Gerckens/Mümmler Lab

AIMS: Coronary artery disease (CAD) is a frequent comorbidity in lung transplant (LuTx) candidates. The impact of allogenic organ transplantation and the corresponding alterations in immune response on the progression of CAD remains poorly understood. In this study, we sought to analyze the effect of donor-recipient overall human leukocyte antigen (HLA) and HLA-DQ mismatch on cardiovascular outcomes following LuTx. METHODS AND RESULTS: This retrospective analysis of adult patients receiving lung transplantation at the LMU University Hospital between 2012 and 2018 included 310 patients, the majority of whom (67.4%) had undergone double lung transplantation. There were no significant differences in the incidence of the primary composite endpoint between patients with high/low HLA mismatches (22 [7.9%] vs. 4 [12.9%]; p = 0.311). Numerically higher rates of the primary endpoint, myocardial infarction, and cardiovascular death in the low HLA mismatch group can partially be explained by differences in baseline rates of CAD and coronary sclerosis. Notably, neither HLA-DQ mismatch nor the occurrence of rejection episodes or cytomegalovirus (CMV) infection was associated with the occurrence of cardiovascular events following transplantation. CONCLUSION: In this study cohort, high HLA mismatch and HLA-DQ mismatch were not associated with increased adverse cardiovascular events. Furthermore, neither transplant rejection nor CMV infection increased the risk for cardiovascular events. The high cardiovascular event rates following LuTx necessitate meticulous cardiovascular follow-up, irrespective of immunological matching.

Objectives: To investigate the role of blood eosinophils in predicting PH in end-stage lung disease. Methods: We conducted a retrospective study of adults with CF, COPD, and ILD who underwent RHC during lung transplant evaluations (2010-2022). Patients were classified by the 2022 ECS/ERS PH guidelines with pulmonary function and laboratory tests, including hemograms. The eosinophil threshold was set at 0.30 G/L. Results: We analyzed 663 patients (n = 89 CF, n = 294 COPD, and n = 280 ILD). Severe PH was more common in ILD (16%) than in CF (4%) and COPD (7%) (p = 0.0002), with higher eosinophil levels in ILD (p = 0.0002). No significant correlation was found between eosinophil levels and hemodynamic parameters (PAPm, PVR, and CI) across CF, COPD, and ILD (PAPm: p = 0.3974, p = 0.4400 and p = 0.2757, respectively; PVR: p = 0.6966, p = 0.1489 and p = 0.1630, respectively; CI: p = 0.9474, p = 0.5705 and p = 0.5945, respectively), nor was a correlation observed in patients not receiving OCS. Linear regression analysis confirmed the lack of association (PAPm: p = 0.3355, p = 0.8552 and p = 0.4146, respectively; PVR: p = 0.6924, p = 0.8935 and p = 0.5459, respectively; CI: p = 0.4260, p = 0.9289 and p = 0.5364, respectively), controlling for 6-MWD, Nt-proBNP, and ICS/OCS dosages. ROC analysis indicated eosinophils were ineffective in distinguishing PH severity levels across these diseases (AUC 0.54, 0.51, and 0.53, respectively). The analysis of eosinophil levels measured 18 ± 6 months prior to baseline found no predictive correlation with the presence of PH either. Eosinophil levels did not differ significantly among PH groups, but eosinophilic COPD was linked to more unclassified PH, higher CO, and greater lung volumes than non-eosinophilic COPD. Conclusions: In our cohort of end-stage CF, COPD, and ILD patients, blood eosinophilia did not predict the presence of PH but was associated with hemodynamic parameters and lung volumes in COPD.

BACKGROUND: Mucus plugging has been identified as an important feature of severe asthma contributing to airway obstruction and disease severity. Recently, improvement of mucus plugging has been found upon treatment with several biologic therapies. OBJECTIVE: We aimed to analyze associations of baseline characteristic with mucus plugging score (MPS) and asked whether MPS at baseline predicts the clinical and functional response to biologic treatment in patients with severe asthma. METHODS: We retrospectively analyzed biologic-naïve patients with a suitable CT scan available at baseline. We calculated the MPS and analyzed correlations with baseline parameters and improvements of biomarkers, pulmonary function and clinical parameters after 4 months of biologic therapy. RESULTS: We included n=113 patients in the baseline cohort, hereof n=101 patients with sufficient data after 4-months of biologic therapy for the follow-up analysis. CT showed mucus plugging in 77% of patients with a median MPS of 4. Multivariate regression analysis showed correlation of MPS with lower FEV1 (rho= -0.24, p=0.009) and DLCO (rho=-0.26 , p= 0.01), and higher FeNO (rho=0.36 p=0.0003) at baseline. Patients received treatment with anti-IgE (8.8%), anti-IL5 (27.4%), anti-IL5R (37.2%), anti-IL4R (25.7%) and anti-TSLP (0,9%) in clinical routine. Baseline MPS correlated with improvements of FEV1 (beta=0.72; p=0.01) and ACT (beta= 0.24; p= 0.001) in multivariate regression analysis. CONCLUSION: Our study suggests that higher MPS correlates with worse pulmonary function at baseline, but also predicts a larger clinical and pulmonary function response to biologic therapies in severe asthma.

