Liproxstatin-1 Alleviates Lung Transplantation-induced Cold Ischemia-Reperfusion Injury by Inhibiting Ferroptosis.

BACKGROUND: Primary graft dysfunction, which is directly related to cold ischemia-reperfusion (CI/R) injury, is a major obstacle in lung transplantation (LTx). Ferroptosis, a novel mode of cell death elicited by iron-dependent lipid peroxidation, has been implicated in ischemic events. This study aimed to investigate the role of ferroptosis in LTx-CI/R injury and the effectiveness of liproxstatin-1 (Lip-1), a ferroptosis inhibitor, in alleviating LTx-CI/R injury. METHODS: LTx-CI/R-induced signal pathway alterations, tissue injury, cell death, inflammatory responses, and ferroptotic features were examined in human lung biopsies, the human bronchial epithelial (BEAS-2B) cells, and the mouse LTx-CI/R model (24-h CI/4-h R). The therapeutic efficacy of Lip-1 was explored and validated both in vitro and in vivo. RESULTS: In human lung tissues, LTx-CI/R activated ferroptosis-related signaling pathway, increased the tissue iron content and lipid peroxidation accumulation, and altered key protein (GPX4, COX2, Nrf2, and SLC7A11) expression and mitochondrial morphology. In BEAS-2B cells, the hallmarks of ferroptosis were significantly evidenced at the setting of both CI and CI/R compared with the control, and the effect of adding Lip-1 only during CI was much better than that of only during reperfusion by Cell Counting Kit-8. Furthermore, Lip-1 administration during CI markedly relieved LTx-CI/R injury in mice, as indicated by significant improvement in lung pathological changes, pulmonary function, inflammation, and ferroptosis. CONCLUSIONS: This study revealed the existence of ferroptosis in the pathophysiology of LTx-CI/R injury. Using Lip-1 to inhibit ferroptosis during CI could ameliorate LTx-CI/R injury, suggesting that Lip-1 administration might be proposed as a new strategy for organ preservation.

[Risk factors of early death after lung transplantation in patients with idiopathic pulmonary fibrosis complicated with pulmonary arterial hypertension].

OBJECTIVE: To investigate the risk factors of early death after lung transplantation in patients with idiopathic pulmonary fibrosis (IPF) complicated with pulmonary arterial hypertension (PAH). METHODS: A retrospective cohort study was conducted. The clinical data of 134 patients with IPF and PAH who underwent lung transplantation at Wuxi People's Hospital Affiliated to Nanjing Medical University from January 2017 to December 2020 were collected. The donor's gender, age, duration of mechanical ventilation, and cold ischemia time, the recipient's gender, age, body mass index (BMI), smoking, history of hypertension and diabetes, preoperative usage of hormones, mean pulmonary arterial pressure (mPAP), cardiac echocardiography and cardiac function, serum creatinine (SCr), N-terminal pro-brain natriuretic peptide (NT-proBNP) as well as surgical type, extracorporeal membrane oxygenation (ECMO) treatment, duration of operation, and plasma and red blood cell infusion ratio were collected. The cumulative survival rates of patients at 30, 60, and 180 days after lung transplantation were calculated by Kaplan-Meier method. The univariate and multivariate Cox proportional hazards regression models were used to analyze the effects of donor, recipient, and surgical factors on early survival in donors after lung transplantation. RESULTS: The majority of donors were male (80.6%). There was 63.4% of the donors older than 35 years old, 80.6% of the donors had mechanical ventilation duration less than 10 days, and the median cold ischemia time was 465.00 (369.25, 556.25) minutes. The recipients were mainly males (83.6%). Most of the patients were younger than 65 years old (70.9%). Most of them had no hypertension (75.4%) or diabetes (67.9%). The median mPAP of recipients was 36 (30, 43) mmHg (1 mmHg ≈ 0.133 kPa). There were 73 patients with single lung transplantation (54.5%), and 61 with double lung transplantation (45.5%). The survival rates of 134 IPF patients with PAH at 30, 60, 180 days after lung transplantation were 81.3%, 76.9%, and 67.4%, respectively. Univariate Cox proportional risk regression analysis showed that recipient preoperative use of hormone [hazard ratio (HR) = 2.079, 95% confidence interval (95%CI) was 1.048-4.128], mPAP ≥ 35 mmHg (HR = 2.136, 95%CI was 1.129-4.044), NT-proBNP ≥ 300 ng/L (HR = 2.411, 95%CI was 1.323-4.392), New York Heart Association (NYHA) cardiac function classification III-IV (HR = 3.021, 95%CI was 1.652-5.523) were the risk factors of early postoperative death in patients with IPF complicated with PAH (all P < 0.05). In the multivariable Cox proportional risk regression analysis, recipient preoperative hormone usage (model 1: HR = 2.072, 95%CI was 1.044-4.114, P = 0.037; model 2: HR = 2.098, 95%CI was 1.057-4.165, P = 0.034), NT-proBNP ≥ 300 ng/L (HR = 2.246, 95%CI was 1.225-4.116, P = 0.009) and NYHA cardiac function classification III-IV (HR = 2.771, 95%CI was 1.495-5.134, P = 0.001) were independent risk factors of early postoperative death in patients with IPF. CONCLUSIONS: Preoperative hormone usage, NT-proBNP ≥ 300 ng/L, NYHA cardiac function classification III-IV are independent risk factors for early death in patients with IPF and PAH after lung transplantation. For these patients, attention should be paid to optimize their functional status before operation. Preoperative reduction of receptor hormone usage and improvement of cardiac function can improve the early survival rate of such patients after lung transplantation.

