Recurrent left ventricular thrombus due to essential thrombocythemia complicated by COVID-19.

Essential thrombocythemia is a risk factor for thrombosis and hemorrhage. During the perioperative period of cardiac surgery, the risk of thrombosis and hemorrhage increases. Coronavirus disease 2019 (COVID-19) is also associated with thrombosis. We present the case of a 69-year-old man with essential thrombocythemia complicated by COVID-19 who developed a left ventricular thrombus. We performed thrombectomy, but the patient developed recurrent left ventricular thrombus 8 days after surgery. Emergency redo thrombectomy was performed followed by aggressive blood-thinning therapy. The postoperative course was complicated by cardiac tamponade requiring surgical drainage 8 days after the second surgery. The patient was discharged home 25 days after the second operation without any complications. Learning objective: Left ventricular thrombus is a rare but fatal complication associated with essential thrombocythemia. COVID-19 has also been reported to cause coagulopathy. This case suggested that after surgery for left ventricular thrombus complicated by multiple risk factors including essential thrombocythemia and COVID-19, aggressive blood-thinning therapy with combination of anticoagulation, antiplatelet, and metabolic antagonist may help prevent recurrent thrombosis.

Initial thickness of the crescent may not be a reliable predictor of complications in type A intramural haematoma.

OBJECTIVES: This study aimed to investigate changes in haematoma thickness during the early period and their association with disease progression in patients who received initial medical treatment for type A intramural haematoma (IMH). METHODS: Medical records and serial computed tomography angiography (CTA) images of patients who did not undergo emergency aortic repair for type A IMH upon presentation were retrospectively reviewed. The haematoma remodelling rate was determined using the following equation: thickness of the haematoma on the first CTA (mm) - thickness of the haematoma on the second CTA (mm)time between the first and second CTAs (h). RESULTS: Among the 40 patients included in this study, 38 were indicated for initial watch-and-wait strategy, whereas 2 were indicated for emergency aortic repair but declined it. During hospitalization, 10 patients developed disease progression, with 2 in-hospital mortality cases. Analysis of the haematoma remodelling rate in 39 patients revealed that such a rate was significantly associated with the reciprocal of the time from onset. Analysis of all 70 CTA examinations performed within 24 h after the onset of IMH showed that haematoma thickness was significantly associated with the logarithm of the time from onset. Initial regression of the haematoma was not necessarily associated with avoidance of disease progression. CONCLUSIONS: In type A IMH, the thickness of the haematoma in the ascending aorta tended to decrease in the very early period; however, prompt regression of the haematoma was not necessarily associated with avoidance of disease progression.

Watch-and-wait strategy for selected patients with type A intramural hematoma.

OBJECTIVE: This single-center retrospective study evaluated early and midterm outcomes of 100 consecutive patients with type A intramural hematoma. METHODS: Initial watch-and-wait strategy was indicated if the maximum aortic diameter was < 50 mm, pain score was < 3/10 on the numerical rating scale, and no ulcer-like projection was observed in the ascending aorta. The primary endpoints of this study were all-cause and aorta-related deaths, and the secondary endpoint was aortic events. RESULTS: Initial watch-and-wait strategy was indicated in 52 patients. Emergency aortic repair was indicated in the remaining 48 patients; 2, 31, and 15 patients died before surgery, underwent emergency surgery, and declined emergency surgery, respectively. Among the watch-and-wait group, 11 (21%) patients underwent aortic repair during hospitalization. In-hospital mortality rates, 5-year survival rates, and 5-year freedom from aorta-related death were not significantly different between the initial watch-and-wait strategy and emergency surgery (2% vs. 6%, 92% vs. 82%, and 100% vs. 94%, respectively). In the initial watch-and-wait strategy group, 5-year freedom from aortic events and freedom from aortic events involving the ascending aorta were 60% and 66%, respectively. CONCLUSIONS: The early and midterm outcomes with the initial watch-and-wait strategy in patients with type A intramural hematoma with a maximum aortic diameter of ≤ 50 mm, pain score of ≤ 3/10, and no ulcer-like projection in the ascending aorta were favorable with no aorta-related death.

