Inhibitory Effect of P22077 on Airway Inflammation in Rats with COPD and Its Mechanism

Abstract

Purpose

Here, we studied the pharmacological effect of P22077 on airway inflammation induced by lipopolysaccharide and cigarette smoke and explored the therapeutic mechanism of P22077 in COPD model RAT.

Patients and Methods

The COPD model was established by lipopolysaccharide combined with fumigation; animals were treated with vehicle or P22077. Serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected for analysis.

Results

Our results showed that P22077 treatment significantly improved the airway inflammation of COPD model RAT and reduced the recruitment of leukocytes in BALF, and hypersecretion of interleukin-18 (IL-18), interleukin-1β (IL-1β) in BALF and serum. H&E staining showed that P22077 treatment could effectively reduce emphysema, immune cell infiltration and airway wall destruction. PAS staining showed that The proliferation of cup cells in the airway wall and the number of bronchial cup cells were significantly reduced in rats treated with P22077. In addition, we found that P22077 treatment suppressed the generation of the NLRP3/ASC/Caspase 1 inflammasome complex to inhibit the inflammatory response caused by IL-1β and IL-18.

Conclusion

Conclusion: P22077 inhibits expression of NLRP3 pathway-related inflammatory factors and proteins and reduces the airway inflammatory response and inflammatory cell aggregation in COPD rats. The underlying mechanism may be related to the down-regulation of NLRP3 inflammatory vesicle signaling pathway expression.

Keywords:

• COPD
• ubiquitinase inhibitors
• P22077
• airway inflammation
• NLRP3

Abbreviations

IL-18, interleukin-18; IL-1β, interleukin-1β; COPD, Chronic obstructive pulmonary disease; AMC, macrophages; NEU, neutrophils; LYM, lymphocytes; HE, hematoxylin-eosin; PAS, Schiff’s periodate stain; USP1, ubiquitin-specific peptidase 1; UAF1, associated factor 1.

Data Sharing Statement

The provided data supporting the findings of this study are included within the article.

Ethics Approval

Ethical clearance was sought from the Ethics Committee of the North Sichuan Medical College, and follow the European Union Directive (2010/63/EU) on the protection of laboratory animals used for scientific causes.

Acknowledgments

The authors acknowledge the laboratory provided by North Sichuan Medical College.

Author Contributions

All authors have made significant contributions to the reported work, encompassing conception, study design, execution, data acquisition, analysis and interpretation. They have actively participated in drafting, revising or critically reviewing the article. Furthermore, they have provided their final approval for the version intended for publication and reached a consensus on the journal of submission. Additionally, they acknowledge their responsibility for all aspects of this research endeavor.

Disclosure

The authors declare that they have no conflicts of interest.