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* Context.--Respiratory infections complicate lung transplantation and increase the risk of allograft dysfunction. Allograft lungs may have different susceptibilities to infection than native lungs, potentially leading to different disease severity in lungs of single lung transplant recipients (SLTRs). Objective.--To study whether infections affect allograft and native lungs differently in SLTRs but similarly in double LTRs (DLTRs). Design.--Using an institutional database of LTRs, medical records were searched, chest computed tomography studies were systematically reviewed, and histopathologic features were recorded per lung lobe and graded semiquantitatively. A multilobar-histopathology score (MLHS) including histopathologic data from each lung and a bilateral ratio ([MLHS.sub.ratio]) comparing histopathologies between both lungs were calculated in SLTRs and compared to DLTRs. Results.--Six SLTRs died of infection involving the lungs. All allografts showed multifocal histopathologic evidence of infection, but at least 1 lobe of the native lung was uninvolved. In 4 of 5 DLTRs, histopathologic evidence of infection was seen in all lung lobes. On computed tomography, multifocal ground-glass and/or nodular opacities were found in a bilateral distribution in all DLTRs but in only 2 of 6 SLTRs. In SLTRs, the [MLHS.sub.Allograft] was higher than [MLHS.sub.Native] (P = .02). The [MLHS.sub.ratio] values of SLTR and DLTR were significantly different (P < .001). Conclusions.--Allograft and native lungs appear to harbor different susceptibilities to infections. The results are important for the management of LTRs. doi: 10.5858/arpa.2023-0227-OA), The median overall survival of lung transplant recipients (LTRs) is only 6.7 years, which is shorter than for other solid organ transplantations. (1) Noncytomegalovirus (nonCMV) infections play a major role [...]

A 45-year-old woman in France who had received a lung transplant in 2016 for end-stage cystic fibrosis (CF) sought care for rhinorrhea on March 1, 2022. Her immunosuppressive regimen included [...]

Preexisting lung-restricted autoantibodies (LRAs) are associated with a higher incidence of primary graft dysfunction (PGD), although it remains unclear whether LRAs can drive its pathogenesis. In syngeneic murine left lung transplant recipients, preexisting LRAs worsened graft dysfunction, which was evident by impaired gas exchange, increased pulmonary edema, and activation of damage-associated pathways in lung epithelial cells. LRA-mediated injury was distinct from ischemia-reperfusion injury since deletion of donor nonclassical monocytes and host neutrophils could not prevent graft dysfunction in LRA-pretreated recipients. Whole LRA IgG molecules were necessary for lung injury, which was mediated by the classical and alternative complement pathways and reversed by complement inhibition. However, deletion of Fc receptors in donor macrophages or mannose-binding lectin in recipient mice failed to rescue lung function. LRA-mediated injury was localized to the transplanted lung and dependent on IL-1[beta]-mediated permeabilization of pulmonary vascular endothelium, which allowed extravasation of antibodies. Genetic deletion or pharmacological inhibition of IL-1R in the donor lungs prevented LRA-induced graft injury. In humans, preexisting LRAs were an independent risk factor for severe PGD and could be treated with plasmapheresis and complement blockade. We conclude that preexisting LRAs can compound ischemia-reperfusion injury to worsen PGD for which complement inhibition may be effective., Introduction Primary graft dysfunction (PGD) affects over 50% of recipients following lung transplantation and has emerged as the principal risk factor for both short-term mortality as well as long-term graft [...]

Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplantation, including a lung that failed to recover on EVLP, can be recovered by cross-circulation of whole blood between explanted human lungs and a Yorkshire swine. This xenogeneic platform provided explanted human lungs a supportive, physiologic milieu and systemic regulation that resulted in functional and histological recovery after 24 h of normothermic support. Our findings suggest that cross-circulation can serve as a complementary approach to clinical EVLP to recover injured donor lungs that could not otherwise be utilized for transplantation, as well as a translational research platform for immunomodulation and advanced organ bioengineering. In a new strategy for increasing the availability of lungs for transplantation, human lungs declined for transplantation because of their poor quality can be recuperated by connecting them to the circulation of a pig., Author(s): Ahmed E. Hozain [sup.1] [sup.2] , John D. O'Neill [sup.1] , Meghan R. Pinezich [sup.1] , Yuliya Tipograf [sup.2] , Rachel Donocoff [sup.3] , Katherine M. Cunningham [sup.1] , [...]