Thromboxane prostanoid signaling in macrophages attenuates lymphedema and facilitates lymphangiogenesis in mice : TP signaling and lymphangiogenesis.

BACKGROUND: Accumulating evidence suggests that prostaglandin E2, an arachidonic acid (AA) metabolite, enhances lymphangiogenesis in response to inflammation. However, thromboxane A2 (TXA2), 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.

Hybrid surgery for blunt aortic injury with rupture: a case report.

BACKGROUND: Blunt thoracic aortic injury is one of the most lethal traumatic injuries. Ruptured cases often result in cardiac arrest before arrival at the hospital, and survival is rare. CASE PRESENTATION: A female patient in her 30 s was struck by an automobile while she was walking across an intersection. She was in a state of shock when emergency services arrived and was in cardiac arrest shortly after arriving at the hospital. A left anterolateral thoracotomy revealed a massive hemothorax secondary to thoracic aortic rupture. In addition, the patient had multiple traumas, including maxillary, pelvic, and lumbar burst fractures. We attempted to directly suture the aortic lesion; however, the increasing blood pressure caused the suture to break. We used a thoracic stent graft while ensuring permissive hypotension. Her postoperative prognosis was positive, and she was transferred to another hospital 85 days later. CONCLUSIONS: We successfully performed a hybrid surgery combining thoracotomy and endovascular repair for this emergency case of blunt thoracic aortic injury with rupture.

Acute Kidney Injury after High-Flow Regional Cerebral Perfusion in Neonatal and Infant Aortic Arch Repair.

OBJECTIVES: We applied high-flow regional cerebral perfusion (HFRCP) for aortic arch reconstruction in neonates and infants by monitoring regional oxygen saturation of the thigh (rSO2T) using near-infrared spectroscopy to maintain peripheral perfusion. This study was designed to investigate the optimal perfusion flow of HFRCP for renal protection. METHODS: From 2009 to 2021, 28 consecutive neonates and infants who underwent aortic arch reconstruction with HFRCP were enrolled. The median age of the patients was 27 days; the median body weight was 3.0 kg. In HFRCP, perfusion flow was targeted at approximately 80-100 mL/kg/min and then lowered corresponding to brain rSO2 levels and blood gas data. Isosorbide dinitrate and chlorpromazine were administered to enhance peripheral perfusion flow. Regional oxygen saturation of the forehead and thighs were monitored. The stage of acute kidney injury (AKI) was classified based on the Kidney Disease Improving Global Outcomes criteria. RESULTS: No patients had neurological events and peritoneal dialysis after surgery. The incidence of AKI was 39.3% with only three patients having greater than stage 2 AKI. The maximum postoperative serum creatinine concentration was negatively associated with the lowest rSO2T during HFRCP. The rSO2T during HFRCP was a predictive factor for postoperative creatinine increase of ≧0.3 mg/dL. The area under receiver operating characteristic curve was 0.78 with the cutoff value of 48% for rSO2T. CONCLUSIONS: The rSO2T during HFRCP is a potential predictor of postoperative renal function. To prevent AKI, the rSO2T should be preserved more than 48% by increasing HFRCP flow.

Outcomes after Rivaroxaban Treatment of Extensive Deep Vein Thrombosis.

