Role and regulation of alveolar protein clearance in influenza virus-induced lung injury
Acute respiratory distress syndrome (ARDS), a common complication of influenza virus (IV) pneumonia, constitutes a significant disease burden with regard to both morbidity and mortality. A hallmark of ARDS is the functional disruption of the alveolar epithelial barrier leading to accumulation of protein-rich alveolar edema. Alveolar protein concentrations often reach 40‑90% of plasma levels, causing severe impairment of gas exchange and promoting deleterious alveolar remodeling, however, to date, no pharmacological therapies exist against this life-threatening condition.
It is well established that clearance of the excess alveolar protein is critical for survival. Protein removal is an active process across the epithelial layercell and is mediated in part by the multi-ligand receptor, megalin. We recently showed established that megalin-mediated protein transport is significantly impaired when lung epithelial cells are treated with bronchoalveolar lavage fluids from patients with IV-induced ARDS. Using infection models of primary rat, murine and human lung cells, transgenic mice, models of isolated ventilated murine lungs allowing protein reabsorption analysies in real-time, together with a Drosophila-based approach allowing direct visualization of protein traffficking and identification of regulatory networks of protein clearance by genome-wide RNAi-mediated gene inactivation selectively in the airways, the project aims to
i) define the molecular mechanisms impairing megalin function and protein transport processes in the IV-infected alveolar epithelium,
ii) investigate the mechanisms impairing protein clearance in a murine model of IV-induced ALI, and
iii) elucidate the regulatory networks of endocytosis traffic to be explored for their relevance for protein clearance in mammalian lungs under physiological and pathological conditions.
Since restoring the ability of the alveolar epithelium to remove excess protein content after IV-induced lung injury may prevent deleterious remodeling and thus could be employed as a therapeutic mean, the ultimate goal of this project is to assess the role and regulation of molecules involved in protein transport in the pathogenesis of the disease, and to evaluate interventions to rescue protein clearance processes as potential novel therapeutic approach.