British journal of pharmacology · 2026
The metalloproteinase ADAM17 promotes acute lung inflammatory responses during pancreatitis.
СтатьяНазвание и аннотация: Перевод в очереди
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Chan Shermin, Hon Karen, Dawson Ruby E, Weng Teresa, Solujic Jelena, Chey Yu C J, Zuiani James D, Perkins Griffith B, Coates P Toby, Drogemuller Chris, Sanderlin Eddie, Huang Lulu, Finnie John, Rose-John Stefan, Badiei Arash, Nguyen Phan, Jenkins Brendan J, Saad Mohamed I
Аннотация
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.
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.