Characterizing soluble immune checkpoint molecules and TGF-ß1,2,3 in pleural effusion of malignant pleural mesothelioma.

The clinical impact of soluble molecules in pleural effusion (PE) is unclear in patients with malignant pleural mesothelioma (MPM). In this single-center, retrospective, observational study, we assessed soluble forms of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and PD-1 ligand 1 (PD-L1) using enzyme-linked immunosorbent assays; three TGF-ß isoforms were measured via multiplex assay in PE of patients with fibrinous pleuritis (FP) or MPM, to assess relationships between the levels of six molecules, clinicopathological characteristics, and efficacy of immune checkpoint inhibitors. Soluble forms of CTLA-4, PD-L1, PD-1, TGF-ß1, TGF-ß2, and TGF-ß3 were variably produced in PE of FP (n = 34) and MPM (n = 79); we found significant relationships between the six molecules and clinicopathological features. Although none of the three soluble immune checkpoint molecules showed diagnostic or prognostic effects in patients with MPM, TGF-ß2 level in PE is a useful differential diagnostic marker between FP and MPM. Both TGF-ß1 and TGF-ß3 levels are promising prognostic markers for MPM. Moreover, we found that higher baseline levels of PD-1 soluble forms predicted the response to anti-PD1 monotherapy. Our findings identify novel diagnostic, prognostic, and predictive biomarkers for anti-PD1 therapy in patients with MPM.

Intraoperative chylous leak diagnosis by preoperative oral administration of ice cream: a case report.

Background: Chylothorax is an intractable postoperative complication of thoracic surgery. Preventing postoperative chylothorax following initial surgery is important. Most cases of chylothorax are caused by injury to the thoracic duct or its branches. However, rare cases might result from injury to the lymphatic vessels in the chest wall. Preoperative oral administration of dairy products is widely recognized as a useful method for identifying the sites of chylous leaks during surgery for chylothoraces. Herein, we report a surgical case of a middle mediastinal tumor, wherein a chylous leak in the chest wall was intraoperatively detected due to scheduled preoperative oral administration of dairy products before the initial surgery, resulting in prevented postoperative chylothorax. Case Description: A 68-year-old male patient underwent computed tomography, revealing a cystic lesion in the middle mediastinum that was suspected to be a thoracic duct cyst or intrathoracic lymphangioma. A cup of ice cream was orally ingested 1 hour before entering the operating room to intraoperatively detect chylous leakage in case of injury to the lymphatic vessels, including the thoracic duct. The mediastinal tumor was removed via thoracoscopic surgery and histologically diagnosed as a schwannoma with cystic degeneration. Intraoperatively, chylous leakage was observed due to injury to a lymphatic vessel in the chest wall, which was repaired by clipping. The postoperative course was uneventful. Conclusions: Preoperative oral administration of dairy products was verified to be a useful method not only at the time of re-operation for postoperative chylothoraces but also at the time of initial surgery in cases where chylothorax is of high concern. Although relatively infrequent, chylothorax due to lymphatic vessel injury in the chest wall should be kept in mind.

A case of primary lung adenocarcinoma mimicking metastatic papillary thyroid carcinoma.

A 61-year-old woman, who had a history of total thyroidectomy for follicular variant of papillary thyroid carcinoma (PTC), visited our hospital for assessment of an enlarging nodule which appeared in the lung with multiple metastatic lesions of PTC which had been stable for 17 years. Wedge resection of the lung was performed. Miliary nodules were confirmed to be metastatic PTCs based on their morphological as well as immunohistochemical findings. As for the main nodule, its morphological features suggested a diagnosis of metastatic PTC, while its immunohistochemical findings were identical with primary lung adenocarcinoma. Further genetic analysis provided no definitive information for the diagnosis of the main nodule. The present case shows the need of comprehensive analyses for differentiation between primary lung adenocarcinoma and metastatic PTCs.