BACKGROUND: Regression of thrombus in response to treatment with direct oral anticoagulants (DOACs) in patients with extensive deep vein thrombosis (DVT) has not been fully evaluated. This study aimed to determine the therapeutic efficacy of rivaroxaban in the treatment of extensive DVT. METHODS: We retrospectively evaluated 76 patients treated with rivaroxaban among 728 new DVT patients, at our hospital from January 2018 to March 2021. Extensive DVT was defined as thrombus connecting to 2 or more segments of the inferior vena cava (IVC), iliac vein, femoral vein, or popliteal vein. Localized DVT was defined as a thrombus confined to 1 segment of the inferior vena cava (IVC), iliac vein, femoral vein, or popliteal vein. We compared the changes in thrombus between the extensive DVT group (36 patients) and the localized DVT group (40 patients). RESULTS: In the localized DVT group, 14 (37%) had total recanalization within 3 weeks after DOAC initiation, and 30 (79%) had total recanalization within 3 months. In the extensive DVT group, only 3 (9%) had total recanalization within 3 weeks after starting DOAC, and even after 3 months, only 5 (15%) had total recanalization. Symptoms (P = 0.01) and extensive DVT (P < 0.01) were significantly associated with the risk for failure of total recanalization. CONCLUSIONS: Rivaroxaban was highly effective for total recanalization of localized DVT but not for symptomatic or extensive DVT. In patients with symptomatic extensive DVT, catheter-based thrombolysis may be considered in selected cases.

Gluteal Blood Flow Monitoring in Endovascular Aneurysm Repair With Internal Iliac Artery Embolization.

BACKGROUND: When an internal iliac artery (IIA) has to be embolized during endovascular aneurysm repair (EVAR), buttock claudication sometimes poses problems. However, there is no established method to evaluate intraoperative blood flow to the gluteal muscles.Methods and Results:Gluteal regional oxygen saturation (rSO2) was monitored using near-infrared spectroscopy (NIRS) during surgery, and changes in rSO2were compared with treatment results. Twenty-seven patients who underwent EVAR and IIA embolization at our institution between April 2019 and May 2020 were included in this study. The association between intraoperative changes in rSO2and postoperative incidence of buttock claudication was analyzed. Furthermore, the presence or absence of communication between the superior and inferior gluteal arteries and the intraoperative changes in rSO2were compared to ascertain whether rSO2reflects blood flow change. Postoperative buttock claudication occurred in 4 of 19 patients (21%) with unilateral occlusion of IIA and in 4 of 8 patients (50%) with bilateral occlusion of IIAs. rSO2was found to decrease significantly further in patients with buttock claudication than in patients without buttock claudication (-15±12% vs. -4±16%, P<0.05). In addition, rSO2was predominantly lower in patients without the communication between the superior and inferior gluteal arteries than in those with the communication. CONCLUSIONS: Gluteal rSO2is useful as an indicator of intraoperative gluteal blood flow.

Risk Factors for Progression of Distal Deep Vein Thrombosis.

BACKGROUND: There is insufficient evidence regarding the optimal treatment method for distal deep vein thrombosis (DVT), including indications for anticoagulation therapy. Treatment results of patients with distal DVT were evaluated to clarify the risk factors that result in extension of distal DVT to the proximal vein and indications for anticoagulation therapy.Methods and Results:Among 430 patients with DVT between January 2018 and December 2019, 253 were diagnosed with distal DVT; 41 patients who had already started anticoagulation therapy were excluded, and the remaining 212 were included as study subjects. Anticoagulation therapy was not started immediately; conservative treatment with compression stockings was performed. Ultrasonography after 2 weeks revealed thrombus disappearance in 39 patients (21%), and thrombus reduction in 38 patients (20%). In contrast, extension of thrombus to the proximal vein was noted in 12 patients (6.3%) and anticoagulation therapy was commenced. After 3 months, the thrombus had disappeared in 75 patients (52%). No patient developed pulmonary thromboembolism during follow-up. With respect to the risk factors for extension to proximal vein during conservative treatment, active cancer (P=0.03), prolonged bed rest (P<0.01), and D-dimer level >8µg/mL (P=0.01) were identified. CONCLUSIONS: It is reasonable to consider anticoagulation therapy in distal DVT patients with active cancer, prolonged bed rest or high D-dimer level.

