Pneumonia is the most frequent infectious disease and the leading cause of infectious child mortality worldwide, and inflicts a considerable socioeconomic burden on industrialized countries. In Germany, 12–17% of all hospitalized community-acquired pneumonia (CAP) patients die despite appropriate antibiotic treatment. Among the primary causes of death due to CAP are the development of acute lung injury / ARDS (Acute respiratory distress syndrome) and sepsis. Dysregulation of the innate immune system leading to harmful hyperinflammation, breakdown of vascular barrier function, and to microcirculatory failure, drives lung injury and its systemic sequelae, all of which contribute to the unfavorable outcome of patients with severe CAP. Furthermore, pneumonia has recently emerged as a risk factor and catalyst for atherosclerosis, frequently culminating in cardiovascular events. The underlying pathomechanisms remain incompletely understood and receive inadequate consideration in clinical practice, highlighting the pressing need for innovative adjunct therapeutic strategies alongside antibiotic treatment. Our research aims to advance knowledge on pneumonia and its sequelae by integrating diverse information from experimental in vitro and in vivo studies, as well as from observational and interventional clinical trials, all of which offer multi-layer data. This approach strives to elucidate pathomechanisms comprehensively, uncover new therapeutic targets, delineate patient subphenotypes, predict treatment outcomes, and ultimately pave the way for precision medicine to improve outcomes for CAP patients.
Mechanical ventilation is a life-sustaining intervention, but it predisposes ventilated patients to lower respiratory tract infections with a high incidence of ventilator-associated pneumonia (VAP). Early identification of patients at risk of developing VAP and timely intervention will not only shorten the duration of mechanical ventilation and hospital stay, but also reduce associated life-threatening events. In this context, we are investigating how ventilator-induced inflammation can further exacerbate pre-existing lung injury by compromising lung barrier function and contributing to an increased risk of pulmonary infection in patients already colonized with pathogenic bacteria (e.g. Pseudomonas aeruginosa). In addition, we aim to develop approaches to prevent the translocation of pulmonary inflammatory mediators and opportunistic pathogens to extrapulmonary organs in order to mitigate multi-organ dysfunction and reduce VAP mortality. Research questions related to this project are being addressed in vitro and in vivo as well as employing patient-derived data and samples.
Circadian rhythms are disrupted in patients admitted to the intensive care unit (ICU), but the associated molecular and cellular changes are not fully understood. We have recently shown that circadian clock function determines the severity of acute lung injury and myeloid cell function during mechanical ventilation (Felten et al., Am J Resp Crit Care Med, 2023). In ongoing efforts, we are using experimental models, transcriptomics tools, and clinical samples/data from ICU patients to gain deeper understanding of the mechanisms by which biological clock function mediates the immune response to infection or sterile injury in mechanically ventilated lungs. The knowledge gained will provide a basis for “circadian medicine” to reduce disease severity and exacerbation of acute lung injury in the ICU.
ARDS (Acute Respiratory Distress Syndrome) is a heterogeneous clinical syndrome characterised by acute, inflammatory lung injury resulting in hypoxaemic respiratory failure. There are currently no pharmacological treatments for ARDS. Dysregulation of the innate immune system leading to harmful hyperinflammation, breakdown of vascular barrier function, and to microcirculatory failure, drives lung injury and its systemic sequelae, all of which contribute to the unfavorable outcome of patients with ARDS. Furthermore, mechanical ventilation aggravates acute lung injury (-> Ventilator-Induced Lung Injury).
Our research aims to advance knowledge on ARDS by integrating diverse information from experimental in vitro and in vivo studies, as well as from observational and interventional clinical trials, all of which offer multi-layer data. This approach strives to elucidate pathomechanisms comprehensively, uncover new therapeutic targets, delineate patient subphenotypes, predict treatment outcomes, and ultimately pave the way for precision medicine to improve outcomes for ARDS patients.
In acute respiratory failure, mechanical ventilation (MV) is a life saving intervention. One third of all patients in intensive care units worldwide are receiving MV. However, particularly in preinjured lungs even minimal MV-associated physical stress is translated into biological signals of inflammation, evoking ventilator-induced lung injury (VILI). VILI is characterized by liberation of cytokines, recruitment of leukocytes to the lung and increased lung permeability, consecutively resulting in lung edema, surfactant dysfunction, impaired lung compliance and deterioration of pulmonary gas exchange. As the necessity to guarantee sufficient gas exchange limits a further substantial reduction of tidal volumes, new adjuvant pharmacological therapies in addition to lung-protective ventilation are needed to prevent VILI. Thus, we aim to enhance the understanding of pathomechanisms underlying VILI in order to develop new therapeutic strategies to limit VILI.
