Activin A Modulates Inflammation in Acute Pancreatitis and Strongly Predicts Severe Disease Independent of Body Mass Index

• Published in: Clinical and translational gastroenterology Vol. 11; no. 5; p. e00152
• Main Authors: Thomas, Alexandra L., Castellanos, Karla, Mancinelli, Georgina, Xia, Yinglin, Bauer, Jessica, Yazici, Cemal, Fantuzzi, Giamila, Hwang, Rosa F., Krett, Nancy L., Papachristou, Georgios I., Whitcomb, David C., Jung, Barbara
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer 01-05-2020; Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins
• Subjects: Activins - antagonists & inhibitors; Activins - blood; Activins - immunology; Activins - metabolism; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Biomarkers - blood; Biomarkers - metabolism; Body Mass Index; Cell Line; Ceruletide - administration & dosage; Ceruletide - toxicity; Cohort Studies; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Glycoproteins; Health risk assessment; Humans; Inflammation; Macrophage Activation - immunology; Macrophages; Mice; Pancreas - drug effects; Pancreas - immunology; Pancreas - pathology; Pancreatitis; Pancreatitis - blood; Pancreatitis - diagnosis; Pancreatitis - drug therapy; Pancreatitis - immunology; Patient Admission; Predictive Value of Tests; Severity of Illness Index
• ISSN: 2155-384X; 2155-384X
• DOI: 10.14309/ctg.0000000000000152

Acute pancreatitis (AP) is a healthcare challenge with considerable mortality. Treatment is limited to supportive care, highlighting the need to investigate disease drivers and prognostic markers. Activin A is an established mediator of inflammatory responses, and its serum levels correlate with AP severity. We hypothesized that activin A is independent of body mass index (BMI) and is a targetable promoter of the AP inflammatory response.
We assessed whether BMI and serum activin A levels are independent markers to determine disease severity in a cohort of patients with AP. To evaluate activin A inhibition as a therapeutic, we used a cerulein-induced murine model of AP and treated mice with activin A-specific neutralizing antibody or immunoglobulin G control, both before and during the development of AP. We measured the production and release of activin A by pancreas and macrophage cell lines and observed the activation of macrophages after activin A treatment.
BMI and activin A independently predicted severe AP in patients. Inhibiting activin A in AP mice reduced disease severity and local immune cell infiltration. Inflammatory stimulation led to activin A production and release by pancreas cells but not by macrophages. Macrophages were activated by activin A, suggesting activin A might promote inflammation in the pancreas in response to injury.
Activin A provides a promising therapeutic target to interrupt the cycle of inflammation and tissue damage in AP progression. Moreover, assessing activin A and BMI in patients on hospital admission could provide important predictive measures for screening patients likely to develop severe disease.