Alveolar epithelial glycocalyx resilience in women during ARDS - The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure, with a dramatic increase in incidence occurring during respiratory pandemics. ARDS, however, is not a uniform disease state but rather represents a shared end-consequence of different pathogenic mechanisms of lung injury. Given this biological heterogeneity, there is increasing interest in precision medicine approaches to ARDS, so that therapies can be targeted to an individual patient’s dominant pathogenic mechanism of injury. While biological sex is known to be a fundamental differentiating factor in a precision medicine framework, strikingly little is known about its impact on ARDS heterogeneity. Emerging data from our collaborative research team indicate that males and female patients with ARDS experience distinct phenotypes of lung injury. Using airspace fluid collected from mechanically-ventilated patients, we found that females with ARDS experienced substantially less degradation of the alveolar epithelial glycocalyx, a glycosaminoglycan-enriched epithelial surface layer necessary for surfactant function and lung homeostasis. Using normal human lungs (donated by brain-dead donors but declined for transplantation) and bronchoalveolar lavage samples collected from healthy volunteers, we observed that female lungs had increased epithelial expression of secretory leukocyte protease inhibitor (SLPI), an antiprotease capable of protecting the epithelial glycocalyx. Overexpression of epithelial SLPI in mice was sufficient to attenuate epithelial glycocalyx shedding after experimental lung injury, leading to preservation of surfactant function. Based upon these compelling human and animal data, we hypothesize that increased alveolar epithelial expression of SLPI increases epithelial glycocalyx resilience, leading to a distinct biologic and phenotypic signature of ARDS. To address this hypothesis, our multi-institutional team of experts in ARDS and glycobiology will employ complementary animal and human studies to investigate the mechanistic relationships between SLPI expression, biological sex, and epithelial glycocalyx resilience. In Aim 1, we will use transgenic (Slpi knockout, adeno-associated viral SLPI overexpression) and pharmacologic approaches to determine the impact of epithelial SLPI expression on epithelial glycocalyx resilience in mice. In Aim 2, we will expand these investigations to human lungs, by (a) leveraging an ongoing NIH-developed human lipopolysaccharide challenge study to determine how the epithelial glycocalyces of healthy males (who express low alveolar SLPI) and females (who express high alveolar SLPI) differentially respond to a standardized pulmonary insult and (b) determining how normal human male and female lungs (donated by brain-dead donors) differentially respond to an infectious insult ex vivo. In Aim 3, we will perform a multicenter observational study of patients with ARDS to determine the real-world impact of epithelial glycocalyx resilience on the phenotypic heterogeneity of ARDS.
