Loss of Nr4a1 ameliorates endothelial cell injury and vascular leakage in lung transplantation from circulatory-death donor.

BACKGROUND: Ischemia-reperfusion injury (IRI) stands as a major trigger for primary graft dysfunction (PGD) in lung transplantation (LTx). Especially in LTx from donation after cardiac death (DCD), effective control of IRI following warm ischemia (WIRI) is crucial to prevent PGD. This study aimed to identify the key factors affecting WIRI in LTx from DCD. METHODS: Previously reported RNA-sequencing dataset of lung WIRI was reanalyzed to identify nuclear receptor subfamily 4 group A member 1 (NR4A1) as the immediate early gene for WIRI. Dynamics of NR4A1 expression were verified using a mouse hilar clamp model. To investigate the role of NR4A1 in WIRI, a mouse model of LTx from DCD was established using Nr4a1 knockout (Nr4a1-/-) mice. RESULTS: NR4A1 was located around vascular cells, and its protein levels in the lungs increased rapidly and transiently during WIRI. LTｘ from Nr4a1-/- donors significantly improved pulmonary graft function compared to wild-type donors (P < 0.001). Histological analysis showed decreased microvascular endothelial cell death (P = 0.007), neutrophil infiltration (P < 0.001), and albumin leakage (P < 0.001). Evans blue permeability assay demonstrated maintained pulmonary microvascular barrier integrity in grafts from Nr4a1-/- donors, correlating with diminished pulmonary edema (P < 0.001). However, NR4A1 did not significantly affect the inflammatory response during WIRI, and IRI was not suppressed when a wild-type donor lung was transplanted into the Nr4a1-/- recipient. CONCLUSIONS: Donor NR4A1 plays a specialized role in the positive regulation of endothelial cell injury and microvascular hyperpermeability. These findings demonstrate the potential of targeting NR4A1 interventions to alleviate PGD and improve outcomes in LTx from DCD.

Augmented humoral response to third and fourth dose of SARS-CoV-2 mRNA vaccines in lung transplant recipients.

BACKGROUND: Since lung transplant recipients (LTRs) exhibit low immunogenicity after two doses of SARS-CoV-2 mRNA vaccines, optimal vaccine strategies for SARS-CoV-2 are required in LTRs. This study aimed to investigate the efficacy and safety of the third and fourth doses of the SARS-CoV-2 mRNA vaccines in LTRs. METHODS: We conducted a single-center study of 73 LTRs and 23 healthy controls (HCs). Participants received two-to-four doses of SARS-CoV-2 mRNA vaccines. The LTRs were divided into three groups based on the number of vaccine dose. IgG titers against SARS-CoV-2 spike protein were measured, and adverse events were assessed. Factors associated with humoral response were analyzed using univariate and multivariate analyses. RESULTS: The Dose 4 group (n = 27) had a higher humoral response rate (P = 0.018) and higher levels of anti-SARS-CoV-2 IgG antibody (P = 0.04) than the Dose 2 group (n = 14). The Dose 3 group (n = 32) had lower humoral response rates (P = 0.005) and levels of anti-SARS-CoV-2 IgG antibody (P = 0.0005) than the HCs (n = 23) even after the same dose. Systemic adverse events were milder in the LTRs than in the HCs (P < 0.05). Increased number of vaccine dose was identified as a predictor of positive humoral response (P = 0.021). CONCLUSION: Booster doses of SARS-CoV-2 mRNA vaccines may enhance humoral response with mild adverse events in LTRs. Repeated vaccination might be warranted for LTRs to prevent SARS-CoV-2 infection.

Postoperative Complications in Living Donors for Lung Transplantation.

Background: Living donor lobar lung transplantation is a life-saving procedure for critically ill patients. This requires 2 healthy donors exposed to risks and without medical benefit. Therefore, the donor's safety and minimal postoperative complications are crucial. This study aimed to investigate the short-term outcomes and identify the risk factors affecting these outcomes. Methods: The data of 175 living donors enrolled between 1998 and 2022 were analyzed. Donors were divided into era 1 (1998-2009) and era 2 (2010-2022). Results: The overall incidence of postoperative complications was 39%, of which 7% were major complications. Donors who underwent surgery on the right side had a higher incidence of delayed pulmonary fistulae (P = 0.01) and elevated liver enzyme levels (P = 0.028). Living donor surgery on the right side (P = 0.01), era 2 (P = 0.01), and the need for plasty (P = 0.04) were predictors of postoperative complications. Conclusions: Updated data on complications and their correlation with postoperative quality of life from this study could aid in the selection of potential donors and facilitate informed consent.

Long-term outcomes of lung transplantation requiring renal replacement therapy: A single-center experience.

