Necrostatin‑1 protects mice from acute lung injury by suppressing necroptosis and reactive oxygen species

Abstract

acute lung injury (ali) is characterized by tissue damage and inflammatory cytokine secretion; however, the therapeutic options available to treat ALI remain limited. Necrostatin-1 (Nec-1) has the ability to attenuate cell necroptosis in various inflammatory diseases. The present study evaluated the protective effects of Nec-1 on a mouse model of lipopolysaccharide-induced ALI. Histological alterations in the lungs were evaluated through hematoxylin and eosin staining, and the expression levels of cytokines in the bronchoalveolar lavage fluid and lung tissues were determined by ELISA. In addition, accumulated production of reactive oxygen species was determined by staining with DCFH-DA probes, western blotting and immunofluorescence. The results revealed that treatment with the necroptosis inhibitor, Nec-1, exerted significant protective effects on ALI-induced inflammation and necroptosis. The key proteins involved in necroptosis were markedly reduced, including receptor-interacting serine/threonine-protein kinase (riP)1 and RIP3. Notably, antioxidant proteins were upregulated by Nec-1, which may attenuate oxidative stress. Furthermore, treatment with Nec-1 markedly suppressed necroptosis in the pulmonary alveoli RLE-6TN cell line. Taken together, these data revealed a novel association between ALI and necroptosis, and suggested that necroptosis inhibitors may be used as effective anti-inflammatory drugs to treat ALI.

Necrostatin-1 Prevents Ferroptosis in a RIPK1- and IDO-Independent Manner in Hepatocellular Carcinoma

“…This mechanism supports the preferential protection of necrostatin-1 for xCT inhibition, rather than GPX4 inhibition ( Figure 1 ). Although necrostatin-1 induced the expression of Nrf2 and heme oxygenase-1 in acute lung injury in mice [ 32 ], we did not observe activation of Nrf2 by necrostatin-1 in our cell models ( Figure 6 D). xCT expression is transcriptionally regulated by ATF4, STAT3/5, or p53 in addition to Nrf2 and stabilized by EGFR, CD44v, and the deubiquitylase OTUB1 [ 25 ].…”

Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

“…It has been shown that serum levels of RIPK3 are elevated in critically ill patients and are associated with the development of ALI/ARDs in sepsis, trauma and COVID-19 patients [15][16][17]. Recent experimental studies have demonstrated that inhibition of necroptosis confers protection against ALI induced by LPS [18][19][20], mechanical ventilation [21], sepsis/systemic inflammatory response syndrome [22][23][24], respiratory syncytial virus infection [25], bacterial pneumonia [26][27][28], trauma [29], and blood transfusion [30]. Hence, the targeting of necroptosis or its modulators holds significant promise for the treatment of ALI/ARDS.…”

Necroptosis in Pulmonary Diseases: A New Therapeutic Target

“…Then MLKL-induced membrane ruptures with the release of DAMPs, causing an excessive inflammatory response and aggravating lung tissue damage in mice ( Wang et al, 2016 ; Chen et al, 2018 ; Fan and Fan, 2018 ). Both inflammation and the degree of lung injury are reduced with Nec-1, which may attenuate oxidative stress ( Wang et al, 2016 ; Lin et al, 2020 ). In a neonatal septic mouse induced by intraperitoneal injection of adult cecal slurry, RIPK1 inhibition by Nec-1 has been reported to play a protective role, decreasing lung injury and increasing survival ( Bolognese et al, 2018 ).…”