Novel Drug/Receptor Codelivery to the Liver-Lung Axis to Overcome Glucocorticoid Resistance and Acute Respiratory Distress Syndrome in Sepsis
Abstract
Peer Reviewed Medical Research Program Topic Areas: Respiratory Health, Sustained Release Drug Delivery 1: What is the critical problem? Acute respiratory distress syndrome (ARDS) is a life-threatening condition caused by combat injuries and lung infections like pneumonia and COVID-19. Pseudomonas aeruginosa (PA) is a World Health Organization (WHO) Priority 1: Critical pathogen that frequently causes ventilator-associated pneumonia, particularly in patients with cystic fibrosis or combat casualties. Due to their potent anti-inflammatory and lung-protective effects, glucocorticoids (GCs) are widely used to treat respiratory diseases, e.g., neonatal respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma. In a large clinical trial, dexamethasone (DEX), a highly potent GC significantly reduced deaths in COVID-19 patients who need oxygenation/ventilation but tended to slightly increase mortality in patients who don’t need oxygenation/ventilation, likely due to the immunosuppressive effects of GCs. Additionally, many patients do not respond to GC therapy due to genetic mutations and/or environmental modifications of the GC receptor (GR). Thus, there is a critical need to develop a targeted GC therapy to achieve tissue-specific drug delivery and overcome the GC non-responsiveness. Such a targeted GC therapy will protect the lung and reduce inflammation in patients with ARDS caused by severe COVID-19 or PA infection. This is important because in combat casualties, PA infection causes higher morbidity and mortality than other infections. 2: Why is it important? Severe COVID-19 and pneumonia cause sepsis that results in hyperinflammation and multi-organ dysfunction syndrome (MODS). MODS is a life-threatening condition that causes the body’s organs to shut down. In addition to lung injury, liver dysfunction and injury is an early event and independent risk factor for sepsis-induced MODS and death. Severe COVID-19 causes a pulmonary GR deficiency. Hepatic GRs are also reduced in septic patients. Experimentally lowering GRs in the liver causes liver failure and increased mortality in septic mice. GR activation has many beneficial effects on the liver and lungs, but it can also cause many side effects on the neuromuscular, adipose, and immune systems. New treatments for ARDS and sepsis should overcome GC non-responsiveness to reduce hyperinflammation and restore organ function without impairing the body’s ability to fight against infections. The liver is the metabolic center essential for survival, and the lung is the first organ to fail in ARDS and MODS. Thus, we believe that developing a novel two-in-one targeted GC therapy that not only overcomes GC non-responsiveness but also specifically targets the liver-lung axis will be safer and more effective for ARDS and sepsis patients compared to the current systemic GC treatment. 3: What are the proposed experiments? As a proof of concept, our preliminary study demonstrated better GC responsiveness of a modified GR (fortified GR) than the wild-type GR. We also created a novel drug/receptor codelivery system in which we can co-deliver the drug (DEX) and the fortified GR protein into both the liver and lung to study how specifically activating GR in the liver and lung affects ARDS and sepsis outcomes. We will: (1) develop a novel two-in-one system of drug/receptor codelivery of DEX and a fortified GR to test its effects on GC non-responsiveness in human lung and liver cells and (2) determine effects of codelivery of DEX and the fortified GR on GC non-responsiveness and MODS in a mouse model of PA-induced ARDS and sepsis. Our central hypothesis is that our innovative two-in-one drug/receptor codelivery system will not only overcome GC non-responsiveness but maximize GC exposure to the liver and lung. By maximizing the beneficial effects of GCs on the liver and lung and minimizing GC’s side effects on other tissues and the immune system, our innovati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310073
Entities
People
- Hong Lu
Organizations
- State University of New York Upstate Medical University
- United States Army