JZL184 modulates lung injury via occludin and TNF-α in two distinct ARDS models

Yusuf Elma; Emine Yılmaz Can; Meryem Akpolat Ferah; Mete Keçeci

doi:10.19161/etd.1647914

TR EN

JZL184 iki farklı ARDS modelinde okludin ve TNF-α yoluyla akciğer hasarını modüle etmektedir

Öz

Amaç: Akut solunum sıkıntısı sendromu (ARDS), yüksek morbidite ve mortaliteye sahip ciddi bir durum olup, şu anda sınırlı terapötik seçenekler ile tedavi edilmektedir. Son veriler, kannabinoidlerin akciğer hastalıkları da dahil olmak üzere doku hasarına karşı koruyucu etkiler sunabileceğini göstermektedir. Akciğer patolojilerindeki faydaları kanıtlanmış olsa da, kannabinoidlerin ARDS mekanizmalarındaki özgül rolü henüz yeterince araştırılmamıştır. Bu çalışma, farklı patofizyolojik mekanizmalara sahip iki ARDS modelinde, özellikle okludin ve TNF-α yoluyla kannabinoidlerin koruyucu etkilerini incelemeyi amaçlamaktadır. Gereç ve Yöntem: Sıçanlar, doğrudan ARDS modeli için LPS ile veya dolaylı ARDS modeli için ANTU ile muamele edilmiştir. Endokannabinoid 2-AG'yi parçalayan MAGL enziminin inhibitörü olan JZL184, LPS veya ANTU verilmeden 30 dakika önce uygulanmıştır. Akciğer doku örnekleri, LPS uygulamasından 24 saat ve ANTU uygulamasından 4 saat sonra toplanmıştır. Akciğer doku örneklerinde MDA, SOD ve katalaz olmak üzere biyokimyasal analizler ile okludin ve TNF-α'nın immünohistokimyasal değerlendirmeleri yapılmıştır. Bulgular: Biyokimyasal analizler, MDA seviyelerinin ANTU ve LPS gruplarında azaldığını, ancak ANTU+JZL184 grubunda arttığını ve LPS+JZL184 grubunda azaldığını göstermiştir, bu da paradoksal etkileri yansıtmaktadır. SOD ve katalaz seviyeleri, ANTU grubunda daha yüksek ve ANTU+JZL184 grubunda daha düşük bulunmuştur. İmmünohistokimyasal analizler ise JZL184 tedavisi sonrasında, endotel ve bronşiolar hücrelerin her ikisinde okludin ekspresyonunun düzeldiğini ve TNF-α seviyelerinin azaldığını göstermiştir. Sonuç: JZL184, her iki ARDS modelinde inflamasyonu hafifletmekte ve okludin ekspresyonunu düzeltmektedir, bu da ARDS için terapötik bir yaklaşım olarak potansiyelini ortaya koymaktadır.

Anahtar Kelimeler

JZL184 modulates lung injury via occludin and TNF-α in two distinct ARDS models

Abstract

Aim: Acute respiratory distress syndrome (ARDS) is a severe condition with high morbidity and mortality, currently treated with limited therapeutic options. Recent studies indicate that cannabinoids could play a protective role in preventing tissue damage, particularly in pulmonary disorders. While their benefits in lung pathologies are established, the specific role of cannabinoids in ARDS mechanisms remains underexplored. This study aims to investigate the protective effects of cannabinoids, particularly through occludin and TNF-α regulation, in two ARDS models with distinct pathophysiological mechanisms. Materials and Methods: Rats were treated with LPS for the direct ARDS model or ANTU for the indirect ARDS model. The inhibitor of MAGL, the enzyme that degrades the endocannabinoid 2-AG, JZL184, was administered 30 minutes prior to the administration of LPS or ANTU. Lung tissue samples were collected 24 hours post-LPS and 4 hours post-ANTU administration. Biochemical analyses, including MDA, SOD and catalase, as well as immunohistochemical evaluations of occludin and TNF-α, were conducted on lung tissue samples. Results: Biochemical analysis showed that MDA levels decreased in the ANTU and LPS groups, but increased in the ANTU+JZL184 group and decreased in the LPS+JZL184 group, reflecting paradoxical effects. SOD and catalase levels were higher in the ANTU group and lower in the ANTU+JZL184 group. Immunohistochemical analysis demonstrated the restoration of occludin expression in both endothelial and bronchiolar cells and a reduction in TNF-α levels following JZL184 treatment. Conclusion: JZL184 attenuates inflammation and restores occludin expression in both ARDS models, indicating its possible use as a therapeutic strategy for ARDS.

Keywords

Supporting Institution

This work was supported by the Scientific Research Projects Coordination Unit of Zonguldak Bulent Ecevit University.

Project Number

Proje no: 2022-43341027-03

Ethical Statement

All experimental procedures described in this study were previously approved by the Ethical Committee of Experimental Animals of Zonguldak Bulent Ecevit University (Protocol No: 2025-04-20/02).

Thanks

Zonguldak Bulent Ecevit University

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Details

Primary Language

English

Subjects

Clinical Sciences (Other)

Journal Section

Research Article

Authors

Yusuf Elma ^*
0000-0002-2670-6875
Türkiye

Emine Yılmaz Can
0000-0003-4022-2233
Türkiye

Meryem Akpolat Ferah
0000-0002-3419-1728
Türkiye

Mete Keçeci
0000-0002-2144-4730
Türkiye

Publication Date

June 10, 2025

Submission Date

February 27, 2025

Acceptance Date

April 8, 2025

Published in Issue

Year 2025 Volume: 64 Number: 2

DOI

https://doi.org/10.19161/etd.1647914

IZ

https://izlik.org/JA37UB29UE

Cite

RIS / Bibtex

Vancouver

1.Yusuf Elma, Emine Yılmaz Can, Meryem Akpolat Ferah, Mete Keçeci. JZL184 modulates lung injury via occludin and TNF-α in two distinct ARDS models. EJM. 2025 Jun. 1;64(2):363-7. doi:10.19161/etd.1647914