The metalloproteinase ADAM17 promotes acute lung inflammatory responses during pancreatitis
Date
2026
Authors
Chan, S.
Hon, K.
Dawson, R.E.
Weng, T.
Solujic, J.
Chey, Y.C.J.
Zuiani, J.D.
Perkins, G.B.
Coates, P.T.
Drogemuller, C.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
British Journal of Pharmacology, 2026; 1-19
Statement of Responsibility
Shermin Chan, Karen Hon, Ruby E. Dawson, Teresa Weng, Jelena Solujic, Yu C. J. Chey, James D. Zuiani, Griffith B. Perkins, P. Toby Coates, Chris Drogemuller, Eddie Sanderlin, Lulu Huang, John Finnie, Stefan Rose-John, Arash Badiei, Phan Nguyen, Brendan J. Jenkins, Mohamed I. Saad
Conference Name
Abstract
Background and Purpose: Acute pancreatitis (AP) is a multifactorial upper gastrointestinal inflammatory disorder that in severe cases (~20% of all AP) is associated with substantial morbidity and mortality, the latter coincident with multiorgan dysfunction, particularly acute lung injury (ALI). Currently, there are no effective therapeutic agents to treat AP-induced ALI. Experimental Approach: The expression and function of the protease A Disintegrin and Metalloproteinase 17 (ADAM17) were investigated in two murine models of AP-associated ALI induced by L-arginine or cerulein (ceruletide). A human lung/pancreatic organoids co-culture model of AP-associated ALI was employed to validate ADAM17 up-regulation in vitro. Key Results: ADAM17 expression was up-regulated in pancreatic and lung tissues of wild-type (WT) mice exposed to AP-associated ALI models. The genetic (Adam17ex/ex mice) and therapeutic (antisense oligonucleotides; ASOs) targeting of ADAM17 to reduce its expression in the lungs of mice ameliorated experimentally induced AP-associated lung inflammation, which coincided with the selective reduction in the extracellular shedding of two ADAM17 substrates, soluble tumour necrosis factor α (TNFα) and soluble interleukin-6 receptor (sIL-6R). ADAM17 targeting in AP-associated ALI also suppressed lung inflammatory cell infiltration, including macrophages, as well as cellular death in the lung alveolar compartment. Furthermore, ADAM17 expression was up-regulated by L-arginine or cerulein (ceruletide) in an in vitro human lung/pancreatic organoids co-culture model of AP-associated ALI. Conclusions and Implications: Our findings indicate that the ADAM17 protease plays a crucial role in the pathogenesis of acute lung inflammatory responses during AP progression, which could pave the way for devising novel therapeutic options to treat AP-induced ALI.
School/Discipline
Dissertation Note
Provenance
Description
OnlinePubl
Access Status
Rights
© 2026 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.