The metalloproteinase ADAM17 promotes acute lung inflammatory responses during pancreatitis

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: 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.