Abstract
MicroRNA-29 (miR-29) is a critical regulator of fibroinflammatory processes in human diseases. In this study, we found a decrease in miR-29a in experimental and human chronic pancreatitis, leading us to investigate the regulatory role of the miR-29a/b1 cluster in acute pancreatitis (AP) utilizing a conditional miR-29a/b1–KO mouse model. miR-29a/b1-sufficient (WT) and -deficient (KO) mice were administered supramaximal caerulein to induce AP and characterized at different time points, utilizing an array of IHC and biochemical analyses for AP parameters. In caerulein-induced WT mice, miR-29a remained dramatically downregulated at injury. Despite high-inflammatory milieu, fibrosis, and parenchymal disarray in the WT mice during early AP, the pancreata fully restored during recovery. miR-29a/b1–KO mice showed significantly greater inflammation, lymphocyte infiltration, macrophage polarization, and ECM deposition, continuing until late recovery with persistent parenchymal disorganization. The increased pancreatic fibrosis was accompanied by enhanced TGFβ1 coupled with persistent αSMA+ PSC activation. Additionally, these mice exhibited higher circulating IL-6 and inflammation in lung parenchyma. Together, this collection of studies indicates that depletion of miR-29a/b1 cluster impacts the fibroinflammatory mechanisms of AP, resulting in (a) aggravated pathogenesis and (b) delayed recovery from the disease, suggesting a protective role of the molecule against AP.
Highlights
Acute pancreatitis (AP), characterized by complex pathophysiological processes, oftentimes results in systemic complications and multiorgan failure [1]
As pancreatitis is a major risk factor for pancreatic ductal adenocarcinoma (PDAC) development, and miR-29a is critical to fibroinflammatory mechanisms and the primary member in the pancreas, we asked whether depletion of miR-29a has a role in pancreatitis, with specific focus on characterizing the function of miR-29a/b1 cluster in AP pathogenesis
The current study investigated the impact of the miR-29a/b1 cluster on pancreas injury and regeneration during AP, utilizing a potentially novel conditional miR-29a/b1–KO mouse model. miR-29 plays a crucial role in fibrosis and ECM remodeling under diverse pathophysiological conditions, including that in the pancreas [8, 21, 38, 39]
Summary
Acute pancreatitis (AP), characterized by complex pathophysiological processes, oftentimes results in systemic complications and multiorgan failure [1]. Elucidating the key pathological mechanisms of AP is essential for clinical management and reducing the risk for PDAC development. Aberrant miRNA expression results in alternation of essential physiological processes in numerous pathological conditions, including AP [5, 6]. Among the 3, miR-29a is the most abundantly expressed member in the pancreas, pancreatic epithelium, and pancreatic stellate cells (PSCs) [7, 8] and originates solely from the miR-29a/b1 cluster. As pancreatitis is a major risk factor for PDAC development, and miR-29a is critical to fibroinflammatory mechanisms and the primary member in the pancreas, we asked whether depletion of miR-29a has a role in pancreatitis, with specific focus on characterizing the function of miR-29a/b1 cluster in AP pathogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
