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

Destekleyen Kurum

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

Proje Numarası

Proje no: 2022-43341027-03

Etik Beyan

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).

Teşekkür

Zonguldak Bulent Ecevit University

Kaynakça

Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967;2(7511):319-23.
Grotberg JC, Reynolds D, Kraft BD. Management of severe acute respiratory distress syndrome: a primer. Crit Care 2023;27(1):289.
Qadir N, Sahetya S, Munshi L, Summers C, Abrams D, Beitler J, Bellani G, Brower RG, Burry L, Chen JT, Hodgson C, Hough CL, Lamontagne F, Law A, Papazian L, Pham T, Rubin E, Siuba M, Telias I, Patolia S, Chaudhuri D, Walkey A, Rochwerg B, Fan E. An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 2024;209(1):24-36.
Latronico N, Eikermann M, Ely EW, Needham DM. Improving management of ARDS: uniting acute management and long-term recovery. Crit Care 2024;28(1):58.
Turcotte C, Chouinard F, Lefebvre JS, Flamand N. Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites. J Leukoc Biol 2015;97(6):1049-70.
Khadangi F, Forgues AS, Tremblay-Pitre S, Dufour-Mailhot A, Henry C, Boucher M, Beaulieu MJ, Morissette M, Fereydoonzad L, Brunet D, Robichaud A, Bossé Y. Intranasal versus intratracheal exposure to lipopolysaccharides in a murine model of acute respiratory distress syndrome. Sci Rep 2021;11(1):7777.
Adar A, Can EY, Elma Y, Ferah MA, Kececi M, Muderrisoglu H, Akbay E, Akıncı S, Coner A, Haberal C, Cakan F, Onalan O. A new and simple parameter for diagnosis pulmonary edema: Expiratory air humidity. Heart Lung 2022;52:165-9.
Comert M, Sipahi EY, Ustun H, Isikdemir F, Numanoglu G, Barut F, Altunkaya H, Ozer Y, Niyazi Ayoglu F, Sipahi TH, Tekin IO, Banoglu ZN. Morphine modulates inducible nitric oxide synthase expression and reduces pulmonary oedema induced by alpha-naphthylthiourea. Eur J Pharmacol 2005;511(2-3):183-9.

