Targeting Intravascular ERO1alpha to Treat Acute Lung Injury
Abstract
Acute lung injury (ALI) is a life-threatening condition, which accounts for 10%-15% of intensive care unit admissions. It results from excessive accumulation of neutrophils (the most abundant white blood cell) to the lungs. Other than the use of antibiotics, replenishing body fluids, and administering oxygen, there is no therapy targeting underlying molecular and cellular mechanisms. Although it is known that neutrophil accumulation is mediated by the interaction between neutrophil surface receptors and adhesion molecules on the vascular endothelium, it remains poorly understood how the receptor-ligand interactions are regulated during inflammation. The goal of this project is to elucidate the molecular mechanism mediating neutrophil-endothelium interactions and to provide insight into the development of effective therapy for attenuating ALI. Based on our preliminary data, we hypothesize that neutrophil endoplasmic reticulum oxidoreductase 1alpha (ERO1alpha) enhances the function of neutrophil surface receptors and contributes to neutrophil adhesion to the lung vascular endothelium during acute lung inflammation. This hypothesis will be tested using mice deficient in ERO1alpha and specific ERO1alpha inhibitors. First, we will determine how neutrophil ERO1alpha regulates neutrophil-endothelium interactions. We will then examine the ability of ERO1alpha inhibitors to mitigate tissue damage in mouse models of ALI. Finally, using the blood of patients with acute respiratory distress syndrome (ARDS, a severe form of ALI), we will study the contribution of ERO1alpha to blood cell clumping and the disease severity in patients. A better understanding of the mechanisms mediating neutrophil-endothelium interactions during acute lung inflammation will provide a platform for designing an effective therapeutic for treating ALI/ARDS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010228
Entities
People
- Jaehyung Cho
Organizations
- United States Army
- University of Illinois at Chicago