Arctiin-encapsulated DSPE-PEG bubble-like nanoparticles inhibit alveolar epithelial type 2 cell senescence to alleviate pulmonary fibrosis via the p38/p53/p21 pathway.

Background: Idiopathic pulmonary fibrosis is a severe and deadly form of diffuse parenchymal lung disease and treatment options are few. Alveolar epithelial type 2 (AEC2) cell senescence is implicated in the pathogenies of IPF. A major bioactive compound from the traditional Chinese medicine Fructus arctii, arctiin (ARC) has robust anti-inflammatory, anti-senescence, and anti-fibrosis functions. However, the potential therapeutic effects of ARC on IPF and the underlying mechanisms involved are still unknown. Methods: First of all, ARC was identified as an active ingredient by network pharmacology analysis and enrichment analysis of F. arctii in treating IPF. We developed ARC-encapsulated DSPE-PEG bubble-like nanoparticles (ARC@DPBNPs) to increase ARC hydrophilicity and achieve high pulmonary delivery efficiency. C57BL/6 mice were used to establish a bleomycin (BLM)-induced pulmonary fibrosis model for assessing the treatment effect of ARC@DPBNPs on lung fibrosis and the anti-senescence properties of AEC2. Meanwhile, p38/p53 signaling in AEC2 was detected in IPF lungs, BLM-induced mice, and an A549 senescence model. The effects of ARC@DPBNPs on p38/p53/p21 were assessed in vivo and in vitro. Results: Pulmonary route of administration of ARC@DPBNPs protected mice against BLM-induced pulmonary fibrosis without causing significant damage to the heart, liver, spleen, or kidney. ARC@DPBNPs blocked BLM-induced AEC2 senescence in vivo and in vitro. The p38/p53/p21 signaling axis was significantly activated in the lung tissues of patients with IPF, senescent AEC2, and BLM-induced lung fibrosis. ARC@DPBNPs attenuated AEC2 senescence and pulmonary fibrosis by inhibiting the p38/p53/p21 pathway. Conclusion: Our data suggest that the p38/p53/p21 signaling axis plays a pivotal role in AEC2 senescence in pulmonary fibrosis. The p38/p53/p21 signaling axis inhibition by ARC@DPBNPs provides an innovative approach to treating pulmonary fibrosis in clinical settings.

The impact of long-term exposure to tacrolimus on chronic kidney disease after lung transplantation: A retrospective analysis from a single transplantation center.

BACKGROUND: Chronic kidney disease (CKD) is a progressive and irreversible complication in lung transplant patients who have received long-term treatment with tacrolimus. This study aimed to verify long-term tacrolimus exposure values in CKD progression. METHODS: We retrospectively analyzed the clinical data of adult lung transplant recipients performed at our center between 2012 and October 2015. Patients who completed the 5-year follow-up period were enrolled in this study. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. RESULTS: Eighty patients were analyzed. Compared with baseline (109 ± 38.1 mL/min/1.73 m2), the average eGFR values of our patients gradually decreased during the fifth-year post transplantation (46.5%, 58.3 ± 28.3 mL/min/1.73 m2), and the decline in eGFR values was particularly pronounced in the first year (31.2%, 74.6 ± 28.91 mL/min/1.73 m2). Moreover, 10 (12.7%), 21 (26.9%), 24 (31.2%), 28 (41.2%), and 48 (60%) patients had eGFR <60 mL/min/1.73 m2 at 3, 6, 1, 3, and 5 years after lung transplantation (LT), respectively. A significant negative correlation was found between tacrolimus dose and eGFR 6 months after LT (P = 0.0414). We found no correlation between the serum tacrolimus concentration and CKD progression. CONCLUSION: eGFR constantly decreased and the incidence of CKD increased during the 5-year follow-up period after LT. The tacrolimus dose had a significant negative correlation with eGFR at 6 months after LT. Meanwhile, whole-blood tacrolimus trough concentrations were not correlated with eGFR decline. When possible, lower dosing within 1 year after LT can reduce potential nephrotoxic side effects.