Preoperative neutrophil-to-lymphocyte ratio correlates with PD-L1 expression in immune cells of patients with malignant pleural mesothelioma and predicts prognosis.

We assessed the prognostic value of five complex inflammatory and nutritional parameters, namely neutrophil-to-lymphocyte ratio (NLR), prognostic nutritional index (PNI), C-reactive protein-to-NLR ratio (C/NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) using data from patients with malignant pleural mesothelioma (MPM) undergoing extrapleural pneumonectomy (EPP). Moreover, the correlation between these five parameters and programmed cell death protein 1 ligand-1 (PD-L1) expression in the tumor microenvironment was evaluated. This study included consecutive MPM patients who underwent EPP. The histological subtype of the eligible patients (n = 61) correlated with all five parameters. Moreover, the PD-L1 expression scores for immune cells correlated with NLR and PLR, and the PD-L1 expression scores for both tumor cells and immune cells were inversely correlated with both PNI and LMR. Univariate analysis elucidated that NLR, PNI, and C/NLR were predictors of 5-year overall survival (OS), and multivariate analysis revealed that NLR was an independent predictor of 5-year OS, suggesting that NLR is a preoperative, prognostic factor for patients with MPM who are scheduled for EPP. To the best of our knowledge, this is the first study to evaluate the prognostic potentials of NLR, PNI, C/NLR, PLR, and LMR simultaneously in patients with MPM who underwent EPP.

Surgical outcome of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy.

OBJECTIVES: Ipsilateral reoperation after pulmonary lobectomy is often challenging because of adhesions from the previous operation. We retrospectively examined the surgical outcome and prognosis of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy using a multicentre database. METHODS: We evaluated the perioperative outcomes and overall survival of 51 patients who underwent pulmonary lobectomy followed by ipsilateral anatomical resection for lung cancer between January 2012 and December 2018. In addition, patients with stage I non-small-cell lung cancer (NSCLC) were compared with 3411 patients with stage I lung cancer who underwent pulmonary resection without a prior ipsilateral lobectomy. RESULTS: Ipsilateral anatomical resections included 10 completion pneumonectomies, 19 pulmonary lobectomies and 22 pulmonary segmentectomies. Operative time was 312.2 ± 134.5 min, and intraoperative bleeding was 522.2 ± 797.5 ml. Intraoperative and postoperative complications occurred in 9 and 15 patients, respectively. However, the 5-year overall survival rate after anatomical resection followed by ipsilateral lobectomy was 83.5%. Furthermore, in patients with c-stage I NSCLC, anatomical resection followed by ipsilateral lobectomy was not associated with worse survival than anatomical resection without prior ipsilateral lobectomy. CONCLUSIONS: Anatomical resection following ipsilateral lobectomy is associated with a high frequency of intraoperative and postoperative complications. However, the 5-year overall survival in patients with c-stage I NSCLC who underwent ipsilateral anatomical resection after pulmonary lobectomy is comparable to that in patients who underwent anatomical resection without prior pulmonary lobectomy.

Effects of tumor-infiltrating CD8+ T cells, PD1/PD-L1 axis, and expression patterns of HLA class I on the prognosis of patients with malignant pleural mesothelioma who underwent extra-pleural pneumonectomy.