The contribution of T-cells after lung transplant (LTx) remains controversial with no current consensus of their role concerning chronic lung allograft dysfunction. Using flow cytometry to assess T-cell subsets of bronchoalveolar lavage fluid (BALF) in 16 cystic fibrosis (CF) LTx recipients, we identified a decline in CD4.sup.+ T-cell frequency and an increase in CD8.sup.+ T-cell frequency in patients who developed severe bronchiolitis obliterans syndrome (BOS) (N = 10) when comparing baseline (6 months post-LTx) and follow-up (most recent bronchoscopy-clinical or surveillance per protocol). Comparing BOS to No BOS cohorts, significant differences were found in CD4+ T-cell frequency [17.4 (12.5, 28.2) vs 46.6 (44.4, 48.4), p = 0.003] and CD8+ T-cell frequency [65.6 (62.8, 75.3) vs 39.2 (32.2, 43.3), p = 0.014], respectively. The mean difference of the CD4:CD8 ratio was 0.87 units lower (95% CI - 1.44 to - 0.30, p = 0.006) than patients without BOS, while the median difference of the CD4:CD8 ratio was 0.92 units lower (95% CI - 1.83 to - 0.009, p = 0.048). Therefore, our results suggest that T-cell profiles measured through flow cytometry of BALF in the CF LTx population are associated with the development of severe BOS. Further work is needed in larger patient populations to validate our findings and to determine if this is useful for recipients who underwent LTx for other indications., Author(s): Don Jr. Hayes [sup.1] [sup.2] [sup.3] [sup.6] [sup.9] , Michael O. Harhay [sup.8] , Kathleen K. Nicol [sup.5] [sup.7] , Namal P. M. Liyanage [sup.4] , Brian C. Keller [...]

Millions of people worldwide with incurable end-stage lung disease die because of inadequate treatment options and limited availability of donor organs for lung transplantation.sup.1. Current bioengineering strategies to regenerate the lung have not been able to replicate its extraordinary cellular diversity and complex three-dimensional arrangement, which are indispensable for life-sustaining gas exchange.sup.2,3. Here we report the successful generation of functional lungs in mice through a conditional blastocyst complementation (CBC) approach that vacates a specific niche in chimeric hosts and allows for initiation of organogenesis by donor mouse pluripotent stem cells (PSCs). We show that wild-type donor PSCs rescued lung formation in genetically defective recipient mouse embryos unable to specify (due to Ctnnb1.sup.cnull mutation) or expand (due to Fgfr2.sup.cnull mutation) early respiratory endodermal progenitors. Rescued neonates survived into adulthood and had lungs functionally indistinguishable from those of wild-type littermates. Efficient chimera formation and lung complementation required newly developed culture conditions that maintained the developmental potential of the donor PSCs and were associated with global DNA hypomethylation and increased H4 histone acetylation. These results pave the way for the development of new strategies for generating lungs in large animals to enable modeling of human lung disease as well as cell-based therapeutic interventions.sup.4-6. Pluripotent stem cells can generate functional lungs when injected into blastocyst-stage mouse embryos, a step toward the goal of growing human lungs in large animals for disease modeling and therapeutic applications., Author(s): Munemasa Mori [sup.1] , Kazuhiro Furuhashi [sup.2] , Jennifer A. Danielsson [sup.3] , Yuichi Hirata [sup.2] , Miwako Kakiuchi [sup.2] , Chyuan-Sheng Lin [sup.4] , Mayu Ohta [sup.1] , [...]

Primary graft dysfunction (PGD) is the leading cause of postoperative mortality in lung transplant recipients and the most important risk factor for development of chronic lung allograft dysfunction. The mechanistic basis for the variability in the incidence and severity of PGD between lung transplant recipients is not known. Using a murine orthotopic vascularized lung transplant model, we found that redundant activation of Toll-like receptors 2 and 4 (TLR2 and -4) on nonclassical monocytes activates MyD88, inducing the release of the neutrophil attractant chemokine CXCL2. Deletion of Itgam (encodes CD11b) in nonclassical monocytes enhanced their production of CXCL2 and worsened PGD, while a CD11b agonist, leukadherin-1, administered only to the donor lung prior to lung transplantation, abrogated CXCL2 production and PGD. The damageassociated molecular pattern molecule HMGB1 was increased in peripheral blood samples from patients undergoing lung transplantation after reperfusion and induced CXCL2 production in nonclassical monocytes via TLR4/MyD88. An inhibitor of HMGB1 administered to the donor and recipient prior to lung transplantation attenuated PGD. Our findings suggest that CD11b acts as a molecular brake to prevent neutrophil recruitment by nonclassical monocytes following lung transplantation, revealing an attractive therapeutic target in the donor lung to prevent PGD in lung transplant recipients., Introduction Primary graft dysfunction (PGD) is a syndrome of acute lung injury that develops in 20% to 30% of recipients in the first 72 hours following lung transplantation (1-3). PGD [...]