Regional thigh tissue oxygen saturation during cardiopulmonary bypass predicts acute kidney injury after cardiac surgery.

Cardiopulmonary bypass-associated acute kidney injury may appear postoperatively, but predictive factors are unclear. We investigated the potential of regional tissue oxygen saturation as a predictor of cardiopulmonary bypass-associated acute kidney injury. We analyzed the clinical data of 150 adult patients not on dialysis who underwent elective cardiac surgical procedures during January 2015-March 2017. Near-infrared spectroscopy was used to measure regional oxygen saturation. Sensors were placed on the patients' forehead, abdomen, and thigh. The incidence of acute kidney injury was 2% at the end of surgery, 13% at 24 h, and 9% at 48 h, with the highest at 24 h after surgery. The multiple regression analysis revealed that the thigh regional oximetry during cardiopulmonary bypass, oxygen delivery index, and neutrophil count at the end of cardiopulmonary bypass and surgery were independent risk factors for acute kidney injury. The receiver-operating characteristic curve analysis suggested that a cutoff of regional oxygen saturation at the thigh of ≤ 67% was predictive of acute kidney injury within 24 h after surgery. In conclusion, the regional oxygen saturation at the thigh during cardiopulmonary bypass is a crucial marker to predict postoperative acute kidney injury in adults undergoing cardiac surgery.

Watch-and-wait strategy for type A intramural haematoma and acute aortic dissection with thrombosed false lumen of the ascending aorta: a Japanese single-centre experience.

OBJECTIVES: In this study, we investigated the early and midterm outcomes of initial watch-and-wait strategy for Stanford type A intramural haematoma and acute aortic dissection with thrombosed false lumen of the ascending aorta in patients with a maximum aortic diameter of ≤50 mm, pain score of ≤3/10 and no ulcer-like projection in the ascending aorta. METHODS: Inpatient and outpatient records were retrospectively reviewed. RESULTS: Of the 81 patients with type A intramural haematoma and acute aortic dissection with the thrombosed false lumen of the ascending aorta between April 2011 and April 2019, a watch-and-wait strategy was selected in 46 patients. The mean age of the patients was 68 years, and 22 (48%) patients were female. Ten patients underwent emergency pericardial drainage for cardiac tamponade at the time of presentation and 8 patients underwent aortic repair during hospitalization for new ulcer-like projection, re-dissection or rupture. In-hospital mortality occurred in 2 (4%) patients. During follow-up, survival at 1 and 2 years was 95% and 92%, respectively. There was no significant difference in survival or aortic events between patients in whom the watch-and-wait strategy and emergency surgical treatment were indicated. CONCLUSIONS: The early and midterm outcomes of the initial watch-and-wait strategy were favourable for type A intramural haematoma and acute aortic dissection with the thrombosed false lumen of the ascending aorta in Japanese patients with a maximum aortic diameter of ≤50 mm, pain score of ≤3/10 and no ulcer-like projection. Further study is required to show the safety of this strategy.

RAMP1 signaling in immune cells regulates inflammation-associated lymphangiogenesis.

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.

[Omental Flap for the Device Infection of the HeartMate II].

Case 1:An 18-year-old male underwent emergent left extracorporeal ventricular assist device(eVAD) implantation for a cardiogenic shock because of dilated cardiomyopathy (DCM). After listing for heart transplant, he underwent a HeartMate II implantation as bridge-to-bridge(BTB) therapy. The omental flap was simultaneously used to prevent device infection that could have been induced by the infected malgranulation around the cannulas of the eVAD. Eventually, he was discharged and waiting for transplantation. Case 2:A 30-year-old male with DCM underwent emergent eVAD implantation for left ventricular support, centrifugal veno-pulmonary artery extracorporeal membrane oxygenation (ECMO) for right ventricular and respiratory support, and mitral valve replacement. After weaning of ECMO, he was listed for a heart transplant and underwent a HeartMate II implantation as BTB therapy. However, liver dysfunction and malnutrition prolonged wound healing. Despite applying vacuum assist closure device to promote wound healing, part of the driveline and pump housing were exposed. Therefore, radical debridement and omentopexy were performed for infection control. He was discharged after complete wound healing.

