Open Research Projects, Research

Maintaining vascular integrity in ARDS with Organ-on-Chip technology

Prinicipal Investigator

Prof. Dr. Wolfgang Kübler
Dr. Lasti Erfinanda

Scientific interest within the context of the graduate college:

Acute respiratory distress syndrome (ARDS) is a serious complication of infectious or sterile lung inflammation, typically as a consequence of pneumonia or sepsis, with high morbidity and mortality (30%-40%) and presently no pharmacological or mechanistic treatment strategies. This critical knowledge and treatment gap became strikingly evident in the recent COVID-19 pandemic, with ARDS as the main cause of death.1,2 ARDS is characterized by a breakdown of the lung vascular barrier and the leak of fluid from the blood into the airspaces, preventing normal lung mechanics and gas exchange. Traditionally, mechanisms of ARDS are studied in animal models, which have, however, translated poorly into the clinical scenario. Here, we will assess mechanisms of lung vascular barrier integrity and regeneration in a novel microphysiological Microvasculature-on-Chip (MOC) model that allows to track vascular morphology and leak as well as the dynamics of individual cell types and their interaction in an unprecedented temporal and spatial context. Here, we will employ this model for the first time to study lung vascular barrier integrity, and to devise strategies for its maintenance in experimental settings mimicking ARDS.

Project description:

Vascular barrier integrity is critical for normal lung function, as it preserves the compartmentalization between blood and airspaces of the lung, and prevents systemic entry and dissemination of inhaled pathogens and environmental pollutants. In the past, we and others have extensively studied mechanisms of lung vascular barrier integrity in animal as well as cell culture models,3-6 which, however, proved challenging to translate into the clinical scenario, and/or provide only limited spatial and temporal information on critical structural and functional changes in a realistic, multicellular 3D arrangement.

Pericytes are important regulators of endothelial homeostasis and vascular barrier integrity in the systemic circulation. As perivascular cells, they are encased within the basement membrane and surround vessels; their attachment to and interaction with endothelial cells stabilizes microvascular networks. Pericytes may be expected to serve similar vessel- and barrier-stabilizing functions in the lung, and ARDS may potentially drive barrier failure by causing pericyte loss or detachment. Counterintuitively, however, ablation of pericytes was recently reported to increase lung injury in a mouse model of ARDS.7 In the present proposal, we want to utilize a recently developed MOC model8,9 that we have – in collaboration with colleagues from the University of Berne and Stanford University – successfully adapted to study formation and integrity of lung microvascular networks formed by primary human lung endothelial cells and pericytes. Specifically, we aim to address the following research questions:

Question 1: What is the role of pericytes in lung vascular barrier integrity? To this end, we will generate self-assembling lung microvascular networks from primary human endothelial cells and pericytes, and probe for pericyte-endothelial interaction (e.g. via gap junctions, integrins, or paracrine mediators by use of high resolution structural and functional imaging, single cell RNA sequencing, and mass-spectrometry based proteomics, metabolomics and glycomics) and the functional role of pericytes and these interactions for barrier integrity (e.g. by targeted pericyte ablation using diphtheria toxin receptor expressing cells).

Question 2: How does ARDS affect pericyte-endothelial interaction, and how does this contribute to barrier failure in lung microvascular networks? In established lung microvascular networks composed of endothelial cells and pericytes, we will assess the effect of ARDS-characteristic stimuli (e.g. proinflammatory cytokines, bacterial exotoxins, infectious pathogens) on pericyte-endothelial interaction and its functional consequences on vascular integrity.

Question 3: Can we target pericyte-endothelial interaction to stabilize and/or restore vascular barrier integrity in ARDS-like settings in vitro? Based on results from questions 1 & 2, we will devise targeted strategies to preserve or restore homeostatic pericyte-endothelial interaction and as such, barrier integrity. Priority will be given to measures that may be implemented into the clinical scenario, e.g. by drug repurposing.
The results from this work are expected to provide novel insights into the intrinsic mechanism that regulate and preserve lung vascular barrier integrity and their exploitation as therapeutic strategy for the treatment of ARDS.

Application details


  1. Voelkel NF, Bogaard HJ, Kuebler WM. ARDS in the time of corona: context and perspective. Am J Physiol Lung Cell Mol Physiol. 2022; 323:L431-L437. doi: 10.1152/ajplung.00432.2021.
  2. Ahmad S, Matalon S, Kuebler WM. Understanding COVID-19 susceptibility and presentation based on its underlying physiology. Physiol Rev. 2022; 102:1579-1585. doi: 10.1152/physrev.00008.2022.
  3. Erfinanda L, Zou L, Gutbier B, […], Mall MA, Witzenrath M, Kuebler WM. Loss of endothelial CFTR drives barrier failure and edema formation in lung infection and can be targeted by CFTR potentiation. Sci Transl Med. 2022; 14:eabg8577. doi: 10.1126/scitranslmed.abg8577.
  4. Jiang T, Samapati R, Klassen S, […], Nüsing R, Uhlig S, Kuebler WM. Stimulation of the EP3 receptor causes lung oedema by activation of TRPC6 in pulmonary endothelial cells. Eur Respir J. 2022; 60:2102635. doi: 10.1183/13993003.02635-2021.
  5. McVey MJ, Maishan M, Foley A, […], Goldenberg NM, Khursigara CM, Kuebler WM. Pseudomonas aeruginosa membrane vesicles cause endothelial barrier failure and lung injury. Eur Respir J. 2022; 59:2101500. doi: 10.1183/13993003.01500-2021.
  6. Michalick L, Weidenfeld S, Grimmer B, […], Witzenrath M, Hippenstiel S, Kuebler WM. Plasma mediators in patients with severe COVID-19 cause lung endothelial barrier failure. Eur Respir J. 2021; 57:2002384. doi: 10.1183/13993003.02384-2020.
  7. Hung CF, Wilson CL, Chow YH, […], Gharib SA, Altemeier WA, Schnapp LM. Effect of lung pericyte-like cell ablation on the bleomycin model of injury and repair. Am J Physiol Lung Cell Mol Physiol. 2022; 322:L607-L616. doi: 10.1152/ajplung.00392.2021.
  8. Bichsel CA, Wang L, Froment L, […], Schmid RA, Guenat OT, Hall SRR. Increased PD-L1 expression and IL-6 secretion characterize human lung tumor-derived perivascular-like cells that promote vascular leakage in a perfusable microvasculature model. Sci Rep. 2017; 7:10636. doi: 10.1038/s41598-017-09928-1.
  9. Bichsel CA, Hall SR, Schmid RA, Guenat OT, Geiser T. Primary human lung pericytes support and stabilize in vitro perfusable microvessels. Tissue Eng Part A. 2015; 21:2166-76. doi: 10.1089/ten.TEA.2014.0545.