The central pathophysiology of ventilator-associated lung injury (VALI) is dynamic tearing and repairing of the lung epithelial cells during mechanical ventilation when the lung is inflated beyond its normal tidal volume. We have shown previously that wounding of alveolar cells plays an important role in the development of VALI symptoms. However, the molecular components to repair alveolar cell injury remain completely mysterious. Previous efforts of our research team identified Mitsugumin 53 (MG53) in striated muscle, which senses changes in oxidative status at the membrane disruption site and shuttles pre-assembled membrane-associated vesicles to patch plasma membrane breakage in skeletal muscle cells. Our pilot study has found that MG53 expresses in lung cells and mg53-/- lung is susceptible to VALI. In this study, we aim to identify the molecular component for the repair of alveolar cells and the contribution of MG53 in VALI. The overall goal of this project is to gain a greater understanding for the role of MG53-mediated membrane repair in VALI and to develop a recombinant protein-based therapy for the treatment of VALI.
The specific aims of this project are: 1) to establish the role of MG53-mediated membrane repair in protection against membrane injury to lung epithelial cells in culture, 2) to determine the in vivo function of MG53 in the development of VALI, and 3) to explore the potential of using recombinant MG53 protein for the treatment of VALI. These studies represent a direct test to determine if MG53 is a central molecule for repair of deformation-induced injury to lung epithelial cells, and whether modulation of MG53-mediated cell membrane repair represents a potential effective mean for the treatment of VALI. In addition, our results will push the efforts for advancing a safe and potent therapy for VALI that involves in large-scale production of a protein naturally exists in the human body.
Ventilator-Associated Lung Injury (VALI) is characterized by symptoms of acute lung injury associated with clinical administration of mechanical ventilation. The major pathology of VALI is caused by extensive deformation of the lung tissue beyond the normal tidal volume. VALI may develop in patients with or without pre-existing lung diseases, and the incidence and mortality rate of VALI are high. The only preventive and treatment measure for VALI is ventilation strategies to reduce tidal volume without substantial decrease in the gas exchange efficiency. Although it is known that injury to lung resident cells is important for the development of VALI symptoms, the mechanisms that help the repair process of lung cells are poorly understood. Here we show that MG53 may be an essential molecule that mediates membrane repair in lung tissue and supplementation of recombinant MG53 improves the ability of lung cells to repair membrane damage. In this project, we will further examine the mechanism of MG53-mediated membrane repair in lung epithelial cells and aim to test the potential of our recombinant protein-based therapy in the treatment of VALI. This project will help to understand the mechanism of VALI and to develop a targeted therapy in treating such lung injuries in clinic.
|Kim, Seong Chul; Kellett, Thomas; Wang, Shaohua et al. (2014) TRIM72 is required for effective repair of alveolar epithelial cell wounding. Am J Physiol Lung Cell Mol Physiol 307:L449-59|