Sipahi E, Hodoglugil U, Ercan ZS, Türker RK. Acute effect of endothelin-1 on lung oedema induced by alpha-naphthylthiourea (ANTU). Pharmacol Res 1996;33(6):375-8.
Sipahi E, Hodoğlugil U, Ustün H, Zengil H, Türker RK, Ercan ZS. An unexpected interaction between NG-nitro-L-arginine methyl ester and L-arginine in alpha-naphthylthiourea-induced pulmonary oedema in rats. Eur J Pharmacol 1997;321(1):45-51.
Sipahi E, Ustün H, Niyazi Ayoglu F. Acute effects of pentobarbital, thiopental and urethane on lung oedema induced by alpha-naphthythiourea (ANTU). Pharmacol Res 2002;45(3):235-9.
Sipahi EY, Ozel Tekin I, Comert M, Barut F, Ustun H, Sipahi TH. Oxidized low-density lipoproteins accumulate in rat lung after experimental lung edema induced by alpha- naphthylthiourea (ANTU). Pharmacol Res 2004;50(6):585-91.
Lin X, Bai H, Barravecchia M, Norman R, Schiralli Lester GM, Kottmann RM, Leonard A, Rahman A, Young JL, Dean DA. Occludin Is Essential to Maintain Normal Alveolar Barrier Integrity and Its Protective Role During ARDS Progression. Int J Mol Sci 2024;25(21):11595.
Fraguas-Sánchez AI, Torres-Suárez AI. Medical Use of Cannabinoids. Drugs 2018;78(16):1665-1703.
Alves P, Amaral C, Teixeira N, Correia-da-Silva G. Cannabis sativa: Much more beyond Δ9-tetrahydrocannabinol. Pharmacol Res 2020;157:104822.
Cascorbi I. Clinical Pharmacology of Cannabinoid Therapeutics: Drug Interactions and Side Effects. Clin Pharmacol Ther 2023;114(5):943-6.
Cristino L, Bisogno T, Di Marzo V. Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol 2020;16(1):9-29.
Bourke SL, Schlag AK, O'Sullivan SE, Nutt DJ, Finn DP. Cannabinoids and the endocannabinoid system in fibromyalgia: A review of preclinical and clinical research. Pharmacol Ther 2022;240:108216.
Bilbao A, Spanagel R. Medical cannabinoids: a pharmacology-based systematic review and meta-analysis for all relevant medical indications. BMC Med 2022;20(1):259.
Das S, Ghosh A, Karmakar V, Khawas S, Vatsha P, Roy KK, Behera PC. Cannabis effectiveness on immunologic potency of pulmonary contagion. J Basic Clin Physiol Pharmacol 2024;35(3):129-42.
Tahamtan A, Samieipoor Y, Nayeri FS, Rahbarimanesh AA, Izadi A, Rashidi-Nezhad A, Tavakoli-Yaraki M, Farahmand M, Bont L, Shokri F, Mokhatri-Azad T, Salimi V. Effects of cannabinoid receptor type 2 in respiratory syncytial virus infection in human subjects and mice. Virulence 2018;9(1):217-30.
Wu X, Chen L, Cheng Y, Zhang Y, Yang W, Pan L, Fu C, Zhu H, Zhang M. A selective CB2R agonist (JWH133) protects against pulmonary fibrosis through inhibiting FAK/ERK/S100A4 signaling pathways. BMC Pulm Med 2023;23(1):440.
Çakır M, Tekin S, Okan A, Çakan P, Doğanyiğit Z. The ameliorating effect of cannabinoid type 2 receptor activation on brain, lung, liver and heart damage in cecal ligation and puncture-induced sepsis model in rats. Int Immunopharmacol 2020;78:105978.
Costola-de-Souza C, Ribeiro A, Ferraz-de-Paula V, Calefi AS, Aloia TP, Gimenes-Júnior JA, de Almeida VI, Pinheiro ML, Palermo-Neto J. Monoacylglycerol lipase (MAGL) inhibition attenuates acute lung injury in mice. PLoS One 2013;8(10):e77706.
Wang J, Xu H, Chen T, Xu C, Zhang X, Zhao S. Effect of Monoacylglycerol Lipase Inhibition on Intestinal Permeability of Rats With Severe Acute Pancreatitis. Front Pharmacol 2022;13:869482.
Paredes-Ruiz KJ, Chavira-Ramos K, Galvan-Arzate S, Rangel-López E, Karasu Ç, Túnez I, Skalny AV, Ke T, Aschner M, Orozco-Morales M, Colín-González AL, Santamaría A. Monoacylglycerol Lipase Inhibition Prevents Short-Term Mitochondrial Dysfunction and Oxidative Damage in Rat Brain Synaptosomal/Mitochondrial Fractions and Cortical Slices: Role of Cannabinoid Receptors. Neurotox Res 2023;41(6):514-25.
Demir Çaltekin M, Özkut MM, Çaltekin İ, Kaymak E, Çakır M, Kara M, Yalvaç ES. The protective effect of JZL184 on ovarian ischemia reperfusion injury and ovarian reserve in rats. J Obstet Gynaecol Res 2021;47(8):2692-704.
Liu M, Gu C, Wang Y. Upregulation of the tight junction protein occludin: effects on ventilation-induced lung injury and mechanisms of action. BMC Pulm Med 2014;14:94.
Cui L, Yang R, Huo D, Li L, Qu X, Wang J, Wang X, Liu H, Chen H, Wang X. Streptococcus pneumoniae extracellular vesicles aggravate alveolar epithelial barrier disruption via autophagic degradation of OCLN (occludin). Autophagy 2024;20(7):1577-96.
Wang J, Zhang X, Yang C, Zhao S. Effect of monoacylglycerol lipase inhibition on intestinal permeability in chronic stress model. Biochem Biophys Res Commun 2020;525(4):962-7. Volume 64 Issue 2, June 2025 / Cilt 64 Sayı 2, Haziran 2025 373
Jiang H, Li H, Cao Y, Zhang R, Zhou L, Zhou Y, Zeng X, Wu J, Wu D, Wu D, Guo X, Li X, Wu H, Li P. Effects of cannabinoid (CBD) on blood brain barrier permeability after brain injury in rats. Brain Res 2021;1768:147586.
Wang Z, Li Y, Cai S, Li R, Cao G. Cannabinoid receptor 2 agonist attenuates blood‑brain barrier damage in a rat model of intracerebral hemorrhage by activating the Rac1 pathway. Int J Mol Med 2018;42(5):2914-22.
Mozooni Z, Ghadyani R, Soleimani S, Ahangar ER, Sheikhpour M, Haghighi M, Motallebi M, Movafagh A, Aghaei-Zarch SM. TNF-α, and TNFRs in gastrointestinal cancers. Pathol Res Pract 2024;263:155665.
Malaviya R, Laskin JD, Laskin DL. Anti-TNFα therapy in inflammatory lung diseases. Pharmacol Ther 2017;180:90-8.
Lu Y, Wu Y, Huang M, Chen J, Zhang Z, Li J, Yang R, Liu Y, Cai S. Fuzhengjiedu formula exerts protective effect against LPS-induced acute lung injury via gut-lung axis. Phytomedicine 2024;123:155190.
Wang X, Lin C, Jin S, Wang Y, Peng Y, Wang X. Cannabidiol alleviates neuroinflammation and attenuates neuropathic pain via targeting FKBP5. Brain Behav Immun 2023;111:365-75.
Henshaw FR, Dewsbury LS, Lim CK, Steiner GZ. The effects of cannabinoids on pro- and anti-inflammatory cytokines: A systematic review of in vivo studies. Cannabis Cannabinoid Res 2021;6(3):177-95.
Vallée A. Cannabidiol and SARS-CoV-2 infection. Front Immunol 2022;13:870787.
Ma H, Xu F, Liu C, Seeram NP. A network pharmacology approach to identify potential molecular targets for cannabidiol's anti-inflammatory activity. Cannabis Cannabinoid Res 2021;6(4):288-99.
Hu H, Yao Y, Liu F, Luo L, Liu J, Wang X, Wang Q. Integrated microbiome and metabolomics revealed the protective effect of baicalin on alveolar bone inflammatory resorption in aging. Phytomedicine 2024;124:155233.
Mao M, Cao X, Liang Y, Li Q, Chen S, Zhou L, Zhang Y, Guo Y. Neuroprotection of rhubarb extract against cerebral ischaemia-reperfusion injury via the gut-brain axis pathway. Phytomedicine 2024;126:155254.

Ayrıntılar

Birincil Dil

İngilizce

Konular

Klinik Tıp Bilimleri (Diğer)

Bölüm

Araştırma Makalesi

Yazarlar

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

Yayımlanma Tarihi

10 Haziran 2025

Gönderilme Tarihi

27 Şubat 2025

Kabul Tarihi

8 Nisan 2025

Yayımlandığı Sayı

Yıl 2025 Cilt: 64 Sayı: 2

DOI

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

IZ

https://izlik.org/JA37UB29UE

Kaynak Göster

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. ETD. 01 Haziran 2025;64(2):363-7. doi:10.19161/etd.1647914