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.
Highlights
The intra-abdominal formation of fibrin is a common pathophysiological pathway involved in the formation of adhesions[6]
Cultures were overlaid with fibrin via incubation with a mixture of fibrinogen and thrombin for two, four and eight hours, and the expression of IL-6, IL-1β, TNFα, VEGF-A, TGFβ1 and VEGF-C were evaluated by RT-PCR (Fig. 1A)
Treating peritoneal mesothelial cells (PMCs) with fibrin led to increased expression of IL-6 (Fig. 1B) and IL-1β (Fig. 1C) at each time interval studied, which were all attenuated by QLT-0267
Summary
The intra-abdominal formation of fibrin is a common pathophysiological pathway involved in the formation of adhesions[6]. Regenerating mesothelial cells possess vital peritoneal fibrinolytic activity, and prevent the formation of adhesions via the lysis of fibrin bands[4]. We proposed that fibrin may have proinflammatory effects that contribute to the formation of fibrosis bands, in addition to 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 barriers[14,15,16]. We aimed to examine the effects of fibrin-induced cytokine production on peritoneal mesothelial cells (PMCs). We aimed to study the in vitro and in vivo effects of QLT-0267 on peritoneal adhesion
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