Improved hemodynamics following endovascular treatment for acquired aortic coarctation: A case report.

A 38-year-old man underwent surgical repair of a type A aortic dissection. After aortic surgery, his left ventricular ejection fraction was progressively reduced from 65% to 15%, causing a refractory low cardiac output depending on the intravenous inotropes. There was a luminal stenosis of the descending aorta due to enlarged pseudolumen. The peak-to-peak pressure gradient at the stenosis was 25 mmHg, which was thought to contribute to the systolic dysfunction. He underwent thoracic endovascular aortic repair (TEVAR) with the use of a bare self-expanding stent. After TEVAR, the peak-to-peak pressure gradient was decreased to 9 mmHg, resulting in hemodynamic improvement. .

Correction to: Cerebral oximetry for cardiac surgery: a preoperative comparison of device characteristics and pitfalls in interpretation.

In the original publication, the length unit of the SCD in Table 1 and Fig. 2 has been incorrectly published as cm. The correct length unit is mm.

Cerebral oximetry for cardiac surgery: a preoperative comparison of device characteristics and pitfalls in interpretation.

Regional cerebral oximetry using near-infrared spectroscopy devices is commonly used for detecting cerebral ischemia during cardiopulmonary bypass, and aim to avoid poor cerebral perfusion which may result in perioperative neurological impairment. Today, several devices that can detect cerebral ischemia are commercially available. Although these devices operate on the same measurement principles, their algorithms for detecting and calculating cerebral ischemia are different and no criteria for directly comparing values measured by such different devices exist. From January 2017 to August 2017, 80 adult cardiovascular surgery patients were enrolled in the prospective study. In each patient, preoperative regional cerebral oxygen saturation values were measured by two different devices and their correlations with various preoperative factors were evaluated. Regional cerebral oxygen saturation levels were significantly higher for values of FORE-SIGHT ELITE (CAS Medical Systems, Branford, CT, USA) (F value) than those of the INVOS 5100C (Medtronic, Minneapolis, MN, USA) (I value). Scalp-cortex distance, hemoglobin concentration, and the presence or absence of hemodialysis showed significant correlations with ratios of measured values specific to each device (F/I). An appropriate device should be selected according to preoperative patient characteristics, and factors influencing regional cerebral oxygen saturation values should be considered to ensure the correct interpretation of measured values. This research was conducted with the approval of the ethics committee of our university (approval number: B16-96).

RAMP1 signaling improves lymphedema and promotes lymphangiogenesis in mice.

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.

Factors associated with a low initial cerebral oxygen saturation value in patients undergoing cardiac surgery.

Regional cerebral oximetry using near-infrared spectroscopy device, an INVOS 5100 C (Medtronic, Minneapolis, MN, USA), during cardiac surgery aims to avoid perioperative neurological impairment, especially during cardiopulmonary bypass. However, it is not uncommon to encounter critically low initial cerebral regional oxygen saturation or a low value unresponsive to intervention. Therefore, it is important to identify factors associated with low saturation value other than true cerebral hypoxia. We investigated the relationship between preoperative regional cerebral oxygen saturation and clinical variables during cardiac surgery. From January 2013 to May 2016, 462 patients underwent elective cardiac surgery. Patient's ≤12 years of age, with acute cerebral infarction, with previous intracranial hemorrhage or neurosurgery, with concomitant aortic surgery, and having off-pump coronary artery bypass surgery were excluded. The remaining 223 patients were monitored by intraoperative regional cerebral oximetry. Univariate analysis found that scalp-cortex distance, cerebrospinal fluid thickness, left ventricular ejection fraction, hemoglobin concentration, estimated glomerular filtration rate, and hemodialysis were significantly correlated with the initial regional oxygen saturation value. Multiple regression analysis revealed that scalp-cortex distance, left ventricular ejection fraction, hemoglobin, and hemodialysis remained as significant variables. A receiver operating characteristic analysis found that for a low initial regional oxygen saturation value of 40%, the thresholds of scalp-cortex distance, left ventricular ejection fraction, and hemoglobin concentration were 17.6 mm, 45.2%, and 7.5 g/dl, respectively. In conclusion, brain atrophy, poor left ventricular function, anemia, and hemodialysis were associated with low initial cerebral regional oxygen saturation values in adult cardiac surgery patients.

