UCLA researchers in the Department of Anesthesiology & Perioperative Medicine have identified a novel method of targeting plasma extracellular vesicles to help suppress inflammation and infection during severe bacterial pneumonia.
BACKGROUND: Direct and indirect lung injury such as through pneumonia or following abdominal infections can lead to critical conditions such as Acute Respiratory Distress Syndrome (ARDS) or Sepsis. Even with current antibiotics and medical technologies, the mortality rate for these pathologies remains high at 40%, with over 350,000 deaths per year in the U.S. alone. Despite advancements within the field, managing ARDS and Sepsis patients remains challenging as there are few therapeutic targets which have shown efficacy in clinical trials. Extracellular vesicles (EVs), particularly those found within plasma or derived from immune cells such as macrophages and neutrophils, are one such target.
EVs are microparticles shed from cell membranes or other intracellular sources which contain biomolecular cargo such as RNA, proteins/receptors, DNA, and other organelles such as mitochondrion. These EVs play a vital role in both regulating physiological homeostasis and acting as catalysts for instigating and prolonging a rapid immune response. Due to their small size and ability to interact with target immune cells, high EV concentrations during injury can lead to a dangerous positive feedback loop from the resulting inflammatory response. Current research aimed towards utilizing EVs as a therapeutic target has attempted to reduce the inflammatory response by neutralizing EVs using compounds like High Molecular Weight Hyaluronic Acid (HMW HA) which bind to EV surface protein receptors. However, such methods have been significantly hampered by the toxicity of break-down products from the compounds used and the lack of lasting conferred protection. As such, there is a pressing need for more targeted therapeutics capable of effectively neutralizing plasma EVs during critical bacterial infections and providing long-lasting suppression of bacterial growth.
INNOVATION: Researchers at UCLA led by Dr. Jae-Woo Lee have identified that the multi-drug resistance-associated protein (MRP1) found on EVs can be inhibited to suppress the inflammatory properties of EV and increase bacterial phagocytosis by immune cells targeted by the EVs during severe bacterial pneumonia. The inventors have repurposed an MPR1-binding drug originally studied in cancer therapies as a novel strategy to target plasma EVs, which drive the inflammatory response during bacterial pneumonia infections. Inhibition of EVs by MRP1 was shown by the inventors to increase bacterial clearance by phagocytosis and reduce inflammation. This innovation exemplifies that MPR1 inhibitors can be used as a potential in vivo therapeutic to treat ARDS and Sepsis.
POTENTIAL APPLICATIONS:
- Treatment of ARDS, Sepsis, and severe bacterial pneumonia
- Combinatorial therapy to improve antibiotic treatments against resistant pathogens
ADVANTAGES:
- MRP1 treatment is reparative to damage tissue rather than inflammatory
- Discourages antibiotic resistance by stimulating infection clearance by macrophages rather than direct bactericidal activity
- Longer lasting protection from inflammation and injury than other EV-modulating therapeutics
DEVELOPMENT-TO-DATE: The inventors have successfully demonstrated that human lung tissue injured with E. coli bacterial pneumonia could be treated ex vivo with the MRP1 inhibitor to restore natural alveolar fluid clearance, suppress inflammation, and reduce total bacteria counts within the injured tissue. MRP1 inhibitor treatment also showed enhanced ability to stimulate macrophage phagocytotic activity for bacterial clearance.
Related Papers (from the inventors only):
Hwang W et al. Role of Extracellular Vesicles in Severe Pneumonia and Sepsis. Expert Opin Biol Ther. 22(6):747–762 (2023)
Liu et al. Therapeutic Effects of Hyaluronic Acid in Bacterial Pneumonia in Ex Vivo Perfused Human Lungs. Am J Respir Crit Care Med. 200(10):1234-1245 (2019).
KEYWORDS: Extracellular vesicles (EV), bacterial pneumonia, extracellular vesicles, MRP1, sepsis, acute respiratory distress syndrome (ARDS), microvesicles