The metalloproteinase ADAM17 promotes acute lung inflammatory responses during pancreatitis

  • Br J Pharmacol. 2026 Aug;183(15):4126-4144. doi: 10.1111/bph.70443.
Shermin Chan  1 ,  Karen Hon  1 ,  Ruby E Dawson  1 ,  Teresa Weng  2  3 ,  Jelena Solujic  4 ,  Yu C J Chey  1 ,  James D Zuiani  5 ,  Griffith B Perkins  5  6 ,  P Toby Coates  5  6 ,  Chris Drogemuller  5  6 ,  Eddie Sanderlin  7 ,  Lulu Huang  7 ,  John Finnie  5 ,  Stefan Rose-John  8 ,  Arash Badiei  4 ,  Phan Nguyen  4 ,  Brendan J Jenkins  1  2  3 ,  Mohamed I Saad  1  2  3
Affiliations
  • 1. South Australian immunoGENomics Cancer Institute (SAiGENCI), Adelaide University, Adelaide, SA, Australia.
  • 2. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • 3. Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
  • 4. Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia.
  • 5. School of Medicine, College of Health, Adelaide University, Adelaide, SA, Australia.
  • 6. Central and Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, SA, Australia.
  • 7. Ionis Pharmaceuticals, Carlsbad, California, USA.
  • 8. Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
PMID: 42021473 DOI: 10.1111/bph.70443
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.

Keywords
ADAM17; acute lung injury; antisense oligonucleotides; inflammation; pancreatitis.
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