Prof. Manfred Frick

Our laboratory has a long-standing interest in the molecular mechanisms regulating surfactant and mucus secretion in the lung. We also aim to develop representative in vitro models of the airways and distal lung to investigate integrated physiological responses and to understand the pathophysiology of lung diseases.

• Molecular mechanisms of surfactant and mucus secretion

Secretion of surfactant and mucus in the alveoli and airways of the lung is essential to maintain lung function. Surfactant and mucus are secreted via exocytosis of intracellular storage granules from specialized secretory epithelial cells.  Exocytosis is a conserved mechanism in eukaryotic cells, comprising several stages that finally result in the fusion of a vesicle with the plasma membrane, opening of a fusion pore and release of vesicle contents. The amount and kinetics of secretion can be regulated at all stages. Our lab is particularly interested how secretion can be adjusted to demand. This entails understanding regulatory mechanisms / switches that shift steady state baseline secretion to high demand stimulated secretion. On the cellular level we are interested in the role of Ca²⁺ for regulating baseline / stimulated secretion and identification of the core exocytic machineries that mediate baseline / stimulated. On the physiological level, we are interested in the integrated response within respiratory epithelia that regulate secretion. In particular, we want to understand how mechanical signals within the alveolus adjust surfactant secretion.

In the past, we have also worked out the complex machinery that is required to expel surfactant from fused storge vesicles (lamellar bodies) following the opening of the fusion pore (“post-fusion” phase).

• In vitro models to investigate the pathophysiology of lung diseases.

Representative in vitro models that recapitulate the unique complexities of the human airways and distal lung should help improve our understanding of human lung disease.

The Frick lab is particularly interested in understanding the onset and progression of idiopathic pulmonary fibrosis (IPF), the development and resolution of acute lung injury (ALI/ARDS) and viral infections in the airway and alveolar epithelia (e.g. SARS-CoV-2).

To answer specific questions, we utilize in vitro models that mimic the cellular composition and the biophysical properties (e.g., ECM composition, physical properties, air-liquid) in the alveolus or airways. A main focus is understanding mechano-transduction pathways in the pathogenesis of IPF and the role of immune cells (PMNs, macrophages) in the disruption and repair of the alveolar air-blood barrier in ALI/ARDS.

Our group emphasizes the role of the airway epithelium in inflammatory lung diseases. Inflammatory lung diseases like chronic obstructive lung disease (COPD), asthma bronchiale and allergic lung diseases are life-threatening syndromes and since they are public diseases, they also cause a massive burden to the health system. 

We focus on the role of the lung epithelium in these inflammatory lung diseases. The lung epithelium forms the surface of the airways and thereby it constitutes the first defense line against airborne particles. It senses perturbations along the airways and orchestrates the immune defense.

The inflammatory responses of the lung tissue itself as well as of the attracted immune cells trigger modifications of epithelial function. We want to elaborate the epithelial mechanisms that are involved in inflammatory lung diseases and want to understand their contribution to lung tissue damage and disease course.

We utilize in-vitro models of the lung epithelium that bases on human primary lung epithelial cells. These models represent the cellular composition and functional properties of the lung epithelium best and enable the elaboration of disease mechanisms on the biophysical, cellular and molecular level. We continuously improve our models to improve translational aspects of our work.

The lipid bilayer of a cell effectively separates the intracellular space from the exterior but does not provide mechanical resistance. Instead the intermediate filaments (IF) that are built of elongated and staggered monomers traverse the interior of the cell to withstand tensile force. The IF subtype keratin (KIF) forms massive bundles and the KIF networks of adjacent cells are connected through desmosomes that function as a joint anchor points for KIFs of both cells.

For our studies we stretch living cells by stretching the elastic growth substrate. Besides general aspects related to KIF behavior after stretch we could show, that cell stretch leads to phosphorylation KIF, altering their mechanical properties. Supposedly this reduces the tensile load on the desmosomes to protect their structural integrity. Currently we scrutinize the response of the desmosomal protein desmoplakin to cell stretch. Its unique molecular structure strongly indicates a mechanosensory function of this molecule by stretch-induced unfolding and exposure of a reactive SH-binding site within.

The keratin network (green) spans the entire cell. Here the focal plane is chosen so that the peripheral keratin bundles are shown that insert in the desmosomes (red). When the cell is stretched the keratin bundles are straightened and the tensile load on the desmosomes increases.

This electron micrograph shows two cells and a desmosome connecting keratin bundles of each cell. The so called desmosomal dense plaque (two of them visible as bright bands) harbour the desmosomal proteins