Leukotriene B4 type-1 receptor signaling promotes liver repair after hepatic ischemia/reperfusion injury through the enhancement of macrophage recruitment.

Recruited macrophages play a critical role in liver repair after acute liver injury. Leukotriene B4 (LTB4) is a potent chemoattractant for macrophages. In this study, we investigated the role of LTB4 receptor type 1 (BLT1) in liver repair during hepatic ischemia/reperfusion (I/R) injury. BLT1-knockout mice (BLT1(-/-)) or their wild-type counterparts (WT) were subjected to partial hepatic I/R. Compared with WT, BLT1(-/-) exhibited delayed liver repair and hepatocyte proliferation accompanied by a 70% reduction in the recruitment of macrophages and a 70-80% attenuation in hepatic expression of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1). Disruption of BLT1 signaling also reduced the expression of EGF by 67% on recruited macrophages expressing VEGFR1 in the injured liver. Treatment of WT mice with an EGF-neutralizing antibody delayed liver repair and reduced macrophage recruitment, compared with control immunoglobulin G (IgG). BLT1 signaling enhanced the expression of VEGF, VEGFR1, and EGF in isolated peritoneal macrophages in vitro. These results indicate that BLT1 signaling plays a role in liver repair after hepatic I/R through enhanced expression of EGF in recruited macrophages and that the development of a specific agonist for BLT1 could be useful for liver recovery from acute liver injury.

COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems.

Bone marrow (BM)-derived hematopoietic cells, which are major components of tumor stroma, determine the tumor microenvironment and regulate tumor phenotypes. Cyclooxygenase (COX)-2 and endogenous prostaglandins are important determinants for tumor growth and tumor-associated angiogenesis; however, their contributions to stromal formation and angiogenesis remain unclear. In this study, we observed that Lewis lung carcinoma cells implanted in wild-type mice formed a tumor mass with extensive stromal formation that was markedly suppressed by COX-2 inhibition, which reduced the recruitment of BM cells. Notably, COX-2 inhibition attenuated CXCL12/CXCR4 expression as well as expression of several other chemokines. Indeed, in a Matrigel model, prostaglandin (PG) E2 enhanced stromal formation and CXCL12/CXCR4 expression. In addition, a COX-2 inhibitor suppressed stromal formation and reduced expression of CXCL12/CXCR4 and a fibroblast marker (S100A4) in a micropore chamber model. Moreover, stromal formation after tumor implantation was suppressed in EP3-/- mice and EP4-/- mice, in which stromal expression of CXCL12/CXCR4 and S100A4 was reduced. The EP3 or EP4 knockout suppressed S100A4+ fibroblasts, CXCL12+, and/or CXCR4+ stromal cells as well. Immunofluorescent analyses revealed that CXCL12+CXCR4+S100A4+ fibroblasts mainly comprised stromal cells and most of these were recruited from the BM. Additionally, either EP3- or EP4-specific agonists stimulated CXCL12 expression by fibroblasts in vitro. The present results address the novel activities of COX-2/PGE2-EP3/EP4 signaling that modulate tumor biology and show that CXCL12/CXCR4 axis may play a crucial role in tumor stromal formation and angiogenesis under the control of prostaglandins.