Programmed cell death protein-1 (PD1), PD1 ligand 1 (PD-L1), and human leukocyte antigen (HLA) class I molecule play pivotal roles in T cell-induced anti-tumor immunity; however, the clinical impact of these parameters in resected malignant pleural mesothelioma (MPM) cases is unknown. We immunohistochemically evaluated the tumor infiltrated lymphocytes (TILs), PD1/PD-L1 axis, and expression of HLA class I in resected specimens from 58 patients with MPM who underwent extra-pleural pneumonectomy (EPP). Higher infiltration of CD3-TIL, CD8-TIL, and PD1-TIL, loss of HLA class I, and overexpression of PD-L1 by tumor cells (PD-L1 TC) or immune cells (PD-L1 IC) were observed in 34 (58.6%), 27 (46.6%), 41 (70.7%), 45 (77.6%), 29 (50.0%), and 33 (56.4%) of 58 cases, respectively. Interestingly, the CD3-TIL score positively correlated with PD-L1 TC and PD1-TIL scores. HLA class I expression level was inversely correlated with the expression levels of PD-L1 TC and PD-L1 IC. Multivariate analysis showed that age, histology, and node metastasis were independent prognostic factors for 5-year overall survival (OS) and loss of HLA class I coincided with a positive prognosis (p = 0.011). The concomitant lack of infiltrating CD8+ T cells with no loss of HLA class I predicted worse 5-year OS (p = 0.007). Moreover, cluster classifications among multiple immunoparameters showed that categories among CD3/PD-L1 TC/HLA class I (p = 0.043), CD8/PD1/HLA class I (p = 0.032), CD8/PD-L1 TC/HLA class I (p = 0.011), and PD1/PD-L1 TC/HLA class I (p = 0.032) predicted 5-year OS in EPP cases for MPM. These immunoparameters could guide surgical indications for patients with MPM.

Prognostic values of preoperative C-reactive protein, albumin, and neutrophil ratios in patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy.

INTRODUCTION: A preoperative validation system for predicting the clinical outcome of extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) is required, as EPP for MPM is one of the most invasive operation types. Recently, several inflammatory and nutritional parameters, such as C-reactive protein (CRP) and albumin, have been re-focused on as useful prognostic factors for several types of cancer; however, few of these reports involved MPM. METHODS: As a retrospective study, clinicopathological characteristics and preoperative inflammatory and nutritional parameters were calculated in consecutive patients with MPM who underwent EPP. The prognostic value of the variables was examined using Cox regression, and the candidate preoperative parameters were entered into a multivariate model to determine their independent effects. RESULTS: Of the 61 eligible cases, the CRP/albumin ratio (CAR) was associated with histology, and the CRP index multiplied by the neutrophil ratio (C-NR index) was associated with histology and pathological stage. Patients with CAR >0.125 had a significantly poor survival outcome, and patients with a C-NR index >0.58 also had a significantly poor prognosis. Multivariate analysis showed that age, histology, CRP, albumin, CAR, and C-NR index were independent predictors of 5-year overall survival. CONCLUSION: Our results demonstrated that the CAR and C-NR indices are promising preoperative predictive parameters for the clinical outcomes of EPP in patients with MPM.

Rapid development and rupture of a pneumatocele caused by pulmonary dissection in the early postoperative period of lung resection: a case report.

Air leakage after lung resection is a common complication usually caused by direct injury to the lung parenchyma. Herein we illustrate a case of pneumatocele that developed rapidly in the right middle lobe and ruptured 16 days after right upper lobectomy. A 73-year-old man with chronic obstructive pulmonary disease underwent thoracoscopic right upper lobectomy and partial thymectomy for primary lung cancer and thymic nodules, respectively. Although a small amount of air leakage was observed after the operation, air leakage completely improved on postoperative day (POD) 2, and the chest drain tube was removed on POD 3. The patient's condition was complicated with eosinophilic pneumonia. Steroid therapy was started on POD 13. Dyspnea suddenly developed immediately after defecation on POD 16. Computed tomography (CT) scan showed a large pneumatocele in the right middle lobe, which was not found by CT scan on POD 11. He underwent reoperation on POD 20, and a large thick-walled pneumatocele in the right middle lobe was directly sewn. Histopathologically, the wall of bulla consisted of thickened visceral pleura and thin lung parenchyma, suggesting that this pneumatocele was induced by dissection of subpleural lung parenchyma.

Shareability of antibacterial and osteoblastic-proliferation activities of zinc-doped hydroxyapatite nanoparticles in vitro.