BACKGROUND: Baseline lung allograft dysfunction (BLAD) is characterized by the failure to achieve normal baseline lung function after double lung transplantation (DLTX) and is associated with a high risk of mortality. In single lung transplant (SLTX) recipients, however, cutoff values and associated factors have not been explored. Here, we aimed to define BLAD in SLTX recipients, investigate its impact on allograft survival, and identify potential risk factors for BLAD in SLTX recipients. METHODS: We performed a retrospective, single-center analysis of the LTX cohort of LMU Munich between 2010 and 2018. In accordance with DLTX cutoffs, BLAD in SLTX recipients was defined as failure to achieve percentage of forced expiratory volume in 1 s and percentage of forced vital capacity of >60% on 2 consecutive tests >3 wk apart. Survival analysis and regression analysis for potential predictors of BLAD were performed. RESULTS: In a cohort of 141 SLTX recipients, 43% of patients met BLAD criteria. SLTX recipients with BLAD demonstrated impaired survival. Native lung hyperinflation was associated with BLAD in obstructive disease, whereas donor/recipient lung size mismatch was associated with BLAD in both obstructive and restrictive underlying diseases. Pulmonary function testing at 3 mo after lung transplantation predicted normal baseline lung function in SLTX recipients with obstructive lung disease. CONCLUSIONS: BLAD in SLTX recipients is as relevant as in DLTX recipients and should generally be considered in the follow-up of LTX recipients. Risk factors for BLAD differed between underlying obstructive and restrictive lung disease. A better understanding of associated factors may help in the development of preventive strategies.

INTRODUCTION: Environmental pollutants injure the mucociliary elevator, thereby provoking disease progression in chronic obstructive pulmonary disease (COPD). Epithelial resilience mechanisms to environmental nanoparticles in health and disease are poorly characterised. METHODS: We delineated the impact of prevalent pollutants such as carbon and zinc oxide nanoparticles, on cellular function and progeny in primary human bronchial epithelial cells (pHBECs) from end-stage COPD (COPD-IV, n=4), early disease (COPD-II, n=3) and pulmonary healthy individuals (n=4). After nanoparticle exposure of pHBECs at air-liquid interface, cell cultures were characterised by functional assays, transcriptome and protein analysis, complemented by single-cell analysis in serial samples of pHBEC cultures focusing on basal cell differentiation. RESULTS: COPD-IV was characterised by a prosecretory phenotype (twofold increase in MUC5AC+) at the expense of the multiciliated epithelium (threefold reduction in Ac-Tub+), resulting in an increased resilience towards particle-induced cell damage (fivefold reduction in transepithelial electrical resistance), as exemplified by environmentally abundant doses of zinc oxide nanoparticles. Exposure of COPD-II cultures to cigarette smoke extract provoked the COPD-IV characteristic, prosecretory phenotype. Time-resolved single-cell transcriptomics revealed an underlying COPD-IV unique basal cell state characterised by a twofold increase in KRT5+ (P=0.018) and LAMB3+ (P=0.050) expression, as well as a significant activation of Wnt-specific (P=0.014) and Notch-specific (P=0.021) genes, especially in precursors of suprabasal and secretory cells. CONCLUSION: We identified COPD stage-specific gene alterations in basal cells that affect the cellular composition of the bronchial elevator and may control disease-specific epithelial resilience mechanisms in response to environmental nanoparticles. The identified phenomena likely inform treatment and prevention strategies.

BACKGROUND: Fibroblast to myofibroblast conversion is a major driver of tissue remodeling in organ fibrosis. Distinct lineages of fibroblasts support homeostatic tissue niche functions, yet, their specific activation states and phenotypic trajectories during injury and repair have remained unclear. METHODS: We combined spatial transcriptomics, multiplexed immunostainings, longitudinal single-cell RNA-seq and genetic lineage tracing to study fibroblast fates during mouse lung regeneration. Our findings were validated in IPF patient tissues in situ as well as in cell differentiation and invasion assays using patient lung fibroblasts. Cell differentiation and invasion assays established a function of SFRP1 in regulating human lung fibroblast invasion in response to TGFβ1. MEASUREMENTS AND MAIN RESULTS: We discovered a transitional fibroblast state characterized by high Sfrp1 expression, derived from both Tcf21-Cre lineage positive and negative cells. Sfrp1+ cells appeared early after injury in peribronchiolar, adventitial and alveolar locations and preceded the emergence of myofibroblasts. We identified lineage specific paracrine signals and inferred converging transcriptional trajectories towards Sfrp1+ transitional fibroblasts and Cthrc1+ myofibroblasts. TGFβ1 downregulated SFRP1 in non-invasive transitional cells and induced their switch to an invasive CTHRC1+ myofibroblast identity. Finally, using loss of function studies we showed that SFRP1 modulates TGFβ1 induced fibroblast invasion and RHOA pathway activity. CONCLUSIONS: Our study reveals the convergence of spatially and transcriptionally distinct fibroblast lineages into transcriptionally uniform myofibroblasts and identifies SFRP1 as a modulator of TGFβ1 driven fibroblast phenotypes in fibrogenesis. These findings are relevant in the context of therapeutic interventions that aim at limiting or reversing fibroblast foci formation.