The umbrella term “Interstitial Lung Disease” denotes a heterogenous group of conditions of lung fibrosis (scarring), mostly resulting from lung inflammation. Therapeutic options are scarce, and lung transplantation is frequently the only treatment.
Our basic and patient-centered research strives to elucidate the pathomechanisms of lung fibrosis, particularly lung fibrosis resulting from acute lung injury, to understand the interplay with infections, to optimize lung transplantation outcome in ILD, and to investigate novel therapies. We intensely collaborate with the Department of Rheumatology at Charité, and also contribute to the INSIGHTS-ILD register.
We are particularly interested in developing novel therapies by studying different models of acute and chronic airway inflammation. Our preclinical research projects led to new critical insights into the pathogenesis of allergic type-2-high asthma focusing on airway hyperresponsiveness, immunological pathways and airway remodeling. We evaluated potential new treatment options for asthma, namely pharmacological inhibition of spleen tyrosine kinase (Tabeling et al. Allergy 2017) and the activation of the pattern recognition receptor NOD1 (Tabeling et al. Am J Respir Cell Mol Biol 2014). We also contributed to new insights in maternal asthma (Sodemann et al. Clin Exp Allergy 2020) and Th17 responses in asthma patients (Bacher et al. Cell 2019). In another approach, we optimized the long-term effects of allergen-specific immunotherapy through vitamin D supplementation (Heine et al. J Immunol 2014).
Further, we established a video bronchoscope in mice to study the effects of multiple unilateral allergen challenges (Dames et al. Am J Resp Cell Mol Biol 2014). This approach is attractive because it significantly reduces the number of animals used.
Despite modern therapy, pulmonary arterial hypertension (PAH) remains a fatal condition. Through collaborative efforts, we have recently uncovered central mechanisms of hypoxic pulmonary vasoconstriction (Tabeling et al. Eur Respir J 2021; Nagaraj et al. Eur Respir J 2017; Tabeling et al. Proc Natl Acad Sci U S A 2015; Wang et al. J Clin Invest 2012) and established the role of functional autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis (Becker et al. Am J Resp Crit Care Med 2014). We further characterized the autoantibody profile of patients with PAH (Tabeling et al. Front Immunol 2022). We are also interested in studying the development of pulmonary vascular hyperresponsiveness and remodeling and its association with pulmonary type 2 inflammation (Tabeling et al. Front Immunol 2022; Heine et al. J Immunol 2014; Schulze et al. FASEB J 2011; Haberberger et al. J Allergy Clin Immunol 2009; Witzenrath et al. Eur Resp J 2006). Current research focuses on spleen tyrosine kinase as a novel therapeutic target in pulmonary hypertension, among others.
Our patient care also contributes to the COMPERA register.
Host-targeted: Numerous ongoing preclinical and clinical studies investigate the safety, tolerability and efficacy of novel treatments targeting the host (patient) response to pathogens and other irritants in the lung.
Pathogen-targeted: We are investigating the potential of antibacterial strategies including bacteriophages (viruses that can kill bacteria) as an adjunct to antibiotic therapy for ventilator-associated pneumonia caused by multidrug-resistant gram-negative bacteria. We have developed an integrated set of in vitro and in vivo experimental models that provide critical data to evaluate the safety and efficacy of phage cocktails, to further develop and optimise them for clinical use in the first German trial on inhaled phages (Phage4Cure) and to understand the mechanistic interplay of phages with the host immune system (MAPVAP consortium). We also study the physiological state of phage-tolerant/resistant bacteria using microbiological, genetic and transcriptomic approaches, in order to develop new strategies to improve antibiotic and/or phage therapeutics efficacy.
Further, antiviral strategies are being tested translationally (e. g. Rohde et al. 2023 Efficacy and safety of zapnometinib in hospitalised adult patients with COVID-19: A randomised, double-blind, placebo-controlled, multi-centre, proof of concept / phase 2 trial (RESPIRE) eClinMed 2023 (accepted for publication).
Prophylaxis: Vaccination is the main prophylactic strategy used worldwide to prevent invasive bacterial diseases. However, existing polysaccharide vaccines have several limitations. An innovative chemical method recently established by our collaborator now allows the rapid synthesis of structurally defined oligosaccharide antigens with optimised immunogenic properties based on the binding specificities and structural features of protective antibodies (Seeberger PH et al. Curr Opin Chem Biol 2009). Together with our collaborators, we are currently evaluating highly promising vaccine candidates for their immunostimulatory and protective capacity in preclinical in vitro and in vivo studies.