Necrostatin-1 attenuates Caspase-1-dependent pyroptosis induced by the RIPK1/ZBP1 pathway in ventilator-induced lung injury.

Abstract

BACKGROUND:

Ventilator-induced lung injury (VILI) is a complex pathophysiological process leading to acute respiratory distress syndrome (ARDS) and poor outcomes in affected patients. As a form of programmed cell death, pyroptosis is proposed to play an important role in the development of ARDS. Here we investigated whether treating mice with the specific RIPK1 inhibitor Necrostatin-1 (Nec-1) before mechanical ventilation could inhibit pyroptosis and alleviate lung injury in a mouse model.

METHODOLOGYS:

Anesthetized C57BL/6J mice received a transtracheal injection of Nec-1 (5 mg/kg) or vehicle (DMSO) 30 min before the experiment which was ventilated for up to 4 h. Lung damage was assessed macroscopically and histologically with oedema measured as the wet/dry ratio of lung tissues. The release of inflammatory mediators into bronchoalveolar lavage fluid (BALF) was assessed by ELISA measurements of TNF-α,interleukin-1β (IL-1β), and IL-6. The expression of RIPK1, ZBP1, caspase-1, and activated (cleaved) caspase-1 were analyzed using western blot and immunohistochemistry, and the levels of gasdermin-D (GSDMD) and IL-1β were analyzed by immunofluorescence staining.

RESULTS:

High tidal ventilation produced time-dependent inflammation and lung injury in mice which could be significantly reduced by pretreatment with Nec-1. Notably, Nec-1 reduced the expression of key pyroptosis mediator proteins in lung tissues exposed to mechanical ventilation, including caspase-1, cleaved caspase-1, and GSDMD together with inhibiting the release of inflammatory cytokines.

CONCLUSION:

Nec-1 pretreatment alleviates pulmonary inflammatory responses and protects the lung from mechanical ventilation damage. The beneficial effects were mediated at least in part by inhibiting caspase-1-dependent pyroptosis through the RIPK1/ZBP1 pathway.

• Authors: Rong-Ge Shao, Qiu-Wen Xie, Ling-Hui Pan, Fei Lin, Ke Qin, Shao-Peng Ming, Jin-Ju Li, Xue-Ke Du
• Journal: Cytokine (Cytokine) Vol. 157 Pg. 155950 (09 2022) ISSN: 1096-0023 [Electronic] England
• PMID: 35780712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Imidazoles
• Indoles
• RNA-Binding Proteins
• Zbp1 protein, mouse
• necrostatin-1
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk1 protein, mouse
• Caspase 1

Topics

• Animals
• Caspase 1
• Imidazoles
• Indoles
• Lung (pathology)
• Mice
• Mice, Inbred C57BL
• Pyroptosis
• RNA-Binding Proteins
• Receptor-Interacting Protein Serine-Threonine Kinases
• Respiratory Distress Syndrome
• Ventilator-Induced Lung Injury (drug therapy)