ABSTRACT
Inflammatory bowel disease (IBD) is characterized by recurring inflammatory disorders in digestive system, and devoid of effective treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9), stimulated via inflammation whose inhibition could decrease secretion of inflammatory factors. We then determined whether inhibition of PCSK9 could improve the inflammation. First, rats model of colitis was first established via administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS), and then verified via determination of body weight loss, myeloperoxidase (MPO) activity, and histopathological analysis of colonic damage. Results showed that treatment with TNBS induced a great body weight loss, MPO activity increase, and serious colonic damage, showing an obviously character of IBD. PCSK9 was elevated in TNBS-induced rats, and PCSK9 inhibition delivered by adenovirus vector increased the body weight, decreased MPO activity, and ameliorated histological change of colon. Second, the protective effect of PCSK9 inhibition against TNBS-induced colitis was accompanied by decrease of proinflammatory factors secretion, including tumor necrosis factor-α, interleukin-1ß, interleukin-6, intercellular adhesion molecule 1, and monocyte chemoattractant protein-1. TNBS could activate toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway, while PCSK9 inhibition suppressed activation of TLR4/NF-κB in TNBS-induced rats. In conclusion, PCSK9 inhibition attenuated TNBS-induced rat colitis through anti-inflammatory effect under inactivation of TLR4/NF-κB, suggesting potential therapeutic strategy in IBD.
Subject(s)
Colitis/prevention & control , Colon/metabolism , NF-kappa B/genetics , Proprotein Convertase 9/genetics , Toll-Like Receptor 4/genetics , Adenoviridae/genetics , Adenoviridae/metabolism , Animals , Body Weight , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Colitis/chemically induced , Colitis/genetics , Colitis/pathology , Colon/drug effects , Colon/pathology , Gene Expression Regulation , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Inflammation , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Male , NF-kappa B/metabolism , PCSK9 Inhibitors , Peroxidase/genetics , Peroxidase/metabolism , Proprotein Convertase 9/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Rats , Rats, Wistar , Signal Transduction , Toll-Like Receptor 4/metabolism , Trinitrobenzenesulfonic Acid/administration & dosage , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Diabetes mellitus can occur after acute pancreatitis (AP), but there are currently no tools for evaluating the risk of developing diabetes after an attack of AP. The aim of the study was to develop a nomogram for prediction of new-onset diabetes mellitus after the first attack of AP. PATIENTS AND METHODS: We enrolled 616 patients with first-attack AP. We collected and statistically analyzed demographic data (age, BMI, and duration of hospitalization) and laboratory data (glucose, low-density lipoprotein cholesterol, triglyceride, and cholesterol). RESULTS: Univariate analysis suggested duration of hospitalization (P=0.0003), BMI (P=0.0059), cholesterol (P=0.0005), triglyceride (P=0.0005), hemoglobin (P=0.0229), and glucose (P<0.001) at admission were significantly associated with newly developed diabetes after the first-attack AP. Multivariate analysis showed that age [odds ratio (OR)=1.01; 95% confidence interval (CI): 1.00-1.03; P=0.045], BMI (OR=1.06; 95% CI: 1.01-1.12; P=0.018), glucose (OR=1.07; 95% CI: 1.02-1.12; P=0.008), triglyceride (OR=1.03; 95% CI: 1.00-1.06; P=0.035), and low-density lipoprotein-cholesterol (OR=1.18; 95% CI: 1.00-1.38; P=0.044) at admission were important predictors. CONCLUSION: The nomogram is a potentially clinically useful tool for predicting new-onset diabetes, which is currently clinically unprecedented. This finding is not confined to the patients with severe AP but is also for patients who have recovered from mild AP. The nomogram must to be validated externally.
