Abstract
Pancreatitis is a common gastrointestinal disorder that causes hospitalization with significant morbidity and mortality.The mechanistic pathophysiology of pancreatitis is complicated,limiting the discovery of phar-macological intervention methods.Here,we show that the administration of ATN-161,an antagonist of Integrin-a5,significantly mitigates the pathological condition of acute pancreatitis induced by caerulein.We find that CK19-positive pancreatic ductal cells align parallel to blood vessels in the pancreas.In the caerulein-induced acute pancreatitis model,the newly emergent CK19-positive cells are highly vascular-ized,with a significant increase in vascular density and endothelial cell number.Single-cell RNA sequencing analysis shows that ductal and endothelial cells are intimate interacting partners,suggesting the existence of a ductal-endothelial interface in the pancreas.Pancreatitis dramatically reduces the crosstalk in the ductal-endothelial interface but promotes the Spp-1/lntegrin-α5 signaling.Blocking this signaling with ATN-161 significantly reduces acinar-to-ductal metaplasia,pathological angiogenesis,and restores other abnormal defects induced by caerulein.Our work reveals the therapeutic potential of ATN-161 as an uncharacterized pharmacological method to alleviate the symptoms of pancreatitis.
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