COPD is frequently associated with mild to moderate pulmonary hypertension (PH). However, a small subset of patients develops severe PH, which is currently haemodynamically defined as mean pulmonary arterial pressure (mPAP) ⩾35 mmHg, or mPAP ⩾25 mmHg in combination with cardiac index <2.0 L•min −1 •m −2 [1, 2]. These cut-offs are, however, arbitrary and mainly based on expert opinion. In this study we aimed to determine prognostically relevant haemodynamic thresholds for severe PH in COPD by using an unbiased approach.We retrospectively analysed COPD patients with at least 1-year follow-up who underwent right heart catheterisation (RHC) and clinical evaluation at our clinic due to suspected PH between 2003 and 2018. RHC was performed in the supine position, with a mid-thoracic zero reference level, as previously described [3]. All data were included into a prospective local database (GRAPHIC (GRAz Pulmonary Hypertension In COPD) registry). Patients undergoing lung transplantation at any time (n=3) were excluded from this analysis. We performed Cox regression analysis, adjusting for age, sex and forced expiratory volume in 1 s (FEV 1 ) with the primary outcome all-cause mortality. For identification of the best prognostic cut-offs, we searched for the lowest p-values. Continuous baseline characteristics of the groups according to the best cut-off were compared using independent t-tests or Mann-Whitney U-test, as appropriate. Continuous variables are described as mean±SD or median (interquartile range), as appropriate. The study was approved by the institutional ethics board (EK: 32-180 ex 19/20) of the Medical University Graz.We included 139 COPD patients (age 68 (62-73) years; 55.4% male; mPAP 35 (27-43) mmHg; pulmonary vascular resistance (PVR) 4.3 (2.9-7.3) WU; FEV 1 56±20% predicted). 72 patients (52%) died during a follow-up of 8.0 (3.8-11.7) years, with a median time to death of 3.0 (1.3-5.2) years. 61 (44%) patients received any PAH drug at any time-point.Out of the examined haemodynamic parameters, after adjustment for age, sex and FEV 1 , PVR (HR 1.09, 95% CI 1.02-1.16; p=0.007) and mPAP (HR 1.03, 95% CI 1.01-1.05; p=0.001) were associated with survival, while pulmonary arterial wedge pressure (PAWP) and cardiac index were not ( p=0.696 and p=0.171). Among all haemodynamic parameters, PVR >5.0 WU was the best prognostic cut-off (HR 2.59, 95% CI 1.58-4.27; p<0.001) (figure 1a). Patients with PVR >5.0 WU were more frequently males ( p<0.001) and had a lower 6-min walk distance (254±112 versus 333±117 m; p<0.001), lower peak oxygen uptake (41±13 versus 61±23% predicted; p<0.001) and higher N-terminal pro brain natriuretic peptide (2288 (694-3634) versus 442 (160-1126) pg•mL −1 ; p<0.001) as compared to patients with PVR ⩽5.0 WU.For mPAP, the p-values for potential cut-off scores showed two equivalent minimal levels, the first at 33 mmHg (HR 2.26, 95% CI 1.37-3.71; p=0.001) (figure 1b) and the second at 45 mmHg (HR 2.44, 95% CI 1.43-4.16; p=0.001). Out of the patients with mPAP ⩾33 mmHg, n=28 (36%) and n=49 ...

A central feature of progressive vascular remodeling is altered smooth muscle cell (SMC) homeostasis; however, the understanding of how different cell populations contribute to this process is limited. Here, we utilized single cell RNA sequencing to provide insight into cellular composition changes within isolated pulmonary arteries (PA) from pulmonary arterial hypertension (PAH) and donor lungs. Our results revealed that remodeling skewed the balanced communication network between immune and structural cells, in particular SMC.Comparative analysis with murine PA showed that human PA harbor heterogeneous SMC populations with an abundant intermediary cluster displaying a gradient transition between SMC and adventitial fibroblasts. Transcriptionally distinct SMC populations were enriched in specific biological processes and could be distinguished into four major clusters: oxygen sensing (enriched in pericytes), contractile, synthetic and fibroblast-like. End-stage remodeling was associated with phenotypic shift of pre-existing SMC populations and accumulation of synthetic SMC in neointima. Distinctly regulated genes in clusters built non-redundant regulatory hubs encompassing stress response and differentiation regulators. The current study provides a blueprint of cellular and molecular changes on a single cell level that are defining pathological vascular remodeling process.