Bilateral lung transplantation for Castleman disease with end-stage bronchiolitis obliterans.

Bronchiolitis obliterans (BO) is a severe complication of Castleman disease (CD), a rare lymphoproliferative disease with unclear pathogenesis. Currently, there are no reports on the safety or outcomes of bilateral lung transplantation in patients with BO due to CD. This study aimed to characterize the clinical manifestations and features of BO and CD. We retrospectively analyzed the medical records of six consecutive patients with BO and CD who underwent bilateral lung transplantation between December 2012 and December 2020. The average age of patients at lung transplantation was 33 ± 15 years, and the age range of patients at diagnosis of CD was about 9-56 years. The body mass index was 15.2 ± 1.9 kg/m2 . The average time from diagnosis to lung transplantation was 4.1 ± 2.7 years. All the patients had unicentric CD (UCD); five had concomitant paraneoplastic pemphigus, and four received extracorporeal membrane oxygenation during surgery. The average hospital stay was 51 ± 53 days. Infection was the most common postoperative complication. CD did not recur in any of the patients. Thus, bilateral lung transplantation is a viable and safe treatment for selected patients with CD and BO, which can improve the quality of life and prolong survival.

Bilateral Lung Transplantation for Patients With Destroyed Lung and Asymmetric Chest Deformity.

Background: Destroyed lung can cause mediastinal displacement and asymmetric chest deformity. Reports on bilateral lung transplantation (LT) to treat destroyed lung and asymmetric chest deformity are rare. This study presents our surgical experience of bilateral LT among patients with destroyed lung and asymmetric chest deformity. Methods: Six patients with destroyed lung and asymmetric chest deformity who underwent bilateral LT at our center from 2005 to 2020 were included in the study. Demographic data, technical data, perioperative details, and short-term follow-up data were reviewed. Results: Three patients underwent bilateral LT via anterolateral incisions in the lateral position without sternal transection, while three patients underwent bilateral LT via clam-shell incisions in the supine position with sternal transection. Only one patient required intraoperative extracorporeal membrane oxygenation. Four patients underwent size-reduced LT. In the other two patients, we restored the mediastinum by releasing mediastinal adhesions to ensure maximal preservation of the donor lung function. Patients in the lateral position group had a higher volume of blood loss, longer operation time, and longer postoperative in-hospital stay than those in the supine position group. However, these differences were not statistically significant. Postoperative computed tomography in the supine position group revealed that the donor lungs were well expanded and the mediastina were in their original positions. Conclusions: Although bilateral LT in patients with destroyed lung and asymmetric chest deformity is high risk, with sufficient preoperative preparation and evaluation, it is safe and feasible to perform bilateral LT for selected patients. For patients without severe chest adhesions, releasing the mediastinal adhesions and restoring the mediastinum through a clam-shell incision in the supine position is a simple and effective method to maximally preserve the donor lung function without pneumonectomy or lobectomy.

Middle lobe preservation and fixation after right upper and lower lobectomy for synchronous lung cancer.

The incidence of multiple lung cancer has been steadily increasing worldwide. Although cases of patients with lung cancers in the right upper and lower lobe have also become more frequently reported in clinical work, simultaneous right upper and lower lobectomy reports with the middle lobe preservation are still quite rare. A total of three patients with lung cancers in the right upper and lower lobe were included in the study. The patients underwent simultaneous right upper and lower lobectomy, whereas the remaining middle lobe was sutured and fixed to the intercostal muscle of the incision to prevent postoperative lobe torsion. There was no procedure to reduce residual space，such as phrenic nerve crush or thoracoplasty. All patients were discharged from the hospital 7 days after the operation. The chest tube was removed 5 days after the operation in two patients. One patient was discharged with the tube because of slight pulmonary leakage, and the tube was removed 2 weeks after the operation. Six months after the operation, the chest computer tomography showed that the middle lobe expanded well and no obvious cavity or pleural effusion was found. The suture of the remaining middle lobe and intercostal muscle of the incision is a simple and effective method that can be used to successfully avoid middle lobe torsion. This strategy is safe and can be used as the first choice for eligible patients.

Successful Radical Pneumonectomy for a Primitive Neuroendodermal Tumor in the Lung: A Case Report and Review of the Literature.

