Hyperlipidemia exacerbates acute pancreatitis via interactions between P38MAPK and oxidative stress

Abstract

BackgroundThe mechanisms involved in the hyperlipidemia-associated acute pancreatitis (HLAP) is not yet fully understood. AimsTo investigate the role of P38MAPK (mitogen-activated protein kinases) and oxidative stress in the pathogenesis of HLAP. MethodsIn AP (acute pancreatitis) patients, the GEO database retrieved gene expression profiles of cytokines, MAPK14, nuclear factor kappa B subunit 1 (NF-κB 1) and superoxide dismutase 2 (SOD 2). GeneMANIA has been used for the prediction of potential interaction mechanisms. Validation was carried out using an experimental AP model and a bi-directional Mendelian randomization (MR) analysis. ResultsCompared to mild AP, patients with severe AP had higher gene expression of MAPK14, NF-κB1, SOD2, IL-1β and IL-6R. GeneMANIA revealed 77.6 % physical interactions among MAPK14, NF-κB1, SOD2, IL-1β and IL-6R. Our results indicated that HLAP group had a more severe pancreatic injury, a stronger inflammatory response with higher serum levels of TNF-α, IL-6 and IL-1β in comparison with the AP group, which were significantly mitigated in HLAP-Pi group. Furthermore, SB 203580 inhibited increasing levels of malondialdehyde (MDA) in serum and of inducible nitric oxide synthase (iNOS), P38MAPK, p-P38MAPK and NF-κB p65 in pancreatic tissue as well as decreasing serum values of SOD and GSH-PX in HLAP group. MR analysis suggested that MAPK14 levels were negatively associated with the SOD levels, by using the inverse variance weighted (IVW) method (b = −0.193: se = 0.225; P = 1.03e-17). Reverse MR analysis indicated that SOD was negatively associated with the MAPK14 levels in the IVW analysis (b = −0.163: se = 0.020; P = 1.38e-15). ConclusionInteractions between P38MAPK and oxidative stress may play an important role in the pathogenesis of HLAP.