Four types of zinc (Zn)-doped hydroxyapatite (Zn-HAp) nanoparticles were prepared using calcium nitrate tetrahydrate as an anti-sintering agent during calcination at 600°C for 1 hr, to prevent calcination-induced aggregation. The Zn content of the nanopowders was determined at 0, 4.3, 9.2, and 14.7% [Zn/(Ca + Zn) × 100] using inductively coupled plasma atomic emission spectroscopic analysis. Based on X-ray diffraction analysis, the products were shown to possess an apatite structure without other crystalline impurities. The cell parameters of Zn-HAp nanoparticles decreased with increasing of Zn content in the HAp structures. This tendency implies that Zn ions substituted for Ca sites in the HAp crystal lattices. To investigate the biological effects of Zn-HAp nanoparticles, cell proliferation activity of MC3T3-E1 osteoblasts and antibacterial activity against Escherichia coli were evaluated in vitro. According to the results obtained, Zn-HAp nanoparticles containing of 14.7% Zn ions was noticeable shown shareability of the conflicting activities at 0.1 mg/mL.

Fibrin glue-induced eosinophilic pleural effusion after pulmonary resection: A case report.

INTRODUCTION AND IMPORTANCE: Prolonged air leakage after pulmonary resection is a common complication, and fibrin glue is used as a sealant to reduce this. Fibrin glue-induced adverse events are generally rare. Herein, we describe a rare case of fibrin glue-induced eosinophilic pleural effusion (EPE). CASE PRESENTATION: A 77-year-old man underwent partial pulmonary resection for right lower lobe lung cancer, and the pulmonary staple stump was subsequently covered with fibrin glue. Antibacterial drugs were administered for the treatment of postoperative pneumonia. However, re-elevation of the inflammatory cell number was observed, and computed tomography revealed an increase in right pleural effusion. Although thoracoscopy was performed based on a possibility of empyema, no empyema was observed. The eosinophil count in the pleural effusion was 11%; thus, the patient was diagnosed with EPE, which was resolved after thoracic drainage, without corticosteroid administration. Fibrin glue was identified as the causative agent, using a drug-induced lymphocyte stimulation test. CLINICAL DISCUSSION: EPE is defined as an eosinophil count of ≥10% in the pleural effusion. If pleural effusion on the surgical side, with fever or an elevated inflammatory cell number, is observed in the early postoperative period after pulmonary resection, empyema should be considered foremost. In this case, the administration of antibacterial drugs was ineffective, and the patient was eventually diagnosed with EPE. CONCLUSION: EPE should be considered as a rare fibrin glue-induced adverse event after pulmonary resection. It is recommended that the leukocyte fraction be examined, if pleural effusion is collected for postoperative pleural effusion.

Suspected fibrin glue-induced acute eosinophilic pneumonia after pulmonary resection: A case report.

Air leakage is a common complication after pulmonary resection, and fibrin glue is used as a sealant to reduce postoperative air leakage. It is generally recognized that fibrin glue-induced adverse events are rare. Herein, we report a rare case of suspected fibrin glue-induced acute eosinophilic pneumonia (AEP). A 72-year-old man underwent right lower lobectomy and mediastinal lymph node dissection for right lower lung cancer. Fibrin glue was sprayed to cover the interlobar surface of the right upper and middle lobes. On postoperative day 10, computed tomography (CT) revealed ground-glass shadows around the interlobar surface of the remaining lobes of the right lung. Although antibacterial drugs were administered for suspected bacterial pneumonia, fever spike, shortness of breath, and exacerbation of ground-glass shadows were observed. Peripheral blood and bronchoalveolar lavage fluid showed increased eosinophil count, supporting the diagnosis of AEP. Pneumonia resolved after prednisolone administration. At one-year follow-up, CT showed no AEP recurrence. Drug-induced pneumonia usually develops in the bilateral lung and rarely in the hemilateral lung. In this case, pneumonia was localized around the site covered with fibrin glue, suggesting fibrin glue-induced AEP. Thus, the use of fibrin glue should be carefully considered during pulmonary resection.