Peripheral primitive neuroendodermal tumors (PNETs) and Ewing's sarcoma belong to the Ewing family of tumors and are small round-cell malignancies originating from spinal cord cells. These tumors account for 5% of all small round-cell malignant neoplasms. PNETs that arise from the lung parenchyma without pleural or chest wall involvement are very rare. We report a case of an adult female with a large pulmonary PNET who had given birth just 1 month prior to the diagnosis. She had cough and expectoration for 6 months, and the preoperative examination showed no metastases. Thus, we performed radical pneumonectomy and lymph node dissection. The patient recovered well without surgical complications and was discharged 7 days after the surgery. Postoperative pathology confirmed that the tumor was a small round-cell malignancy, and the tumor cells were positive for CD99, Friend leukemia virus integration 1 (FLI-1), and neuron-specific enolase (NSE), which was consistent with the diagnosis of a PNET. For primary large pulmonary PNETs, radical pneumonectomy may be a safe surgical method, worthy of further application in clinical practice.

Optimal margins for early stage peripheral lung adenocarcinoma resection.

BACKGROUND: A pathologically confirmed negative margin is required when performing sublobar resection in patients with early stage peripheral lung adenocarcinoma. However, the optimal margin distance to ensure complete tumor resection while preserving healthy lung tissue remains unknown. We aimed to establish a reliable distance range for negative margins. METHODS: A total of 52 intraoperative para-cancer tissue specimens from patients with peripheral lung adenocarcinoma with pathological tumors ≤2 cm in size were examined. Depending on the distance from the tumor edge (D), the para-cancer tissues were divided into the following five groups: D < 0.5 cm (group I); 0.5 cm ≤ D < 1.0 cm (group II); 1.0 cm ≤ D < 1.5 cm (group III); 1.5 cm ≤ D < 2.0 cm (group IV); and D ≥ 2.0 cm (group V). During pathological examination of the specimens under a microscope, the presence of atypical adenomatous hyperplasia or more severe lesions was considered unsafe, whereas the presence of normal lung tissue or benign hyperplasia was considered safe. RESULTS: Group V, in which the margin was the farthest from the tumor edge, was the safest. There were significant safety differences in between groups I and V (χ2 = 26.217, P < 0.001). Significant safety differences also existed between groups II and V (χ2 = 9.420, P < 0.005). There were no significant safety differences between group III or IV and group V (P = 0.207; P = 0.610). CONCLUSIONS: We suggest that when performing sublobar resection in patients with early stage peripheral lung adenocarcinoma with pathological tumor sizes ≤2 cm, the resection margin distance should be ≥1 cm to ensure a negative margin.

A Retrospective Study of Lung Transplantation in Patients With Lymphangioleiomyomatosis: Challenges and Outcomes.

Background: Lymphangioleiomyomatosis (LAM) is a rare systemic disease that generally leads to a progressive decline in pulmonary function. Experience, especially from the Asian population, including combined drug therapy before and after lung transplantation (LT) in LAM, is still limited. This study aimed to summarize the clinical data from patients with pulmonary LAM who underwent LT at centers in China. Methods: A retrospective review of all patients with LAM undergoing LT at the two largest centers in China between 2010 and 2018 was conducted. Pre- and posttransplant data were assessed and analyzed. Results: Overall, 25 patients with LAM underwent bilateral LT. The mean age was 35.0 ± 8.6 years at diagnosis and 36.8 ± 9.3 years at the time of transplant. Before LT, only six patients could complete pulmonary function test; the reachable mean forced expiratory volume in one second (FEV1) before LT was 15.9 ± 6.9%. Twenty-one patients (84%) had a recurrent pneumothorax, four (16.0%) of which required pleurodesis. Eight patients (32%) were treated with sirolimus pretransplant for 3.9 years (1-9 years). The average intra-surgery bleeding volume was 1,280 ± 730 ml in need of a transfusion of 1,316 ± 874 ml due to moderate-to-severe adhesion and pretransplant pleurodesis. The causes of death of four patients (16%) included primary graft dysfunction, bronchial dehiscence with long-term use of sirolimus, and uncontrollable infections. The median follow-up time from LT was 41.1 ± 25.0 months. Conclusions: LT for LAM patients from the Asian population has been reinforced from the data that we presented. Peri-transplantation use of sirolimus and LAM-related complications should be further defined and under constant surveillance.

Pediatric lung transplantation in the largest lung transplantation center of China: embarking on a long road.

