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NLRP3 gene silencing ameliorates phosgene-induced acute lung injury in rats by inhibiting NLRP3 inflammasome and proinflammatory factors, but not anti-inflammatory factors
- Source :
- The Journal of Toxicological Sciences. 45:625-637
- Publication Year :
- 2020
- Publisher :
- Japanese Society of Toxicology, 2020.
-
Abstract
- NOD-like receptor protein 3 (NLRP3) is involved in acute lung injury (ALI), but its exact role in phosgene-induced ALI is not clearly understood. The aim of the study is to explore the potential therapeutic effect of NLRP3 inflammasome modulation in the management of phosgene-induced ALI. ALI was induced in rats by phosgene exposure at 8.33 g/m3 for 5 min, 30 hr before intravenous injection of adenovirus-NLRP3 shRNA (Ad/NLRP3-shRNA). The histological changes in the lung were evaluated. Bronchoalveolar lavage fluid (BALF) neutrophils were counted (smear), and protein content was measured using the BCA assay. The wet/dry ratio of lung tissue (W/D) was measured. TUNEL staining for DNA damage was used to indirectly assess pyroptosis. NLRP3 inflammasome was assessed by immunohistochemistry, RT-PCR, western blotting. Cytokines were measured by ELISA. Histological analyses revealed reduced severity in phosgene-induced ALI with Ad/NLRP3-shRNA pretreatment. TUNEL staining indicated decreased pyroptosis in Psg-Ad/NLRP3-shRNA rats. Decreased mRNA and protein levels of NLRP3 and caspase-1 (all P 0.05), were found in Psg-Ad/NLRP3-shRNA rats. Immunohistochemistry revealed that Ad/NLRP3-shRNA pretreatment inhibited NLRP3 inflammasome activation. Reduced level of pro-inflammatory interleukin (IL)-1β, IL-18, IL-33, and tumor necrosis factor (TNF)-α (all P 0.05), were found in serum and BALF from Ad/NLRP3-shRNA rats. NLRP3 gene silencing exerts beneficial effects on phosgene-induced lung injury by inhibiting NLRP3 inflammasome activation and pro-inflammatory factors, but not anti-inflammatory factors. Disruption of NLRP3 inflammasome activation might be used as a therapeutic modality for the treatment of phosgene-induced ALI.
- Subjects :
- Male
Inflammasomes
Acute Lung Injury
010501 environmental sciences
Lung injury
Pharmacology
Toxicology
030226 pharmacology & pharmacy
01 natural sciences
Proinflammatory cytokine
Rats, Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
NLR Family, Pyrin Domain-Containing 3 Protein
Animals
Medicine
Gene Silencing
RNA, Small Interfering
Phosgene
0105 earth and related environmental sciences
TUNEL assay
integumentary system
medicine.diagnostic_test
business.industry
Pyroptosis
Interleukin
Inflammasome
Genetic Therapy
respiratory system
Interleukin-10
respiratory tract diseases
Bronchoalveolar lavage
Injections, Intravenous
Cytokines
Tumor necrosis factor alpha
Interleukin-4
Inflammation Mediators
business
Biomarkers
medicine.drug
Subjects
Details
- ISSN :
- 18803989 and 03881350
- Volume :
- 45
- Database :
- OpenAIRE
- Journal :
- The Journal of Toxicological Sciences
- Accession number :
- edsair.doi.dedup.....07ef6ae01d319446b495ab81f420b59d