The Small Molecule Inhibitor QLT-0267 Decreases the Production of Fibrin-Induced Inflammatory Cytokines and Prevents Post-Surgical Peritoneal Adhesions

Scientific Reports, Jun 2018

Peritoneal adhesions develop after abdominal surgery, trauma or intraperitoneal infections, and have important consequences. The deposition of peritoneal fibrin is a common pathophysiological pathway for the formation of adhesions. Here, we aimed to examine the effects of fibrin-induced cytokine production on peritoneal mesothelial cells (PMCs), and to block the effects of fibrin using an integrin-linked kinase (ILK) inhibitor, QLT-0267. PMCs were cultured from the enzymatic disaggregation of rat omentum. After the PMCs were covered with fibrin, the expression of IL-1β, IL-6, TNFα and VEGF-A increased. This increase in cytokine production was attenuated by QLT-0267, which acted via the inhibition of both the ILK and focal adhesion kinase (FAK) pathways, and subsequently via the GSK-3β pathway. We found that QLT-0267 decreased both the severity of peritoneal adhesion and the serum levels of IL-6 in our post-surgical adhesion mouse model. In conclusion, our study provides novel evidence that fibrin-induced cytokine production may involve in the mechanism of peritoneal adhesion formation. Furthermore, the use of the small molecule inhibitor QLT-0267 is a new strategy in preventing peritoneal adhesion in patients undergoing abdominal surgery.

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The Small Molecule Inhibitor QLT-0267 Decreases the Production of Fibrin-Induced Inflammatory Cytokines and Prevents Post-Surgical Peritoneal Adhesions

Abstract Peritoneal adhesions develop after abdominal surgery, trauma or intraperitoneal infections, and have important consequences. The deposition of peritoneal fibrin is a common pathophysiological pathway for the formation of adhesions. Here, we aimed to examine the effects of fibrin-induced cytokine production on peritoneal mesothelial cells (PMCs), and to block the effects of fibrin using an integrin-linked kinase (ILK) inhibitor, QLT-0267. PMCs were cultured from the enzymatic disaggregation of rat omentum. After the PMCs were covered with fibrin, the expression of IL-1β, IL-6, TNFα and VEGF-A increased. This increase in cytokine production was attenuated by QLT-0267, which acted via the inhibition of both the ILK and focal adhesion kinase (FAK) pathways, and subsequently via the GSK-3β pathway. We found that QLT-0267 decreased both the severity of peritoneal adhesion and the serum levels of IL-6 in our post-surgical adhesion mouse model. In conclusion, our study provides novel evidence that fibrin-induced cytokine production may involve in the mechanism of peritoneal adhesion formation. Furthermore, the use of the small molecule inhibitor QLT-0267 is a new strategy in preventing peritoneal adhesion in patients undergoing abdominal surgery. Introduction Intra-abdominal adhesions develop after abdominal surgery, trauma or intraperitoneal infections. Adhesions are the main cause of intestinal obstruction in the developed world1, and are reported to cause 32% of acute intestinal obstruction and 65–75% of all small bowel obstructions2. Peritoneal adhesions have important consequences to patients, surgeons and the health system3,4. Over the decades, there has been much research into the biochemical and cellular processes that lead to adhesion formation and preventions for peritoneal adhesion5. The intra-abdominal formation of fibrin is a common pathophysiological pathway involved in the formation of adhesions6. The abdominal cavity is lined by the peritoneum, which consists of a single layer of mesothelial cells and a submesothelial layer. Peritoneal trauma results in mesothelial damage and is accompanied by inflammation. Mesothelial cells detach from the basal membrane and create denuded areas, which results in inflammatory reactions7. The inflammatory reaction causes influx of inflammatory cells and leads to a fibrinous exudate8. When two peritoneal surfaces coated with fibrinous matrix come into apposition, a band or bridge often forms, which becomes the base around which an adhesion is organised. Regenerating mesothelial cells possess vital peritoneal fibrinolytic activity, and prevent the formation of adhesions via the lysis of fibrin bands4. It has been shown that adhesion formation is inversely correlated with the fibrinolytic activity of the peritoneum, and bacterial peritonitis causes fibrinolytic activity to decrease9,10. If the fibrinolytic mechanism fails, the adhesions will become fibrous and organized. Therefore, early balance between fibrin deposition and degradation seems to be the critical factor in adhesion formation. Furthermore, the peritoneal inflammatory status appears to be a crucial factor in determining the duration and extent of the imbalance between fibrin formation and dissolution11. Suppression of inflammation and augmentation of fibrinolytic activity may be promising anti-adhesion treatment strategies11. Fibrin has been investigated as a matrix to promote wound healing, as demonstrated by several cells interacting with the fibrin matrix. Endothelial cells, smooth muscle cells, fibroblasts and leukocytes can bind directly to fibrin and/or fibrinogen via cell surface integrin receptors and non-integrin receptors12. These cells may infiltrate into the fibrin matrix and induce many actions such as angiogenesis12, fibroblast proliferation and wound healing with fibrosis13. However, the effects of fibrin and fibrinogen in relation to cytokine production in the pathogenesis of peritoneal adhesion have not been elucidated. Therefore, we proposed that fibrin may have proinflammatory effects that contribute to the formation of fibrosis bands, in addition to simply apposing two peritoneal organs to initiate adhesion. Various strategies have been employed over many years to prevent adhesion formation, such as reducing peritoneal damage by using laparoscopic surgery; preventing fibrin formation using heparin; inhibiting inflammatory reactions using steroids, non-steroidal anti-inflammatory drugs or vitamin E; promoting fibrinolysis using thrombolytic agents; and the use of physical barriers14,15,16. At present, minimizing peritoneal damage during surgery is the most important strategy to prevent adhesion2,14,17. Recently, a meta-analysis that included 28 trials (5191 patients) concluded that oxidised regenerated cellulose and hyaluronate carboxymethylcellulose can reduce adhesions18. However, there still are concerns that the use of barriers may increase the incidence of anastom (...truncated)


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Cheng-Chung Fang, Tzung-Hsin Chou, Jenq-Wen Huang, Chien-Chang Lee, Shyr-Chyr Chen. The Small Molecule Inhibitor QLT-0267 Decreases the Production of Fibrin-Induced Inflammatory Cytokines and Prevents Post-Surgical Peritoneal Adhesions, Scientific Reports, 2018, Issue: 8, DOI: 10.1038/s41598-018-25994-5