Mechanisms of peritoneal adhesions and peritoneal inflammation
Embargo Date
2027-09-24
OA Version
Citation
Abstract
BACKGROUND: Peritoneal fibrosis and peritoneal adhesion are two long-term complications of peritoneal inflammation and peritoneal infection. Both conditions result from structural and functional alterations in the histological structure of the peritoneal membrane as a result of increased cytokine expression and subsequent aberrant peritoneal healing. Current treatments for both conditions lack preventive components and mainly focus on controlling the symptoms. Pharmacological manipulations to prevent such complications represent an attractive option, especially one emerging from mechanistic analysis. The aryl hydrocarbon receptor (AhR) has been linked to adaptive immune responses and modulates inflammatory responses. In this study, we posited that AhR signaling would be activated in the peritoneal membrane in response to infection and that AhR inhibitors abrogate the pro-inflammatory and pro-fibrotic mediators involved in this peritoneal injury model. METHODS: A group of 24 mice were randomized into 4 groups (N=6). The controls mice were wild-type mice on normal chow diet. The next condition received a daily injection of lipopolysaccharide (LPS) for 5 days. The next group received an injection of LPS and CH22319, a known AhR inhibitor, daily for 5 days. The last condition tested the protective effects of an alternative AHR inhibitor, BAY2416964. Mice in this group were injected intraperitoneally with LPS and BAY2416964 daily for 5 days. After the last injection, mice were immediately sacrificed and the peritoneum was harvested.
RESULTS: The peritoneum of mice in the LPS intraperitoneal (IP) injection alone group could be characterized by increased peritoneal membrane thickness, a marked increase in inflammatory infiltrates, and several inflammatory foci. The peritoneal membrane thickness was protected from LPS with both the AhR inhibitors, however, peritoneal membrane was better preserved with BAY2416964 compared to CH223191 (P=0.0044). The inflammatory infiltrates were reduced in both conditions treated with LPS and AhR inhibitors. Additionally, tissue factor (TF) expression, a downstream target of AhR, and several proinflammatory cytokines were downregulated with treatment of AhR inhibitors (BAY2416964 and CH223191).
CONCLUSION: This body of work shows the activation of AhR in the LPS model. AhR inhibition protected the peritoneum and reduced a set of the pro-inflammatory and pro-fibrotic cytokines. AhR inhibitors can be explored further to maintain peritoneal membrane in the setting of infection and inflammation.
Description
2024
License
Attribution-NoDerivatives 4.0 International