Biology subjects

Brandenberger, C.

Publications and source records attributed to Brandenberger, C..

3 recordsLinked to original sources

bioRxiv2026

Lung microvascular rarefaction impairs pulmonary gas exchange and exacerbates heart failure with preserved ejection fraction

BackgroundDyspnea and exercise intolerance are the primary clinical symptoms of heart failure. Heart failure patients experience frequent hypoxemic episodes, yet underlying mechanisms and relevance remain poorly understood. In a cohort of heart failure patients and multiple animal models, we identify pulmonary capillary rarefaction driven by excessive autophagy in endothelial cells as a novel mechanism of hypoxemia and cardiac disease progression. MethodsA cohort of heart failure with preserved ejection fraction (HFpEF) patients was analyzed for parameters of left ventricular (LV) dysfunction and pulmonary gas exchange. Morphological and cellular mechanisms of impaired pulmonary oxygenation were assessed in three animal models of heart failure, namely two HFpEF models, SU5416-treated ZSF1 obese rats and high fat diet/L-NAME treated mice, and in rats subjected to aortic banding. Lung microvascular rarefaction was quantified by micro-computed tomography, stereology, flow cytometry and dye efflux. Cellular mechanisms of capillary loss were analyzed by single-cell transcriptomics, electron microscopy and immunofluorescence, and in mice with endothelial-specific deletion of the autophagy gene Atg7 (Atg7EN-KO). ResultsIn 234 HFpEF patients, advancing NYHA class was associated with progressive worsening of arterial oxygen saturation at rest and during exercise and a reduced lung diffusing capacity. Impaired gas diffusion correlated with indices of LV diastolic dysfunction. Impaired oxygenation and reduced exercise capacity were similarly evident in animal models of left heart disease, which showed a distinct loss of pulmonary microvessels and capillaries. Lung microvascular endothelial cells in HFpEF showed characteristics of increased autophagic flux and apoptosis. Relative to their wild type HFpEF controls, Atg7EN-KO mice had less capillary loss, restored normoxemia, improved exercise tolerance, and mitigated LV diastolic dysfunction. Additional studies in HFpEF mice corroborated the functional relevance of impaired gas exchange for the progression of left heart disease by demonstrating that additional hypoxia aggravated, whereas moderate hyperoxia improved LV function. ConclusionOur findings identify pulmonary microvascular rarefaction as a novel pathomechanism in heart failure that i) contributes to dyspnea and exercise intolerance, ii) impairs pulmonary gas exchange and iii) accelerates LV disease progression. Strategies targeting this axis such as moderate oxygen therapy may mitigate cardiopulmonary morbidity in heart failure. Clinical Trial RegistrationRegistered in the DRKS (Deutsches Register fur klinische Studien) as trial# DRKS00032974 at https://drks.de/search/en/trial/DRKS00032974.

physiology↗

bioRxiv2025

Telomerase modRNA offers a novel RNA-based approach to treat human pulmonary fibrosis

Pulmonary Fibrosis (PF) is a life-threatening illness that is characterized by progressive scarring in the lung interstitium. There is an urgent need for new PF therapies because current treatments only slow down the progression of fibrosis and the median life expectancy post-diagnosis is only 4 to 6 years. Since PF patients frequently exhibit telomere attrition, overexpressing telomerase, the enzyme responsible for synthesizing telomeres represents a compelling therapeutic option. In this study, we in vitro transcribed human telomerase reverse transcriptase (hTERT) mRNA using modified nucleosides (modRNA). ModRNA hTERT treatment led to transient activation of telomerase activity in a dose-dependent manner in MRC-5 cells and, importantly, in primary human alveolar type II pneumocytes (ATII cells). Consequently, the proliferative capacity was increased, concomitant with reduced DNA damage and elongated telomere length. Notably, induction of cellular immune response was only detectable at the highest modRNA concentration, and returned to normal levels within 48 hours. Next, we demonstrated that circularized, exonuclease-resistant modRNA hTERT extended the transient expression profile which may be clinically advantageous. Finally, we provided therapeutic proof of concept in organotypic 3D ex vivo human precision-cut lung slices derived from end-stage PF patients. Intriguingly, a single modRNA hTERT treatment inhibited senescence as indicated by significantly lower levels of senescence-associated {beta}-galactosidase, and pro-inflammatory IL6 and IL8. Concurrently, the key fibrosis mediators TGF{beta} and COL1A1 were markedly reduced. In conclusion, the data presented herein provide initial evidence for the potential of RNA-based hTERT therapy for treating human lung fibrosis.

molecular biology↗

bioRxiv2024

Overventilation-induced airspace acidification increases susceptibility to Pseudomonas pneumonia

Ventilator-associated pneumonia (VAP) is the most frequent nosocomial infection in critically ill patients. Local pH variations affect bacterial growth. Whether airway acidification contributes to the pathogenesis and pathophysiology of Pseudomonas aeruginosa (PA)-induced VAP is currently unknown. This study was undertaken to investigate the role and mechanisms of airspace acidification by mechanical ventilation (MV) in PA-induced VAP. C57BL/6J mice were subjected to high (HVt: 34 mL/kg) or low (LVt: 9 mL/kg) tidal volume MV for 4 h. PA was instilled via the tracheal tube, and animals were allowed to recover from sedation and breathe spontaneously for 24 h following extubation. Fluorescence microscopy was applied to determine alveolar pH in ex vivo perfused and ventilated murine lungs. Bacterial growth and adhesion on cyclically stretched A549 and human alveolar epithelial cells was examined. Upon PA infection, HVt mice showed increased alveolo-capillary permeability, elevated lung and blood leukocyte counts, and higher bacterial load in lungs and extrapulmonary organs as compared to LVt controls. HVt MV induced acidification of alveolar lining fluid (ALF) in lungs and decreased pulmonary expression of Na+/H+ exchanger 1 (NHE1). Inhibition of NHE1 enhanced PA growth in vitro on alveolar epithelial cells and increased pulmonary bacterial loads in LVt-MV mice in vivo. In a novel murine VAP model, key characteristics of PA-VAP were replicated. HVt MV induced mild VILI with acidification of airway lining fluid, increasing susceptibility to PA pneumonia. NHE1 was identified as critical factor for MV-induced airspace acidification, and thus as potential target to combat PA-VAP.

immunology↗