MMP2 and MMP9 contribute to lung ischemia–reperfusion injury via promoting pyroptosis in mice

Abstract

Background Lung ischemia–reperfusion injury (LIRI) is a cause of poor prognosis in several lung diseases and after lung transplantation. In LIRI, matrix metalloproteinases and pyroptosis indicators change in parallel, both of them involvement of inflammatory modulation, but it is unclear whether they are related to each other. Methods We analyzed the matrix metalloproteinases (MMPs) changes from RNA sequencing (RNA-Seq) data of human transplantation and rat ischemia–reperfusion lung tissues in the Group on Earth Observations (GEO) database. Then established the mouse LIRI model to validate the changes. Further, the severity of lung injury was measured after intervening the matrix metalloproteinases changes with their selective inhibitor during Lung ischemia–reperfusion. Meanwhile, lung, pyroptosis was assessed by assaying the activity of Caspase-1 and interleukin 1β (IL-1β) before and after intervening the matrix metalloproteinases changes. Results The RNA-Seq data revealed that matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9) mRNA expression was elevated both in human lung transplantation and rat lung ischemia–reperfusion tissues, consistent with the change in our mouse model. At the same time, the activity of Caspase-1 and IL-1β were increased after LIRI. While, the lung injury was attenuated for the use of MMP2 and MMP9 selective inhibitor SB-3CT. Likewise, lung pyroptosis alleviated when treatment the mice with SB-3CT in LIRI. Conclusion We conclude that MMP2 and MMP9 are involved in the process of LIRI, the mechanism of which is related to the promotion of lung pyroptosis.

Identification of Neutrophil Extracellular Trap-Related Gene Expression Signatures in Ischemia Reperfusion Injury During Lung Transplantation: A Transcriptome Analysis and Clinical Validation

“…63 In addition, increased activity of Caspase-1 and IL-1β were observed after IRI, and the lung pyroptosis and injury alleviated when treatment the mice with MMP9 selective inhibitor SB-3CT, suggesting MMP9 involvement in IRI after lung transplant, potentially associated with promoting lung pyroptosis. 64 The transcriptome analysis in this study showed elevated MMP9 mRNA levels after reperfusion, and we observed a significant difference in MMP9 plasma levels between pre-and post-transplant of total 24 lung transplant patients. Nonetheless, no significant peri-reperfusion differences were observed in patients with PGD 2 grade or above, possibly due to the limited sample volume.…”

Pyroptosis: A Newly Discovered Therapeutic Target for Ischemia-Reperfusion Injury

“…In the respiratory organ, pretreatment with recombinant high-mobility group box 1 protein (rHMGB1) inhibited pyroptosis of alveolar macrophages through the Keap1/Nrf2/HO-1 signaling pathway, thus fighting against lung I/R injury [ 114 ]. In addition, it has been suggested that matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9) contribute to lung I/R injury via the promotion of lung pyroptosis [ 115 ]. In summary, all the above results provide new insights into inhibiting pyroptosis in the treatment of I/R injury in these organs.…”

Cellular and molecular mechanisms of cell damage and cell death in ischemia–reperfusion injury in organ transplantation

“…This promising laboratory finding suggests that disulfiram could be a potential pharmacological tool to provide more insights in the context of pyroptosis and its role in organ transplantation. Although pyroptosis has not been extensively studied in the context of organ transplantation, a growing body of experimental evidence implicates its involvement in various IRI models of transplantable solid organs [ 93 – 97 ]. Collectively, the preclinical and clinical findings suggest that inhibition of pyroptotic pathway could provide effective and innovative therapeutic approach to attenuate IRI and its associated complications after organ transplantation.…”