Abstract
Around 95% of cancer patients undergoing radiotherapy experience cutaneous side effects, and some develop radiation wounds or fibrosis. Currently, there is no effective treatment for these indications. We show here that plasminogen administration enhanced the healing of radiation wounds via pleiotropic effects on gene expression. Using RNA sequencing, we found that plasminogen downregulated the expression of genes in the TLR, TNF, WNT, MAPK, and TGF-β signaling pathways, and enhanced the anti-inflammatory effect of arachidonic acid, leading to significantly decreased inflammation and improved remodeling of granulation tissue compared with placebo treatment. In addition, plasminogen induced metabolic changes, including decreased glycolysis. Importantly, many of the factors downregulated by plasminogen are pro-fibrotic. Therefore, in radiation wounds with excessive inflammation, plasminogen is able to enhance and redirect the healing process, such that it more closely resembles physiological healing with significantly reduced risk for developing fibrosis. This makes plasminogen an attractive drug candidate for the treatment of radiation wounds in cancer patients.
Highlights
Ionizing radiation is an important treatment tool for various tumors, but it often has dose-limiting pathological effects on noncancerous “normal” tissue[1,2,3,4]
We have previously shown that plasminogen plays a regulatory role in the initiation and termination of the inflammatory phase during wound healing, and that plasminogen supplementation restores the healing of acute wounds in plasminogen-deficient mice, and enhances healing in both wild-type and db/db diabetic mice[14,15,16]
We have previously shown that plasminogen accumulates in burn wounds in wild-type mice, and activates an inflammatory response during the healing process[14]
Summary
Ionizing radiation is an important treatment tool for various tumors, but it often has dose-limiting pathological effects on noncancerous “normal” tissue[1,2,3,4]. The sensitivity of tissues to irradiation depends on the number of dividing cells. Normal tissues with a relatively high proliferative capacity, such as the skin, are more severely affected by radiotherapy[1]. Radiation skin injuries are divided into acute and late injuries. Acute injuries appear within hours to weeks after irradiation, and include skin erythema, edema, desquamation, and/or ulcers. Most patients undergoing radiotherapy develop some type of acute skin reaction. Late side effects of irradiation, such as ulceration or fibrosis, can develop months to years after the treatment[2]
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