Abstract
The pathophysiological mechanism involved in side effects of radiation therapy, and especially the role of the endothelium remains unclear. Previous results showed that plasminogen activator inhibitor-type 1 (PAI-1) contributes to radiation-induced intestinal injury and suggested that this role could be driven by an endothelium-dependent mechanism. We investigated whether endothelial-specific PAI-1 deletion could affect radiation-induced intestinal injury. We created a mouse model with a specific deletion of PAI-1 in the endothelium (PAI-1KOendo) by a Cre-LoxP system. In a model of radiation enteropathy, survival and intestinal radiation injury were followed as well as intestinal gene transcriptional profile and inflammatory cells intestinal infiltration. Irradiated PAI-1KOendo mice exhibited increased survival, reduced acute enteritis severity and attenuated late fibrosis compared with irradiated PAI-1flx/flx mice. Double E-cadherin/TUNEL labeling confirmed a reduced epithelial cell apoptosis in irradiated PAI-1KOendo. High-throughput gene expression combined with bioinformatic analyses revealed a putative involvement of macrophages. We observed a decrease in CD68+cells in irradiated intestinal tissues from PAI-1KOendo mice as well as modifications associated with M1/M2 polarization. This work shows that PAI-1 plays a role in radiation-induced intestinal injury by an endothelium-dependent mechanism and demonstrates in vivo that the endothelium is directly involved in the progression of radiation-induced enteritis.
Highlights
Challenge is to improve our knowledge of the pathophysiological mechanisms involved in the progression of radiation enteropathy
We hypothesized that the pool of plasminogen activator inhibitor-type 1 (PAI-1) produced by endothelial cells could be involved in the development and progression of radiation-induced intestinal damage
In a model of radiation enteropathy, intestinal PAI-1 expression increased from 5 h to up to 6 weeks post-exposure, while endothelial PAI-1 deletion partially limited this radiation-induced PAI-1 up-regulation (Fig. 2a)
Summary
Challenge is to improve our knowledge of the pathophysiological mechanisms involved in the progression of radiation enteropathy. The contemporary view involves several cell types and molecular mechanisms, which together form an orchestrated response, and contribute to the initiation, progression and chronicity of radiation-induced injury[3]. Irradiation leads to endothelial cell apoptosis, increased vascular permeability, and acquisition of a pro-inflammatory and pro-coagulant phenotype. These modifications strongly participate in the development of radiation-induced damage, notably in the bowel[6]. We have used tissue-specific knockout models to study the role of the endothelial compartment in the progression of radiation-induced intestinal injury. We hypothesized that the pool of plasminogen activator inhibitor-type 1 (PAI-1) produced by endothelial cells could be involved in the development and progression of radiation-induced intestinal damage. We investigated whether specific PAI-1 deletion in the endothelium affects the intestinal response to radiation exposure, and show that the endothelium is directly involved in the progression of radiation-induced enteritis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