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Introduction: Idiopathic pulmonary fibrosis (IPF) is a deadly condition characterized by progressive respiratory dysfunction. Exacerbations due to airway infections are believed to promote disease progression, and presence of Streptococcus in the lung microbiome has been associated with progression of IPF and mortality. The aim of this study was to analyze the effect of lung fibrosis on susceptibility to pneumococcal pneumonia and bacteremia. Methods: The effects of subclinical (low dose) infection with Streptococcus pneumoniae were studied in a well characterized fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of spontaneous, progressive pulmonary fibrosis. Forty-eight hours after transnasal infection with Streptococcus pneumoniae, bacterial load was assessed in lung tissue, bronchoalveolar lavage (BAL), blood and spleen. Leukocyte subsets and cytokine levels were analyzed in BAL and blood. Lung compliance and arterial blood gases were assessed. Results: In contrast to wildtype mice, low dose lung infection with Streptococcus pneumoniae in Fra-2 TG mice resulted in substantial pneumonia including weight loss, increased lung bacterial load and bacteremia. BAL alveolar macrophages were reduced in Fra-2 TG mice compared to the corresponding WT mice. Proinflammatory cytokines and chemokines (IL-1β, IL-6, TNF-α, CXCL1) were elevated upon infection in BAL supernatant and plasma of Fra-2 TG mice. Lung compliance was decreased in Fra-2 TG mice following low dose infection with Streptococcus pneumoniae. Conclusions: Pulmonary fibrosis increases susceptibility to pneumococcal pneumonia and bacteremia possibly via impaired alveolar bacterial clearance.

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) poses a serious threat to healthcare systems worldwide. Binding of the virus to angiotensin‐converting enzyme 2 (ACE2) is an important step in the infection mechanism. However, it is unknown if ACE2 expression in patients with chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary arterial hypertension (IPAH), or pulmonary fibrosis (PF), is changed as compared to controls. We used lung samples from patients with COPD ( n = 28), IPAH ( n = 10), and PF ( n = 10) as well as healthy control donor ( n = 10) tissue samples to investigate the expression of ACE2 and related cofactors that might influence the course of SARS‐CoV‐2 infection. Expression levels of the ACE2 receptor, the putative receptor CD147/ BSG , and the viral entry cofactors TMPRSS2 (transmembrane serine protease 2), EZR , and FURIN were determined by quantitative PCR and in open‐access RNA sequencing datasets. Immunohistochemical and single‐cell RNA sequencing (scRNAseq) analyses were used for localization and coexpression, respectively. Soluble ACE2 (sACE2) plasma levels were analyzed by enzyme‐linked immunosorbent assay. In COPD as compared to donor, IPAH, and PF lung tissue, gene expression of ACE2 , TMPRSS2 , and EZR was significantly elevated, but circulating sACE2 levels were significantly reduced in COPD and PF plasma compared to healthy control and IPAH plasma samples. Lung tissue expressions of FURIN and CD147/ BSG were downregulated in COPD. None of these changes were associated with changes in pulmonary hemodynamics. Histological analysis revealed coexpression of ACE2, TMPRSS2, and Ezrin in bronchial regions and epithelial cells. This was confirmed by scRNAseq analysis. There were no significant expression changes of the analyzed molecules in the lung tissue of IPAH and idiopathic PF as compared to control. In conclusion, we reveal increased ACE2 and TMPRSS2 expression in lung tissue with a concomitant decrease of protective sACE2 in COPD patients. These changes represent the possible risk factors for an increased susceptibility of COPD patients to SARS‐CoV‐2 infection.

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