Lung transplantation (LT) has been an effective treatment for carefully selected children with end-stage lung diseases. The aim of this retrospective study is to introduce our experience at the largest LT center in Wuxi, China and to compare the outcomes of pediatric LT between children with idiopathic pulmonary arterial hypertension (IPAH) and other end-stage lung diseases. Ten pediatric patients undergoing LT from 2007 to 2019 were included. Sequential bilateral lung transplantation (BLT) with bilateral anterior thoracotomies was performed in all patients, seven of whom also underwent reduced size LT. Eight children survived until the end of our follow-up period on July 31st, 2019, with the longest survival of 11 years. Extracorporeal membrane oxygenation (ECMO) was intraoperatively used in all IPAH children and one non-IPAH child. Left heart function of IPAH children, though initially compromised, recovered after surgery. Statistically significant differences in operation time and post-operative mechanical ventilation between IPAH group and non-IPAH group were observed without discernible impact on post-LT survival. Pediatric LT appears to be a safe treatment for IPAH children to improve longevity and quality of life and ECMO may help reduce the risk of surgery and the postoperative complications.

Abdominal cocoon with bilateral cryptorchidism and seminoma in the right testis: a case report and review of literature.

BACKGROUND: Abdominal cocoon is a rare peritoneal lesion and is difficult to diagnose because of its lack of special clinical manifestations. Until now, there is no case report of abdominal cocoon combined with cryptorchidism and seminoma. CASE PRESENTATION: A case of abdominal cocoon with cryptorchidism and seminoma was diagnosed and treated in our hospital. The patient had no symptoms except occasional abdominal pain. He underwent laparoscopy because of bilateral cryptorchidism and seminoma in the right testis. During the surgery, he was diagnosed with abdominal cocoon due to the thick fibrous tissues which was tightly adhered and encased part of intestine like a cocoon. Enterolysis and bilateral cryptochiectomy were performed after the diagnosis and nutritional and symptomatic support was provided after the surgery. The patient recovered well and was discharged soon. The postoperative pathological examination confirmed the presence of bilateral cryptorchidism and seminoma in the patient's right testis. CONCLUSION: There are only a handful of cases where a patient has both abdominal cocoon and cryptorchidism. Since the etiologies of both diseases remain unknown, further research is required to investigate effective diagnosis and treatment for the diseases and explore the potential connection between the two diseases.

Mitotic Arrest-Deficient Protein 2B Overexpressed in Lung Cancer Promotes Proliferation, EMT, and Metastasis.

As the noncatalytic subunit of mammalian DNA polymerase, mitotic arrest-deficient protein 2B (MAD2B) has been reported to play a role in cell cycle regulation, DNA damage tolerance, gene expression, and carcinogenesis. Although its expression is known to be associated with poor prognosis in several types of human cancers, the significance of MAD2B expression in lung malignancies is still unclear. Our study showed that MAD2B expression significantly increased in lung cancer, especially in the metastatic tissues. We also found that knockdown of MAD2B inhibited the migration, invasion, and epithelial-mesenchymal transition of lung cancer cells in vitro and the metastasis in vivo, while overexpression of MAD2B had the opposite effect. Microarray and Western blotting data indicated that slug might be its downstream target since knockdown of MAD2B inhibited, while overexpression increased, the expression of slug. Moreover, the expression of MAD2B was found to be positively correlated with slug in lung cancer tissues as well. Collectively, these findings indicate an oncogenic role of MAD2B in lung cancer, and slug might be involved in the process.

[On the preparation and mechanical properties of PVA hydrogel bionic cartilage/bone composite artificial articular implants].

In view of the problems that conventional artificial cartilages have no bioactivity and are prone to peel off in repeated uses as a result of insufficient strength to bond with subchondral bone, we have designed and prepared a novel kind of PVA-BG composite hydrogel as bionic artificial articular cartilage/bone composite implants. The effects of processes and conditions of preparation on the mechanical properties of implant were explored. In addition, the relationships between compression strain rate, BG content, PVA hydrogels thickness and compressive tangent modulus were also explicated. We also analyzed the effects of cancellous bone aperture, BG and PVA content on the shear strength of bonding interface of artificial articular cartilage with cancellous bone. Meanwhile, the bonding interface of artificial articular cartilage and cancellous bone was characterized by scanning electron microscopy. It was revealed that the compressive modulus of composite implants was correspondingly increased with the adding of BG content and the augments of PVA hydrogel thickness. The compressive modulus and bonding interface were both related to the apertures of cancellous bone. The compressive modulus of composite implants was 1.6-2.23 MPa and the shear strength of bonding interface was 0.63-1.21 MPa. These results demonstrated that the connection between artificial articular cartilage and cancellous bone was adequately firm.