Lymph node (LN) fibroblastic reticular cells (FRCs) define LN niches and regulate lymphocyte homeostasis through producing diverse extracellular matrix (ECM) components. We examined the role of ECM laminin [alpha]4 (Lama4) using FRC-Lama4 conditional KO Pdgfrb-[Cre.sup.-/-] * [Lama4.sup.fl/fl] mice. Single-cell RNA-sequencing (scRNA-Seq) data showed the promoter gene Pdgfrb was exclusively expressed in FRCs. Depleting FRC-Lama4 reduced Tregs and dendritic cells, decreased high endothelial venules, impaired the conduit system, and downregulated T cell survival factors in LNs. FRC-Lama4 depletion impaired the homing of lymphocytes to LNs in homeostasis and after allografting. Alloantigen-specific T cells proliferated, were activated to greater degrees in LNs lacking FRC-Lama4, and were more prone to differentiate into effector phenotypes relative to the Treg phenotype. In murine cardiac transplantation, tolerogenic immunosuppression was not effective in FRC-Lama4 recipients, which produced more alloantibodies than WT. After lung transplantation, FRC-Lama4-KO mice had more severe graft rejection with fewer Tregs in their LNs. Overall, FRC-Lama4 critically contributes to a tolerogenic LN niche by supporting T cell migration, constraining T cell activation and proliferation, and promoting Treg differentiation. Hence, it serves as a therapeutic target for immunoengineering., Introduction Mammalian lymph nodes (LNs) serve as the primary initiation sites of immune responses, acting by choreographing the interactions of T cells, B cells, macrophages, and dendritic cell (DCs). The [...]

Background Non-cystic fibrosis bronchiectasis (NCFB) is a heterogeneous disease. There are few studies about prognostic factors in these patients. Our study aims to assess mortality rates and related factors in a cohort of patients and test the ability of the BSI and FACED scores in predicting mortality in this cohort. Methods This was a prospective cohort analysis of 70 patients with NCFB recruited from May 2008 to August 2010. At baseline, patients underwent clinical evaluation, pulmonary function tests, 6-min walk test, and quality of life assessment. Outcomes were defined as favorable (survivors) and unfavorable (survivors who underwent lung transplantation and death from all causes). Baseline records provided data for determination of BSI and FACED. Results Twenty-seven patients (38.57%) died and 1 (1.43%) underwent lung transplantation. Mean time for occurrence of unfavorable outcomes was 74.67 ± 4.00 months. Main cause of death was an acute infectious exacerbation of bronchiectasis (60.7). Cox regression identified age (p = 0.035; HR 1.04; CI 1.01-1.08), FEV.sub.1 % of predicted (p = 0.045; HR 0.97; CI 0.93-0.99), and MEP (p = 0.016; HR 0.96; CI 0.94-0.99) as independent predictors of unfavorable outcomes. FACED was better at predicting unfavorable outcomes in our cohort (log-rank test, FACED p = 0.001 and BSI p = 0.286). In ROC analysis, both scores were similar in predicting unfavorable outcomes (BSI 0.65; FACED 0.66). Conclusions Older age, lower FEV.sub.1 % of predicted, and lower MEP were independently linked to unfavorable outcomes. FACED and BSI were not accurate in predicting mortality in our cohort., Author(s): Betina Charvet Machado [sup.1] , Patrícia Santos Jacques [sup.1] , Louise Piva Penteado [sup.2] , Paulo de Tarso Roth Dalcin [sup.3] Author Affiliations: (Aff1) 0000 0001 2200 7498, grid.8532.c, [...]

