVEGFR-2 gene into Lewis lung carcinoma cells (LLC), which were designated as LLC-sVEGFR-2 cells. Proteins secreted into the culture supernatant by these cells were detected by western blotting using specific antibodies. To examine lymphangiogenesis by primary lung cancer in vivo, LLC-sVEGFR-2 cells were subcutaneously injected into C57BL/6 mice. At 14days after injection, immunohistochemistry was performed using an antibody directed against lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), a marker of lymphatics. Expression of mRNA for VEGFR-2, VEGFR-3 and matrix metalloproteinases (MMPs) was also determined by real-time PCR. Furthermore, LLC-sVEGFR-2 cells were directly inoculated into the left lung in C57BL/6 mice and the number of micro-metastases in pulmonary lymph nodes was determined. Introduction of sVEGFR-2 into LLC cells resulted in secretion of sVEGFR-2 protein into the culture supernatant. There were fewer LYVE-1 positive lymphatics after inoculation of LLC-sVEGFR-2 into mice compared with the control group. In addition, VEGFR-2, VEGFR-3, and MMPs gene expression was suppressed in the primary tumors of the LLC-sVEGFR-2 group compared with the control group. Furthermore, there were fewer micro-metastases in the pulmonary lymph nodes of the LLC-sVEGFR-2 group compared with the control group after cells were directly inoculated into the lung. These findings indicate that introduction of sVEGFR-2 suppressed lymphangiogenesis in primary lung cancer and also suppressed lymphogenic metastasis by inhibiting VEGF-C, followed by down-regulation of VEGFR-2, VEGFR-3 and MMPs. Accordingly, sVEGFR-2 might be a promising target for treatment of cancer by regulating lymphangiogenesis and lymphogenic metastasis., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)