Radiation-induced vascular inflammation : translational studies

Radiotherapy has been shown to increase the risk for localized cardiovascular disease in a growing population of cancer survivors. However, irradiation, as a risk factor for vascular complications in free flap surgery, has been debated. Furthermore, the mechanisms behind radiation-induced vascular disease are not fully understood, and there is yet no available targeted treatment. We investigated vascular complications in preoperatively irradiated microvascular reconstructions and the vascular inflammatory response in the human blood vessels and evaluated if interleukin-1 blockade could ameliorate radiation-induced vascular inflammation in Apoe-/- mice.

Paper I is a retrospective cohort study supporting that radiotherapy increases the risk for flap failure in microvascular autologous reconstructive surgery. There was a lower surgical complication rate in reconstructions performed at less than 6 weeks compared to delayed reconstructions performed 6-15 weeks after the last radiotherapy session. Paper II-IV are experimental studies analyzing gene and protein expression patterns in human-irradiated blood vessels. Irradiated and non-irradiated biopsies were collected from the same patient at the same time during microvascular reconstructive surgery and analyzed pairwise. Paper II shows that radiotherapy induced vascular inflammation in both arteries and veins years after last radiotherapy treatment as measured by pentraxin 3 (PTX3). Irradiation induced PTX3 expression in endothelial cells, smooth muscle cells and macrophages in the arterial vessel wall. Paper III demonstrates the involvement of the pro-inflammatory 5-LO/leukotriene axis and vasa vasorum expansion together with macrophage accumulation in the adventitia of irradiated human arteries. Paper IV shows an up-regulation of the NLRP3 inflammasome/IL-1β axis and macrophage accumulation in irradiated human arteries. Treatment with the recombinant IL-1Ra anakinra dampened the radiation-induced inflammatory response in locally irradiated Apoe-/- mice.

In conclusion, we demonstrated that irradiation induces an inflammatory response in human blood vessels that may contribute to the observed vascular complications after free flap transfer in irradiated subjects. Chronic vascular inflammation was seen in all layers of irradiated human arteries, and anti-IL-1 may be a potential treatment based on our animal study. However, further studies are needed before an intervention could be tested in a cancer setting.

List of scientific papers

I. Tall J, Björklund T Christersdottir, Skogh AC, Arnander C, Halle M. Vascular complications after radiotherapy in head and neck free flap reconstruction: clinical outcome related to vascular biology. Annals of Plastic Surgery. 2015;3(309-15).
https://doi.org/10.1097/SAP.0000000000000081

II. Christersdottir Björklund T, Reilly SJ, Gahm C, Bottazzi B, Mantovani A, Tornvall P, Halle M. Increased long-term expression of pentraxin 3 in irradiated human arteries and veins compared to internal controls from free tissue. Journal of Translational Medicine. 2013;11(223).
https://doi.org/10.1186/1479-5876-11-223

III. Halle M, Christersdottir T, Bäck M. Chronic adventitial inflammation, vasa vasorum expansion, and 5-lipoxygenase up-regulation in irradiated arteries from cancer survivors. The FASEB Journal. 2016;11(3845-52).
https://doi.org/10.1096/fj.201600620R

IV. Christersdottir T, Pirault J, Gisterå A, Bergman O, Baumgartner R, Lundberg AM, Eriksson P, Yan ZQ, Paulsson-Berne G, Hansson GK, Olofsson PS, Halle M. Prevention of radiotherapy-induced arterial inflammation by IL-1 blockade. [Accepted]
https://doi.org/10.1093/eurheartj/ehz206