In this study, we demonstrate that forkhead box F1 (FOXF1), a mesenchymal transcriptional factor essential for lung development, was retained in a topographically distinct mesenchymal stromal cell population along the bronchovascular space in an adult lung and identify this distinct subset of collagen-expressing cells as key players in lung allograft remodeling and fibrosis. Using Foxf1-tdTomato BAC (Foxfi-tdTomato) and Foxf1-tdTomato Col1a1-GFP mice, we show that [Lin.sup.-][Foxf1.sup.+] cells encompassed the stem cell antigen [1.sup.+][CD34.sup.+] ([Sca1.sup.+][CD34.sup.+]) subset of collagen 1-expressing mesenchymal cells (MCs) with a capacity to generate CFU and lung epithelial organoids. Histologically, FOXF1- expressing MCs formed a 3D network along the conducting airways; FOXF1 was noted to be conspicuously absent in MCs in the alveolar compartment. Bulk and single-cell RNA-Seq confirmed distinct transcriptional signatures of [Foxf1.sup.-] and [Foxf1.sup.-] MCs, with Foxf1-expressing cells delineated by their high expression of the transcription factor glioma-associated oncogene 1 (Gli1) and low expression of integrin [alpha]8 (Itga), versus other collagen-expressing MCs. [FOXF1.sup.+][Gli1.sup.+] MCs showed proximity to Sonic hedgehog-expressing (Shh-expressing) bronchial epithelium, and mesenchymal expression of Foxf1 and Gli1 was found to be dependent on paracrine Shh signaling in epithelial organoids. Using a murine lung transplant model, we show dysregulation of epithelial-mesenchymal SHH/GLI1/ FOXF1 crosstalk and expansion of this specific peribronchial MC population in chronically rejecting fibrotic lung allografts., Introduction It is increasingly recognized that characterization of mesenchymal cell (MC) populations within distinct anatomic locations is key to understanding local homeostatic and regenerative processes as well as delineating unique [...]

Pulmonary ischemia-reperfusion injury (IRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. IRI causes early mortality and has no effective therapies. While NK cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, we demonstrated that NK cells were increased in frequency and cytotoxicity in 2 different IRI mouse models. We showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell-deficient mouse strain but restored with adoptive transfer of NK cells. Mechanistically, NK cell NKG2D receptor ligands were induced on lung endothelial and epithelial cells following IRI, and antibody-mediated NK cell depletion or NKG2D stress receptor blockade abrogated acute lung injury. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury., Introduction Pulmonary ischemia-reperfusion injury (IRI) is a severe complication following lung transplant that causes primary graft dysfunction (PGD) within 72 hours in one-third of all lung transplant surgeries. Lung transplant [...]

Purpose Bilateral lung transplantation results in complete denervation of the lung and might impair hypercapnic ventilatory response (HCVR). However, experimental and clinical findings are scarce and conflicting. Therefore, this study investigated the relationship between HCVR and exercise capacity after long-term bilateral lung transplantation. Methods This cross-sectional analysis enrolled 46 bilateral lung transplant recipients between October 2011 and July 2012 who underwent cardiopulmonary exercise testing to evaluate maximum workload, and carbon dioxide (CO.sub.2) rebreathing. CO.sub.2 rebreathing was also evaluated in 35 control subjects. Results In lung transplant recipients age was 54 ± 11 years, body mass index (BMI) 25.4 ± 4.1 kg/m.sup.2, and time after transplantation 4.5 ± 2.5 years (range 9 months to 10 years). Controls were aged 41 ± 12 years and had a BMI of 24.9 ± 4.0 kg/m.sup.2. There were significant differences between lung transplant recipients and controls in forced expiratory volume in 1 s (76 ± 22 vs. 94 ± 12 % predicted, p < 0.001) and inspiratory vital capacity (91 ± 20 vs. 105 ± 14 % predicted, p = 0.001). Blood gases did not differ significantly in patients versus controls. HCVR in lung transplant recipients was 1.44 ± 1.07 L/min/mmHg compared with 2.09 ± 1.14 L/min/mmHg in controls (p = 0.001). Exercise capacity in lung transplant recipients (73 ± 24 W) was 49 % predicted. Linear regression analysis showed that exercise capacity was significantly associated with HCVR. A 1 L/min/mmHg decrease in HCVR decreased exercise capacity by 50 W. Conclusion HCVR is reduced in long-term bilateral lung transplant recipients and this might explain the observed impairment of exercise capacity., Author(s): Manuela J. Scherer[sup.1] , Gerhard Weinreich[sup.1] , Bjoern E. Kleibrink[sup.1] , Thomas Rabis[sup.1] , Markus Kamler[sup.2] , Helmut Teschler[sup.1] , Urte Sommerwerck[sup.1] [sup.3] Author Affiliations: (1) Department of Pneumology, [...]

Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes., Introduction Lung transplantation remains the optimal treatment to prolong survival and improve quality of life for patients with end-stage lung disease (1). While outcomes after lung transplantation continue to improve, [...]