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Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation
Published on: July 6, 2019
Fine particulate matter-induced lung inflammation is mediated by pyroptosis in mice
1International Collaborative Laboratory for Air Pollution Health Effects and Intervention, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province 453003, China.
Background:
Exposure to ambient air-borne fine particulate matter (PM2.5) increases respiratory morbidity and mortality. The mechanisms underlying PM2.5-induced adverse effects remain unclear. This study aimed to uncover the molecular mechanisms of PM2.5-induced lung toxicity using a mouse model.
Methods:
Scanning electron microscopy and inductively coupled plasma mass spectrometry were used to examine and analyze PM2.5 morphology and element compositions, respectively. Twenty four male mice were randomly divided into three groups: control (PBS), PM2.5 (4.0 mg/kg b.w.), and PM2.5 + Z-YVAD-FMK. In the latter group, the pan-caspase inhibitor (Z-YVAD-FMK) was intraperitoneally injected into mice at a dose of 12.5 mg/kg body weight prior to intratracheal instillation of PM2.5 (4.0 mg/kg b.w.) every other day for a total of 3 times (n = 8 in each group). Bronchoalveolar lavage fluids (BALFs) were collected 24 h after the last instillation of PM2.5. Levels of total proteins (TP), lactate dehydrogenase (LDH), IL-1β and IL-18 were analyzed for biomarkers of cell injury and inflammation. Additionally, histological alterations of lung tissues were assessed by hematoxylin-eosin staining. mRNA and protein expression of Caspase1, NLRP3 and GSDMD were examined by real-time fluorescent quantitative PCR and immunohistochemical staining.
Results:
Exposure to PM2.5 increased levels of TP, LDH, IL-1β, IL-18 and inflammatory cell counts in lung. The mRNA and protein expression of Caspase1, NLRP3 and GSDMD were increased. Inhibition of the NALRP3/Caspase-1 signaling pathway ameliorated PM2.5-induced lung injury and inflammation, partially through suppressing pyroptosis in lung.
Conclusion:
PM2.5 exposure induces lung injury and inflammation, which is mediated by the NALRP3/Caspase-1 signaling pathway.
Insights
Fine particulate matter (PM$_{2.5}$) exposure causes lung injury and inflammation. This study reveals that the NLRP3/Caspase-1 pathway mediates these effects, suggesting a potential therapeutic target for PM$_{2.5}$-induced respiratory diseases.
Area of Science:
- Environmental Health
- Toxicology
- Molecular Biology
Background:
- Ambient fine particulate matter (PM$_{2.5}$) exposure is a significant risk factor for respiratory morbidity and mortality.
- The precise molecular mechanisms driving PM$_{2.5}$-induced lung toxicity are not fully understood.
- This research investigates the cellular and molecular pathways involved in PM$_{2.5}$-induced lung damage.
Purpose of the Study:
- To elucidate the molecular mechanisms of lung toxicity induced by PM$_{2.5}$ exposure.
- To investigate the role of the NLRP3 inflammasome and Caspase-1 in PM$_{2.5}$-induced lung inflammation and injury.
- To evaluate the therapeutic potential of inhibiting the NLRP3/Caspase-1 pathway.
Main Methods:
- PM$_{2.5}$ characterization using scanning electron microscopy and inductively coupled plasma mass spectrometry.
- A mouse model exposed to PM$_{2.5}$ with or without a pan-caspase inhibitor (Z-YVAD-FMK).
- Analysis of bronchoalveolar lavage fluid (BALF) for inflammatory markers and assessment of lung histology, gene, and protein expression.
Main Results:
- PM$_{2.5}$ exposure significantly increased lung injury markers (total protein, LDH), inflammatory cell counts, and levels of IL-1β and IL-18.
- Upregulation of Caspase-1, NLRP3, and GSDMD at both mRNA and protein levels was observed following PM$_{2.5}$ exposure.
- Inhibition of the NLRP3/Caspase-1 pathway attenuated PM$_{2.5}$-induced lung injury and inflammation, partly by suppressing pyroptosis.
Conclusions:
- PM$_{2.5}$ exposure triggers lung injury and inflammation through the activation of the NLRP3/Caspase-1 signaling pathway.
- The NLRP3/Caspase-1 pathway, involving pyroptosis, plays a critical role in the pathogenesis of PM$_{2.5}$-induced lung toxicity.
- Targeting the NLRP3/Caspase-1 pathway presents a potential therapeutic strategy for mitigating PM$_{2.5}$-related lung diseases.