BACKGROUND: Life-long immunosuppressive therapy after lung transplantation (LT) may lead to end-stage renal disease (ESRD), requiring renal replacement therapy (RRT). We aimed to investigate the characteristics and long-term outcomes of patients undergoing LT and requiring RRT. METHODS: This study was a single-center, retrospective cohort study. The patients were divided into the RRT (n = 15) and non-RRT (n = 170) groups. We summarized the clinical features of patients in the RRT group and compared patient characteristics, overall survival, and chronic lung allograft dysfunction (CLAD)-free survival between the two groups. RESULTS: The cumulative incidences of ESRD requiring RRT after LT at 5, 10, and 15 years were 0.8 %, 7.6 %, and 25.2 %, respectively. In the RRT group, all 15 patients underwent hemodialysis but not peritoneal dialysis, and two patients underwent living-donor kidney transplantation. The median follow-up period was longer in the RRT group than in the non-RRT group (P < 0.001). The CLAD-free survival and overall survival did not differ between the two groups. The 5-year survival rate even after the initiation of hemodialysis was 53.3 %, and the leading cause of death in the RRT group was infection. CONCLUSIONS: Favorable long-term outcomes can be achieved by RRT for ESRD after LT.

Surgery Outcomes for Pulmonary Metastases from Renal Cell Carcinoma.

Pulmonary metastatic resection is a standard therapy for renal cell carcinoma (RCC). Although patients with pulmonary metastases who do not undergo any treatment have poor prognoses, it has been reported that resection for pulmonary metastases yields good clinical outcomes. We investigated the prognoses of the 10 Japanese patients (eight males, two females) who underwent a surgical resection of pulmonary metastasectomy from RCC at our institution between April 1, 2012 and March 31, 2020 and analyzed the prognostic factors. We determined the prognoses and calculated the 5-year overall survival (OS) and disease-free survival (DFS) rates. To identify prognostic factors, we compared the median DFS duration for each factor. Elderly patients (median age, 75.5 years) were more predominant compared to previous studies, and all 10 patients underwent a complete resection. The 5-year DFS rate was 30.5% (95%CI: 0.045-0.63) and the 5-year OS rate was 80% (95%CI: 0.20-0.97). The following factors were associated with better prognosis: female, disease-free interval≥36 months, and metastases size<12 mm. These results indicate that complete resection for pulmonary metastases from RCC resulted in good clinical outcomes, particularly for patients with better prognostic factors.

Thoracoscopic Localization of Small Peripheral Pulmonary Lesions Using Percutaneous Computed Tomography-guided Pleural Dye Marking: A Retrospective Analysis.

Small pulmonary lesions are often difficult to localize during thoracoscopic surgery. We describe a new com-puted tomography (CT)-guided pleural dye-marking method for small peripheral pulmonary lesions that does not involve a visceral pleural puncture. We used this technique for 23 lesions (22 patients) who underwent tho-racoscopic partial lung resection (Nov. 2016-Jan. 2018). With the patient in the lateral decubitus position, pre-operative CT-guided marking on the skin over the lesion was performed. During the surgery, we marked the visceral pleura with a skin marker directly or with an infant-size nutrition catheter with crystal violet at the tip through a venous indwelling needle inserted perpendicular to the skin marking. We localized and resected the lesions in all cases, without complications. The median nodule size measured histopathologically was 8 (4-20) mm overall, and 7 (0-20) mm of the solid part; the median distance from the visceral pleura to the nodule was 9 (1-33) mm. The median operation time was 67 (37-180) min. The median postoperative hospital stay was 3 (3-11) days. Our CT-guided pleural dye-marking method is useful and safe for the localization of small periph-eral pulmonary lesions in thoracoscopic partial lung resections.

Resected case of stage IV pleomorphic carcinoma of the lung with long-term survival.

BACKGROUND: No established treatments for pulmonary pleomorphic carcinoma exist because of its rarity, and the prognosis is poorer than that of other non-small cell lung cancers. CASE REPORT: We present a case of stage IV pleomorphic carcinoma; the patient was a 66-year-old male. He was referred to our hospital because of a right adrenal hemorrhage and a lung tumor. A systemic examination revealed that the lung tumor was a primary lung cancer and that the adrenal hemorrhage was due to a metastatic cancer. We performed an adrenalectomy and resection of the lung tumor and obtained a diagnosis of pleomorphic carcinoma with adrenal metastasis. The patient has remained recurrence-free for 6 years since the surgery. CONCLUSIONS: We report a patient with stage IV pleomorphic carcinoma of the lung and an oligometastasis in whom a complete resection enabled a good outcome. Additional reports are needed to clarify definite prognostic factors and the optimal treatment for pleomorphic carcinoma.

Antiobesity Action of ACAM by Modulating the Dynamics of Cell Adhesion and Actin Polymerization in Adipocytes.

Coxsackie virus and adenovirus receptor-like membrane protein (CLMP) was identified as the tight junction-associated transmembrane protein of epithelial cells with homophilic binding activities. CLMP is also recognized as adipocyte adhesion molecule (ACAM), and it is upregulated in mature adipocytes in rodents and humans with obesity. Here, we present that aP2 promoter-driven ACAM transgenic mice are protected from obesity and diabetes with the prominent reduction of adipose tissue mass and smaller size of adipocytes. ACAM is abundantly expressed on plasma membrane of mature adipocytes and associated with formation of phalloidin-positive polymerized form of cortical actin (F-actin). By electron microscopy, the structure of zonula adherens with an intercellular space of ∼10-20 nm was observed with strict parallelism of the adjoining cell membranes over distances of 1-20 µm, where ACAM and γ-actin are abundantly expressed. The formation of zonula adherens may increase the mechanical strength, inhibit the adipocyte hypertrophy, and improve the insulin sensitivity.