Preserving lung integrity and harnessing inflammation to treat vesicant-induced lung injury

Pulmonary exposure to adverse environments or vesicant agents can induce acute lung injury as well as prolonged inflammation and fibrotic remodeling. Sulfur mustard (SM) and nitrogen mustard (NM) are alkylating vesicant agents which cause extensive lung injuries. One consequence of vesicant exposure is the disruption of the intrinsic cell membrane repair function due to oxidative stress and inflammation. Development of therapeutic approaches that target the repair process of lung injury and mitigate inflammation can potentially provide effective means to alleviate the deleterious impact of vesicant or environmental insults in the lung. MG53 is a vital component of cell membrane repair and lung protection. We have previously shown that intravenous or inhalational administration of recombinant human MG53 protein (rhMG53) has therapeutic benefits to preserve lung function under trauma or pathological conditions. Here we provide novel findings to show that exposure of lung epithelial cells to NM disrupts the intrinsic membrane repair function for MG53. Systemic application of rhMG53 can alleviate NM-induced lung injury in mice. In addition to facilitating cell membrane repair, MG53 also dampens excessive inflammation. We find that human macrophages express MG53; and loss of MG53 leads to hyper-inflammation due to activation of NFĸB and increased vulnerability to vesicant-induced cell death. Based on these findings, we hypothesize that the dual function of MG53 in tissue-repair and limiting inflammation can mitigate vesicant-induced lung injury. Our goal is to translate the basic findings of MG53 into potential means to counteract vesicant-induced lung injury, by targeting both the acute phase of injury and the inflammatory component of fibrotic remodeling. We will investigate the physiological role and molecular mechanisms of MG53 in tissue repair and inflammation associated with vesicant-induced lung injury. Proof-of-concept studies will be conducted with rhMG53 in mouse and rat models of vesicant-induced lung injuries to determine the efficacy and safety windows of rhMG53 in rescuing lung function. Project Number: 1R01ES037603-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Chuanxi Cai (+1 co-PI) | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $1,460,280 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZES1 LWJ-W (CR)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11196394