Administration of a recombinant secretory leukocyte protease inhibitor prevents aortic aneurysm growth in mice.

Abstract

Pharmacological interventions to inhibit the progression of aortic aneurysm (AA) have not yet been established. We previously reported that mesenchymal stem cells (MSCs) provide a potential foundation for less invasive treatment of AA. In this study, we investigated the secretory proteins from MSC supernatants to clarify the therapeutic effects of MSCs. Furthermore, we treated thoracoabdominal aortic aneurysm (TAAA) mice with two anti-inflammatory proteins from among these secretory proteins to confirm their therapeutic effects. Protein profiles of MSC-secreted factors were analyzed using protein microarrays, and two anti-inflammatory proteins, namely progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI), were identified. Apolipoprotein E-deficient mice were continuously infused with angiotensin II via an osmotic pump for 4 weeks to induce TAAA formation, and then recombinant rPGRN and/or rSLPI were administered intraperitoneally. Mice were sacrificed at 8 weeks, and aortas were analyzed for protein expression and also stained with Elastica van Gieson and immunofluorescence to detect inflammatory cells. Intraperitoneal administration of rSLPI inhibited TAAA growth more than rPGRN alone or the combination of rPGRN and rSLPI, by inducing the following effects: downregulation of inflammatory cytokines and chemokines, specifically IL-1β, IL-6, TNF-α, and MCP-1; reduced NO production; decreased phosphorylated NF-κB levels; and decreased elastin destruction and infiltration of inflammatory cells. We identified anti-inflammatory proteins, including PGRN and SLPI, in the MSC supernatants and showed that the administration of rSLPI inhibited TAAA progression in mice. These promising preliminary data present a new approach for the treatment of less invasive TAAA.