MG53 as a Novel Therapeutic Protein to Treat Acute Lung Injury

Abstract

Introduction Lung injury has several inciting etiologies ranging from trauma (contusion and hemorrhage) to ischemia reperfusion injury. Reflective of the injury, tissue and cellular injury increases proportionally with the injury stress and is an area of potential intervention to mitigate the injury. This study aims to evaluate the therapeutic benefits of recombinant human MG53 (rhMG53) protein in porcine models of acute lung injury (ALI). Materials and Methods We utilized live cell imaging to monitor the movement of MG53 in cultured human bronchial epithelial cells following mechanical injury. The in vivo efficacy of rhMG53 was evaluated in a porcine model of hemorrhagic shock/contusive lung injury. Varying doses of rhMG53 (0, 0.2, or 1 mg/kg) were administered intravenously to pigs after induction of hemorrhagic shock/contusive induced ALI. Ex vivo lung perfusion system enabled assessment of the isolated porcine lung after a warm ischemic induced injury with rhMG53 supplementation in the perfusate (1 mg/mL). Results MG53-mediated cell membrane repair is preserved in human bronchial epithelial cells. rhMG53 mitigates lung injury in the porcine model of combined hemorrhagic shock/contusive lung injury. Ex vivo lung perfusion administration of rhMG53 reduces warm ischemia-induced injury to the isolated porcine lung. Conclusions MG53 is an endogenous protein that circulates in the bloodstream. Therapeutic treatment with exogenous rhMG53 may be part of a strategy to restore (partially or completely) structural morphology and/or functional lung integrity. Systemic administration of rhMG53 constitutes a potential effective therapeutic means to combat ALI.

The Emerging Roles of Tripartite Motif Proteins (TRIMs) in Acute Lung Injury

“…We recently found that TRIM65 selectively targeted vascular cell adhesion molecule 1 (VCAM-1) and promoted its ubiquitination and degradation, by which it critically controlled the duration and magnitude of pulmonary inflammation in ALI [ 45 ]. Particularly, Whitson and his colleagues reported that TRIM72 (also known as MG53) could function as a novel therapeutic protein to treat ALI [ 46 ]. Here, we discuss our current understanding of TRIMs as E3 ligases that executes its effector functions in ALI ( Table 1 ).…”

“…The extracellular recombinant protein protects cultured lung epithelial cells against anoxia/reoxygenation-induced injuries [ 97 ]. Most recently, Whitson et al had evaluated the therapeutic benefits of recombinant human TRIM72 protein in porcine models of ALI and found that recombinant TRIM72 protein can mitigate lung injury in the porcine model of combined hemorrhagic shock/contusive lung injury and reduce warm ischemia-induced injury to the isolated porcine lung through ex vivo lung perfusion administration [ 46 ]. These findings revealed that TRIM72 plays a critical role in ALI, and exogenous-recombinant TRIM72 protein may be a shelf stable therapeutic agent with the potential to restore lung function and lessen the impact of ALI.…”

TRIM72 exerts antitumor effects in breast cancer and modulates lactate production and MCT4 promoter activity by interacting with PPP3CA

“…Later studies have suggested that upregulation of TRIM72 contributes to insulin resistance [14][15][16]; however, most of the results could not be repeated in more recent investigations [17][18][19]. New data have suggested that treatment with TRIM72 can repair membrane damage and facilitate tissue regeneration [20][21][22]. Further studies have also demonstrated that TRIM72 has remarkable protective effects on cells under inflammatory, hypoxic, and oxidative stress conditions [23,24].…”

MG53 attenuates nitrogen mustard‐induced acute lung injury

“…MG53 knockout mice ( mg53 −/− ) develop pulmonary pathology due to defective membrane repair 22 . We have shown that the recombinant human MG53 protein (rhMG53) when administered either intravenously (IV) or via aerosol has the ability to effectively mitigate lung ischaemia‐reperfusion injury, lipopolysaccharide‐induced inflammation and porcine pancreatic elastase (PPE)‐induced emphysema in rodents and pigs 23 . In addition to membrane repair, recent studies demonstrate an anti‐inflammatory function of MG53 in dampening NF‐kB signalling, and knockdown of MG53 leads to hyper‐inflammation in human macrophages 24,25 …”

“…22 We have shown that the recombinant human MG53 protein (rhMG53) when administered either intravenously (IV) or via aerosol has the ability to effectively mitigate lung ischaemia-reperfusion injury, lipopolysaccharide-induced inflammation and porcine pancreatic elastase (PPE)-induced emphysema in rodents and pigs. 23 In addition to membrane repair, recent studies demonstrate an anti-inflammatory function of MG53 in dampening NF-kB signalling, and knockdown of MG53 leads to hyper-inflammation in human macrophages. 24,25 Herein, we provide data to support the physiologic function of MG53 in lung protection and the potential therapeutic value of rhMG53 to treat vesicant-induced lung injury.…”