Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine Lupus

Diffuse alveolar haemorrhage (DAH) is a rapidly developing condition owing to a lack of effective treatment and resulting in a high mortality rate in systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) contain numerous antigens and proinflammatory substances that directly damag...

Full description

Saved in:
Bibliographic Details
Published in:Journal of immunology research 2023-03, Vol.2023, p.4743975-14
Main Authors: Han, Xinai, Zhang, Xiaoming, Song, Rui, Li, Shiqi, Zou, Shujing, Tan, Quanguang, Liu, Tianyang, Luo, Shugeng, Wu, Zhe, Jie, Hongyu, Wang, Jinhong
Format: Article
Language:English
Subjects:
Alveoli
Animals
Antigens
Body weight
Cell activation
Cells
Edema
Elastase
Endothelium
Epithelial cells
Extracellular Traps
Hemorrhage
Hemorrhage - metabolism
Hemorrhage - pathology
Immunofluorescence
Immunohistochemistry
Immunology
Inflammation
Kinases
Leukocyte Elastase - metabolism
Leukocytes (neutrophilic)
Lupus
Lupus Erythematosus, Systemic
Mice
Neutrophils
Permeability
Systemic lupus erythematosus
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Diffuse alveolar haemorrhage (DAH) is a rapidly developing condition owing to a lack of effective treatment and resulting in a high mortality rate in systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) contain numerous antigens and proinflammatory substances that directly damage the vascular endothelium and aggravate vascular inflammation, which is considered an important pathogenic factor of DAH in SLE. Therefore, blocking the release of NETs from neutrophils is an important target for the treatment of DAH in SLE. In this study, we investigated whether the inhibition of neutrophils releasing NETs could relieve DAH in SLE. Necrostatin-1 (Nec-1), a small molecule, has been reported to inhibit the release of NETs by neutrophils. In vitro experiments revealed that Nec-1 inhibited alveolar epithelial cell damage by preventing the release of NETs. Furthermore, vivo studies showed that Nec-1 alleviated lupus pulmonary haemorrhage in mice by reducing lung pathology severity, body weight, and serum inflammatory cytokine levels. Mechanistically, Nec-1 prevented NET release by inhibiting neutrophil elastase (NE) activation and N-Gasdermin D (N-GSDMD) expression. Additionally, immunohistochemistry and immunofluorescence findings showed that Nec-1 decreased NE expression in the lung tissues of mice with lupus pulmonary haemorrhage. Thus, NETs released by neutrophils contributed to the pathogenesis of DAH in SLE, and Nec-1 showed protective effects by the inhibition of NET production via the reduction of NE activation and N-GSDMD expression.
ISSN:2314-8861
2314-7156
DOI:10.1155/2023/4743975