Tegafur-uracil-induced pericardial effusion during adjuvant chemotherapy for resected lung adenocarcinoma: A case report.

In Japan, oral administration of tegafur-uracil is recommended as postoperative adjuvant chemotherapy for patients diagnosed with primary lung adenocarcinomas of >2 cm size and staged as IA, IB, and IIA. Reports on chemotherapy-induced pericardial effusion are rare. Herein, we report a rare case of tegafur-uracil-induced pericardial effusion during postoperative adjuvant chemotherapy for primary lung cancer. A 60-year-old man underwent left lower lobectomy and mediastinal lymph node dissection for left lower lung adenocarcinoma. Lung cancer was staged as IB, and tegafur-uracil was administered as postoperative adjuvant chemotherapy from 1 month after the surgery. A computed tomography (CT) scan revealed a pericardial effusion 5 months after the surgery. A malignant pericardial effusion was suspected, and tegafur-uracil was discontinued. Pericardiocentesis could not be performed owing to a small amount of pericardial effusion. An 18 F-fluorodeoxyglucose (FDG) positron emission tomography/CT scan revealed no abnormal FDG uptake. During a short follow-up period after discontinuation of tegafur-uracil, a CT scan revealed a decrease in pericardial effusion, suggesting that the pericardial effusion was induced by tegafur-uracil. Follow-up of pericardial effusion is required while administering tegafur-uracil. In cases of pericardial effusion without symptoms and no suspicious metastatic lesions in other organs, we should be concerned about tegafur-uracil-induced pericardial effusion.

Treatment strategy for primary lung cancer in a lung highly compressed by giant emphysematous bullae: A case report.

Lung cancer sometimes develops on the wall of a giant emphysematous bulla (GEB). Herein, we describe a rare case in which lung cancer developed in lung tissue compressed by GEBs. A 62-year-old man underwent a computed tomography (CT) scan that revealed two right GEBs. A tumor was suspected in the highly compressed right upper lobe. Since the right bronchus was significantly shifted toward the mediastinum, it was difficult to perform a bronchoscopy. We inserted thoracic drains into the GEBs, and a subsequent CT scan revealed re-expansion of the remaining right lung and a 3.3 cm tumor in the right upper lobe. The shift of the right bronchus was improved, and bronchoscopy was performed. The tumor was diagnosed as non-small cell lung cancer (NSCLC). Additionally, the GEBs were found to have originated from the right lower lobe. We performed a right upper lobectomy, mediastinal lymph node dissection, and bullectomy of the GEBs via video-assisted thoracoscopic surgery. In preoperative evaluation of a GEB, assessing re-expansion and lung lesions of the remaining lung is important, and intracavity drainage of a GEB may be useful. KEY POINTS: Significant findings of the study Cancer that develops in lung tissue highly compressed by a giant emphysematous bulla is difficult to diagnose. In the preoperative evaluation of a giant emphysematous bulla, assessing re-expansion and lung lesions of the remaining lung is important. What this study adds After performing intracavity drainage of a giant emphysematous bulla, the remaining lung re-expands, and the bronchial shift improves; subsequently, bronchoscopy makes it possible to diagnose lung cancer in the remaining lung.

Penetrating pulmonary injury due to a thrown rusty nail while using a lawn mower: a case report.

