Therapeutic Effects of Hyaluronic Acid in Bacterial Pneumonia in Ex Vivo Perfused Human Lungs

Rationale: Recent studies have demonstrated that extracellular vesicles (EVs) released during acute lung injury (ALI) were inflammatory. Objectives: The current study was undertaken to test the role of EVs induced and released from severe Escherichia coli pneumonia (E. coli EVs) in the pathogenesis of ALI and to determine whether high-molecular-weight (HMW) hyaluronic acid (HA) administration would suppress lung injury from E. coli EVs or bacterial pneumonia. Methods: E. coli EVs were collected from the perfusate of an ex vivo perfused human lung injured with intrabronchial E. coli bacteria for 6 hours by ultracentrifugation and then given intrabronchially or intravenously to naive human lungs. One hour later, HMW HA was instilled into the perfusate (n=5-6). In separate experiments, HMW HA was given after E. coli bacterial pneumonia (n=6-10). In vitro experiments were conducted to evaluate binding of EVs to HMW HA and uptake of EVs by human monocytes. Measurements and Main Results: Administration of HMW HA ameliorated the impairment of alveolar fluid clearance, protein permeability, and acute inflammation from E. coli EVs or pneumonia and reduced total bacteria counts after E. coli pneumonia. HMW HA bound to E. coli EVs, inhibiting the uptake of EVs by human monocytes, an effect associated with reduced TNF alpha (tumor necrosis factor a) secretion. Surprisingly, HMW HA increased E. coli bacteria phagocytosis by monocytes. Conclusions: EVs induced and released during severe bacterial pneumonia were inflammatory and induced ALI, and HMW HA administration was effective in inhibiting the uptake of EVs by target cells and decreasing lung injury from E. coli EVs or bacterial pneumonia.