TRIM72 promotes alveolar epithelial cell membrane repair and ameliorates lung fibrosis

Abstract

Background: Chronic tissue injury was shown to induce progressive scarring in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), while an array of repair/regeneration and stress responses come to equilibrium to determine the outcome of injury at the organ level. In the lung, type I alveolar epithelial (ATI) cells constitute the epithelial barrier, while type II alveolar epithelial (ATII) cells play a pivotal role in regenerating the injured distal lungs. It had been demonstrated that eukaryotic cells possess repair machinery that can quickly patch the damaged plasma membrane after injury, and our previous studies discovered the membrane-mending role of Tripartite motif containing 72 (TRIM72) that expresses in a limited number of tissues including the lung. Nevertheless, the role of alveolar epithelial cell (AEC) repair in the pathogenesis of IPF has not been examined yet. Method: In this study, we tested the specific roles of TRIM72 in the repair of ATII cells and the development of lung fibrosis. The role of membrane repair was accessed by saponin assay on isolated primary ATII cells and rat ATII cell line. The anti-fibrotic potential of TRIM72 was tested with bleomycin-treated transgenic mice. Results: We showed that TRIM72 was upregulated following various injuries and in human IPF lungs. However, TRIM72 expression in ATII cells of the IPF lungs had aberrant subcellular localization. In vitro studies showed that TRIM72 repairs membrane injury of immortalized and primary ATIIs, leading to inhibition of stress-induced p53 activation and reduction in cell apoptosis. In vivo studies demonstrated that TRIM72 protects the integrity of the alveolar epithelial layer and reduces lung fibrosis. Conclusion: Our results suggest that TRIM72 protects injured lungs and ameliorates fibrosis through promoting post-injury repair of AECs.

MG53, A Tissue Repair Protein with Broad Applications in Regenerative Medicine

“…Repetitive administration of rhMG53 improves pulmonary structure associated with chronic lung injury in mice [ 6 ]. Published data from other investigators also confirm the beneficial effects of inhalational rhMG53 to treat lung injury [ 13 , 67 ].…”

“…In addition to MG53′s protective role in cardiac and muscular pathology, MG53-mediated repair machinery protects against injury to non-muscle organs including I/R or contrast-induced acute kidney injury [ 5 , 15 ], stress-induced damage in lungs [ 6 , 13 , 14 , 67 ], chronic skin wounds [ 68 ], and hepatic I/R injury in liver transplantation and hepatic resections [ 20 ]. The most recent publication on the function of MG53 predicts more involvement of the protein in other diseases [ 69 ].…”

Plasma membrane integrity: implications for health and disease

“…Lysosomal exocytosis partially accounts for these vesicle fusion events, and in pneumocytes, this process is dependent on purinergic signaling [ 259 ]. Caveolar endocytosis, promoted by MG53 activity, is another prominent form of repair in type I cells [ 240 , 260 ] and while MG53 also fosters resealing in type II cells, its role in this context remains unclear [ 261 ]. Abnormalities in caveolae may accelerate ventilator-induced damage in pulmonary fibrosis patients who display reduced levels of caveolin-1 and mislocalization of MG53 [ 241 , 261 ].…”

“…Caveolar endocytosis, promoted by MG53 activity, is another prominent form of repair in type I cells [ 240 , 260 ] and while MG53 also fosters resealing in type II cells, its role in this context remains unclear [ 261 ]. Abnormalities in caveolae may accelerate ventilator-induced damage in pulmonary fibrosis patients who display reduced levels of caveolin-1 and mislocalization of MG53 [ 241 , 261 ]. It is foreseeable that functional differences between these two cell types, such as surfactant secretion, may influence their resistance to injury and repair capacity.…”

Identification and Validation of Aging-Related Genes in Idiopathic Pulmonary Fibrosis

“…At present, the key treatment approaches for IPF are based mainly on the symptoms and have low therapeutic effects; the 5 year survival rate after diagnosis is less than 50%, and the median survival time is only 2–3 years ( Kistler et al, 2014 ; Yoshihara et al, 2020 ). Increasing evidence shows that different biological functions such as cell proliferation, apoptosis, senescence, and autophagy play a role in IPF pathogenesis ( Predescu et al, 2017 ; Cong et al, 2020 ; Krempaska et al, 2020 ). Among these, cell senescence plays a major role.…”