Accidents while using lawn mowers are often reported, but chest injuries are rare. We report a case of a penetrating pulmonary injury due to a rusty nail thrown by a lawn mower. A 63-year-old man injured his left precordium by a thrown object while using a lawn mower; he thereafter visited a nearby hospital. A computed tomography image showed a left-sided pneumothorax and a penetrating pulmonary injury of the left upper lobe due to a foreign body. Pneumothorax was treated with thoracic drainage and resolved. He was transferred to our hospital on the second day after the injury, and video-assisted thoracoscopic surgery was performed to remove the foreign body. Surgical findings showed a penetrating wound in the left upper lobe and leakage of pus from its margin. The foreign body was a rusty nail. The penetrating wound was treated by partial pulmonary resection to control the infection. Histopathological findings revealed the formation of a lung abscess. Penetrating pulmonary injuries do not require surgical treatment for most patients. However, residual foreign bodies can cause lung abscesses. The removal of foreign bodies depends on the type of injury as well as the type and location of the foreign body. Theoretically, the foreign body should be removed and the penetrating pulmonary injury should be treated, if possible, to control infection.

Contralateral pulmonary resection using selective bronchial blockade in postpneumonectomy patients.

BACKGROUND: Pulmonary resection is occasionally performed in postpneumonectomy patients with contralateral lung lesions, such as metachronous or metastatic lung cancer. Careful intraoperative respiratory management is essential in such patients. This study evaluated the respiratory management of postpneumonectomy patients who underwent contralateral pulmonary resection with selective bronchial blockade of the lobe or segment to be resected. METHODS: We retrospectively analyzed the surgical findings and safety of surgery in six patients who underwent contralateral pulmonary resection with selective bronchial blockade after pneumonectomy for non-small cell lung cancer (NSCLC). RESULTS: The percutaneous oxygen saturation did not decrease in any of the patients during bronchial blockade under high oxygen concentration. The median blockade time was 57.5 minutes. The operative field was tolerable secured under conditions of partial lung collapse, and partial pulmonary resection was performed as planned. Postoperatively, one patient developed acute respiratory distress syndrome due to acute exacerbation of interstitial pneumonia; however, no patients died within one month postoperatively. Two patients underwent pulmonary resection in order to obtain adequate tissue specimens to evaluate the biomarkers of multiple lung metastases. On histopathology, one patient tested positive for anaplastic lymphoma kinase (ALK) and was subsequently administered an ALK inhibitor, which prolonged survival. CONCLUSIONS: In all patients, intraoperative respiratory condition under partial lung collapse remained stable, and all partial pulmonary resections were safely performed. However, surgical indications should be carefully reviewed preoperatively in patients with interstitial pneumonia. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Contralateral partial pulmonary resection was performed using selective bronchial blockade in postpneumonectomy patients. Percutaneous oxygen saturation did not decrease during the bronchial blockade under high oxygen concentration, and the operative field was tolerable secured under conditions of partial lung collapse. WHAT THIS STUDY ADDS: Oxygen concentration can be set to the minimum level, sufficient to maintain oxygenation, during contralateral partial pulmonary resection with selective bronchial blockade.

Extending the piezoelectric transducer bandwidth of an optical interferometer by suppressing resonance using a high dimensional IIR filter implemented on an FPGA.

This paper considers the application of Field Programmable Gate Array (FPGA)-based infinite impulse response (IIR) filtering to increase the usable bandwidth of a piezoelectric transducer used in optical phase locking. We experimentally perform system identification of the interferometer with the cross-correlation method integrated on the controller hardware. Our model is then used to implement an inverse filter designed to suppress the low frequency resonant modes of the piezoelectric transducer. This filter is realized as a 24th-order IIR filter on the FPGA, while the total input-output delay is kept at 350 ns. The combination of the inverse filter and the piezoelectric transducer works as a nearly flat response position actuator, allowing us to use a proportional-integral (PI) control in order to achieve stability of the closed-loop system with significant improvements over a non-filtered PI control. Finally, because this controller is completely digital, it is straightforward to reproduce. Our control scheme is suitable for many experiments that require highly accurate control of flexible structures.

Right upper lobectomy in lung cancer with double aortic arch: A case report.

