Inhibition of a Disintegrin and Metalloproteinase With Thrombospondin Type 1 Motif, Member 13 Activity by Peptidylarginine Deiminase IV Exacerbates Pancreatic Necrosis in Acute Pancreatitis.

BACKGROUND & AIMS: Dysregulation of the von Willebrand factor and its protease, a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13, has been implicated in the pathogenesis of pancreatic necrosis during acute pancreatitis, but the underlying mechanisms remain incompletely understood. NETosis and their enzyme component, peptidylarginine deiminase type IV, have been proposed to inhibit a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13. We aimed to determine whether peptidylarginine deiminase type IV-mediated inhibition of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 contributes to the progression of pancreatic injury in acute pancreatitis.

METHODS: Serum a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 activity and peptidylarginine deiminase type IV levels were prospectively assessed in 30 patients with acute pancreatitis. Peptidylarginine deiminase type IV-a disintegrin and a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 interactions were examined in vitro and in vivo. Experimental acute pancreatitis was induced in mice using cerulein plus lipopolysaccharide or L-arginine, with interventions including recombinant human a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13, the peptidylarginine deiminase type IV inhibitor Cl-amidine, and genetic knockout models (Pad4-/- and Adamts13-/-).

RESULTS: Patients with acute pancreatitis and >30% pancreatic necrosis exhibited significantly reduced a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 activity, elevated peptidylarginine deiminase type IV levels, and accumulation of large von Willebrand factor multimers. In mouse acute pancreatitis models, a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 deficiency worsened pancreatic necrosis and systemic injury, whereas recombinant human a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 treatment conferred protection. Mechanistically, peptidylarginine deiminase type IV suppressed a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 activity both in vitro and in vivo; this inhibition was reversed by Cl-amidine. Peptidylarginine deiminase type IV inhibition attenuated acute pancreatitis severity, but this effect was abolished in Adamts13-/- mice, demonstrating that peptidylarginine deiminase type IV aggravates acute pancreatitis primarily through a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 suppression.

CONCLUSIONS: An early imbalance in the von Willebrand factor-a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 axis and peptidylarginine deiminase type IV activation is a hallmark of both clinical and experimental acute pancreatitis. By inhibiting a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 activity, peptidylarginine deiminase type IV promotes pancreatic necrosis and exacerbates disease severity. Targeting peptidylarginine deiminase type IV or restoring a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 activity may represent a promising therapeutic strategy to protect against pancreatic injury in acute pancreatitis.