Preconditioning with rHMGB1 ameliorates lung ischemia–reperfusion injury by inhibiting alveolar macrophage pyroptosis via the Keap1/Nrf2/HO-1 signaling pathway

Abstract

Background: Lung ischemia-reperfusion injury (LIRI) is a complex pathophysiological process that can lead to poor patient outcomes. Inflammasome-dependent macrophage pyroptosis contributes to organ damage caused by ischemia/reperfusion injury. Oxidative stress and antioxidant enzymes also play an important role in LIRI. In this study, we conducted experiments to investigate whether and how preconditioning with rHMGB1 could ameliorate LIRI in a mouse model. Methods: Adult male BALB/c mice were anesthetized, the left hilus pulmonis was clamped, and reperfusion was performed. rHMGB1 was administered via intraperitoneal injection before anesthesia, and brusatol was given intraperitoneally every other day before surgery. We measured pathohistological lung tissue damage, wet/dry mass ratios of pulmonary tissue, and levels of inflammatory mediators to assess the extent of lung injury. Alveolar macrophage pyroptosis was evaluated by measuring release of lactate dehydrogenase, caspase-1 expression was assessed using flow cytometry, and gasdermin-D expression was analyzed using immunofluorescent staining. Levels of oxidative stress markers and antioxidant enzymes were also analyzed. Results: Preconditioning with rHMGB1 significantly ameliorated lung injury induced by ischemia-reperfusion, based on measurements of morphology, wet/dry mass ratios, as well as expression of IL-1β, IL-6, NF-κB, and HMGB1 in lung tissues. It also alleviated alveolar macrophage pyroptosis, reduced oxidative stress and restored the activity of antioxidant enzymes. These beneficial effects were mediated at least in part by the Keap1/Nrf2/HO-1 pathway, since they were reversed by the pathway inhibitor brusatol. Conclusions: Preconditioning with rHMGB1 may protect against LIRI by suppressing alveolar macrophage pyroptosis. This appears to involve reduction of oxidative stress and promotion of antioxidant enzyme activity via the Keap1/ Nrf2/HO-1 pathway.

VX765, a Specific Caspase-1 Inhibitor, Alleviates Lung Ischemia Reperfusion Injury by Suppressing Endothelial Pyroptosis and Barrier Dysfunction

“…Studies have indicated that endothelial barrier dysfunction is a key factor in ischemia/reperfusion (I/R) injury [ 6 ]. The findings of our previous study were consistent with these other studies as we showed that lung I/R released large amounts of inflammatory factors and induced endothelial barrier dysfunction [ 7 ]. Recent studies also demonstrated that pyroptosis plays a key role in I/R injury [ 8 – 10 ], although it remains unclear whether pyroptosis is related to LIRI-induced endothelial barrier dysfunction.…”

Lung Inflation With Hydrogen During the Cold Ischemia Phase Alleviates Lung Ischemia-Reperfusion Injury by Inhibiting Pyroptosis in Rats

“…Moderate pyroptosis can act as a self-protective mechanism against infection, and severe pyroptosis can aggravate lung injury ( Man et al, 2017 ). Fei et al (2020) found that severe pyroptosis was present in a mouse model of lung IRI and inhibited pyroptosis via the alveolar macrophage pathway to ameliorate lung IRI with recombinant high-mobility group box 1. Xu et al (2018) found that in a mouse model of lung IRI, pyroptosis in the lung was more severe 2 h after reperfusion than 1 or 6 h after reperfusion.…”

Loganin Attenuates Septic Acute Renal Injury with the Participation of AKT and Nrf2/HO-1 Signaling Pathways

“… 12 Under various pathologic conditions, the strong correlation between oxidative stress injury and nuclear factor E2-related factor 2 (Nrf2) has been previously proved. 13–15 The preceding study has pointed out that Nrf2/HO-1 pathway is one of the most recognized signaling closely associated with oxidative and anti-oxidative balance. 16 , 17 Under normal circumstances, the cap “n” collar subfamily of basic region-leucine zipper transcription factor Nrf2 is restricted in the cytoplasm by binding to its ligand Kelch-like ECH associating protein 1 (Keap1).…”