Double aortic arch (DAA) is a rare congenital anomaly of the heart and aorta in which a vascular ring that surrounds the trachea and esophagus is formed. In most patients, respiratory distress and dysphagia develop in childhood, and asymptomatic adult patients are rarely known. Herein, we describe a patient with lung cancer and DAA. A 66-year-old man who had DAA underwent video-assisted thoracoscopic right upper lobectomy and mediastinal lymph node dissection for primary lung cancer. Lymph node dissection of the right upper mediastinum revealed that the right recurrent laryngeal nerve branched from the right vagus nerve just beneath the right aortic arch. Additionally, the right aortic arch narrowed the space surrounding the trachea, superior vena cava, and arch of the azygos vein, impeding the stapling of the truncus anterior artery and right upper lobe pulmonary vein with the video-assisted thoracoscopic approach. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: In double aortic arch, the recurrent laryngeal nerve branches from the vagus nerve just beneath the ipsilateral aortic arch. The right aortic arch narrows the space surrounding the trachea, superior vena cava, and arch of the azygos vein. WHAT THIS STUDY ADDS: The anatomy of a double aortic arch impedes mediastinal lymph node dissection on the ventral side of the trachea. Handling autosuture devices for stapling pulmonary arteries and veins is also difficult.

Prolonged warm ischemia exacerbated acute rejection after lung transplantation from donation after cardiac death in a mouse.

OBJECTIVE: In lung transplantation (LTx) from donation after cardiac death (DCD), the donor lungs are inevitably exposed to warm ischemic time (WIT) between the cardiac arrest and the initiation of cold preservation. We conducted this study to examine the effect of prolonged WIT on lung allograft rejection in a murine model of LTx from DCD. METHODS: Allogeneic BALB/c → B6 LTx from DCD was performed with a WIT of 15 min (WIT15 group, n = 5) or 60 min (WIT60 group, n = 5). Recipients were immunosuppressed by perioperative costimulatory blockade. The lung allografts were analyzed by histology and flow cytometry on day 7 after the LTx. RESULTS: Histologically, the rejection grade in the WIT60 group was significantly higher than that in the WIT15 group (3.4 ± 0.4 vs. 2.2 ± 0.2, P = 0.0278). Moreover, the intragraft CD8+ to CD4+ T cell ratio in the WIT60 group was significantly higher than that in the WIT15 group (2.3 ± 0.12 vs. 1.2 ± 0.11, P < 0.0001). CONCLUSIONS: Prolonged WIT could exacerbate the severity of lung allograft rejection after LTx from DCD. Minimization of the WIT could improve the outcomes after LTx from DCD.

SPRED2 deficiency may lead to lung ischemia-reperfusion injury via ERK1/2 signaling pathway activation.

PURPOSE: Inflammatory changes during lung ischemia-reperfusion injury (IRI) are related to the activation of the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. Sprouty-related EVH1 (enabled/vasodilator-stimulated phosphoprotein homology 1)-domain-containing proteins (SPREDs) are known inhibitors of ERK1/2 signaling. The role of SPRED2 in lung IRI was examined in a left hilar clamp mouse model. METHODS: C57BL/6 wild-type (WT) and Spred2-/- mice were used in the left hilar clamp model. Experimental groups underwent 30 min of left hilar clamping followed by 1 h of reperfusion. U0126, an ERK1/2 inhibitor, was administered to Spred2-/- mice with reperfused lungs. RESULTS: The partial pressures of oxygen of the Spred2-/- mice after reperfusion were significantly worse than those of WT mice (p < 0.01). Spred2-/- mice displayed more severe injuries than WT mice with increased neutrophil infiltration observed by a histological evaluation and flow cytometry (p < 0.001). This severe inflammation was inhibited by U0126. In addition, the rate of ERK1 activation was significantly higher in the lungs of Spred2-/- mice after reperfusion than in WT mice according to a Western blot analysis (p < 0.05). CONCLUSION: The activation of the ERK1/2 signaling pathway influences the severity of lung IRI, causing inflammation with neutrophil infiltration. SPRED2 may be a promising target for the suppression of lung IRI.