The role of HMGB1 in the lung response to bacterial injury

The objective of this project is to enable new therapies for bacterial pneumonia that rescue failed injury responses to allow healing and a return to normal lung function. Pneumonia, infection of the lower airways with dysregulated inflammation, is the leading cause of infectious disease and death in the United States. Macrophages are key responders to bacterial lung injury that clear microorganisms, remove damaged tissue, and promote epithelial repair. When the macrophage lung injury response (LIR) fails, additional innate immune cells are recruited into the damaged lung, leading to increased levels of pro-inflammatory proteases, cytokines, chemokines, and damage-associated molecular pattern molecules. Dysregulated inflammation itself then further compromises phagocytosis and limits epithelial repair. Thus, there is an urgent need to pinpoint and target mechanisms that derail productive lung injury responses and trigger self-damaging inflammation in these patients. This study will meet this unmet need by developing a therapeutic strategy to replace a failed component of the macrophage LIR and allow healing in patients with bacterial lung injury. HMGB1 (high mobility group box 1) has been extensively characterized as both a biomarker and cause of self-damaging inflammation in the lung. However, a growing body of evidence has demonstrated that HMGB1 is vital for bacterial clearance and epithelial restitution after injury. Macrophage HMGB1 appears to be particularly important for productive LIR since mice conditionally deficient in macrophage HMGB1 exhibit severe pulmonary inflammation and lung damage after lipopolysaccharide (LPS) challenge. This suggests that high extracellular HMGB1 (EHMGB1) in pneumonia patients indicates a failed HMGB1 function. Injured lung contains copious amounts of active proteases that could disable EHMGB1. The protease cathepsin G (CatG) is found at high levels in the inflamed lung, it also cleaves HMGB1 in the anti-inflammatory Box A portion of the protein. This led us to hypothesize that CatG cleaves macrophage produced HMGB1 in pneumonia, leading to dysfunctional HMGB1 and a non-productive, highly inflammatory LIR. In the proposed studies we will study HMGB1 functions in LIR using lung fluid samples from patients with lung injury and in vivo and in vitro models of lung injury caused by Pseudomonas aeruginosa or Staphylococcus aureus. We will also test a therapeutic approach that replaces the failed function of HMGB1 to support lung healing during pneumonia. This project will deliver a deep, mechanistic understanding of how a critical function of the productive LIR is lost in bacterial pneumonia and a novel therapeutic approach designed to correct this dysfunctional LIR. This therapeutic approach will have applications in bacterial pneumonia, acute lung injury of sepsis, and inflammatory lung diseases. Project Number: 1R01HL178625-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Jeannette Messer | Institution: CLEVELAND CLINIC LERNER COM-CWRU, CLEVELAND, OH | Award Amount: $656,988 | Activity Code: R01 | Study Section: Lung Immunology and Infection Study Section[LII] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17862501