SLPI mediates protection against alveolar epithelial glycocalyx degradation during lung injury

• Applicant: Dr. Katharina Emily Marie Hellenthal
• Subject Area: Anaesthesiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562957570

Acute respiratory distress syndrome (ARDS) is a life-threatening condition in critical illness and can be triggered by pneumonia, aspiration, sepsis, pancreatitis or major trauma. Despite great efforts in investigation of treatment strategies, it is associated with a high mortality rate of up to 30-40% and long-term morbidity among survivors. The alveolar epithelial glycocalyx makes up the apical lining of the pulmonary epithelium and is crucial for lung homeostasis. Here, the epithelial glycocalyx creates a hydrophilic environment that facilitates interactions with surfactant proteins, which dissipate alveolar surface tension and oppose end-expiratory airspace collapse. Recently, the group of Prof. Eric P. Schmidt (Massachusetts General Hospital, Harvard) identified that matrix metalloproteinase-induced alveolar epithelial glycocalyx shedding causes surfactant dysfunction, a critical event in onset and propagation of ARDS. Surprisingly, women with ARDS demonstrated reduced alveolar epithelial glycocalyx shedding, which was associated with improved ARDS outcomes. However, to date, the impact of sex and gender on lung injury pathophysiology or ARDS heterogeneity is unknown, while ARDS therapy is mainly supportive lacking personalized treatment strategies. In preliminary analyses, Prof. Schmidt found that the only protease/antiprotease differentially expressed between the lungs of male and female organ donors is secretory leukocyte protease inhibitor (SLPI) that prevents processing of matrix metalloproteinase proenzymes into mature, activated matrix metalloproteinases. I here now hypothesize that increased alveolar epithelial SLPI expression - naturally occurring in human women - is sufficient to increase epithelial glycocalyx resilience against a pulmonary insult. To test this hypothesis, I will elucidate if conditional gene knockout/adeno-associated viral overexpression of alveolar type II epithelial SLPI increases/decreases epithelial glycocalyx shedding. Further, I will evaluate administration of exogenous SLPI as a novel therapeutic strategy in ARDS. I will induce sterile (lipopolysaccharide) or infectious (influenza, MRSA, Pseudomonas) lung injury in mice. These different ARDS models are each characterized by a different protease responsible for epithelial glycocalyx shedding. At peak injury and disease recovery, I will determine glycocalyx resilience, surfactant function and severity of lung injury. My goal with this project is to uncover a novel strategy to preserve organ function and improve outcome of patients on intensive care units suffering from ARDS, particularly those at elevated risk for glycocalyx loss (i.e., men or women with low SLPI levels).

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Eric W. Schmidt