Large Conductance Potassium Channels Protect from Bacterial Pneumonia
Abstract
Critical Problem: Bacterial pneumonia is an infection that inflames the air sacs in one or both lungs. When this happens, the lung air sacs fill up with fluid, making it difficult to breath. Severe cases of bacterial pneumonia can lead to Acute Respiratory Distress Syndrome (ARDS), and according to the World Health Organization pneumonia accounts for 1.4 million deaths worldwide. The one million patients hospitalized with bacterial pneumonia each year add billions to our healthcare budget in the U.S. Besides the general population, bacterial pneumonia has significantly compromised the readiness of troops in U.S. military schools and training camps, including Marine Corps, Army Ranger recruits. Moreover, pneumococcal vaccines have not reduced pneumonia symptoms. Besides attempts to minimize mortality rates using antimicrobial and oxygen therapy, no targeted approaches exist that improve bacterial pneumonia patient outcomes. Thus, due to increasing antibiotic resistance and adverse reactions among the general population, military Service Members, and their families and beneficiaries, we face an urgent need to (i) identify new targets for rational anti-inflammatory drug design to improve patient outcomes, (ii) improve bacterial pneumonia models to better understand the disease process, and (iii) identify potential adverse reactions of newly developed drugs before reaching human clinical trials. All of these aspects are high priority topics for the Department of Defense. It has been shown in hyperoxia-induced Acute Lung Injury (ALI) that increase in a potassium ion flux through small holes in the lung cell membranes, so-called small potassium channels, changes the electric potential (membrane potential, Em) between the interior and the exterior of a cell. This leads to a decrease in intracellular calcium, inflammatory molecule release, thus, inflammation. However, it is unknown whether activation of big potassium channels (BK) could protect from bacterial pneumonia. We now propose a novel approach to reduce inflammation in bacterial infected lungs by pharmacologically altering cellular membrane potential, which will counteract the injurious effects of bacterial lung infections. In this study, we hypothesize that pharmacological activation of BK channels protects from bacterial pneumonia by hyperpolarizing the Em and decreasing calcium levels in two primarily affected cell types: primary human alveolar epithelial, facing the air-filled lung spaces, and pulmonary endothelial cells, facing the blood-filled lung spaces. Programmatic Relevance: We address major FY21 PRMRP Topic Areas and Areas of Encouragement within Respiratory Health: (i) Development and/or testing of novel and/or innovative treatments including precision medicine approaches, to prevent or delay the progression of ALI/ARDS; (ii) research on the etiology and prevention of ARDS caused by host responses to trauma, transfusion, mechanical ventilation, burns, infection, hemorrhagic shock, inhalation, and/or oxygen exposure; and (iii) strategies to stabilize and support the safe transport of patients with ARDS in order to optimize therapeutic interventions, particularly in operational scenarios requiring prolonged or extended care and/or longer transport times prior to definitive care. Innovation: (i) A novel hypothesis proposing that BK activation protects from bacterial pneumonia, thus establishing BK activators as new anti-inflammatory approach. (ii) Application of a novel computer algorithm to predict adverse effects of BK activators. (iii) Use of a clinically relevant bacterial pneumonia treatment model, by delaying delivery of oxygen therapy and BK activators until clinically-relevant symptoms arise. (iv) Creative disease models and approaches: (a) utilization of a live lung chip model using co-seeded primary human alveolar epithelial/endothelial cells and (b) cutting-edge, multidisciplinary approaches designed to analyze level of inflammation, potass
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210040
Entities
People
- Tatiana Zyrianova
Organizations
- United States Army
- University of California, Los Angeles