Lost in translation: do animal studies add value to the management of abdominal aortic aneurysms?

The work outlined by Li et al. (1) in their recently published work demonstrated a protective effect of IL-33 in a murine model of abdominal aortic aneurysm (AAA). Through a series of elegant experiments, the authors found that both the administration of exogenous IL-33 and overexpression of IL-33 in transgenic mice blunted AAA growth. Two separate models were used in this research. The first consisted of calcium phosphate (CaPO₄) induction by applying CaCl₂ followed by phosphate buffered saline (PBS) to the infrarenal aorta. Control mice were treated with sodium chloride (NaCl) alone. The second murine model involved the induction of AAA through exposure of the infrarenal aorta to 100% porcine pancreatic elastase versus heat-inactivated elastase in control mice.

A number of key observations were made with regard to the CaPO₄ model. First, IL-33 levels (in both the 10- and 18-kDa active forms) were found to be elevated in adventitia fibroblasts from AAA compared to NaCl treated mice. Increased expression of the IL-33 receptor ST2 in AAA lesions compared with controls was also detected on immunoblot analysis. CD45⁻ cells were found to be major IL-33 expressors in AAA. Exogenous IL-33 (administered intraperitoneally) was found to reduce aortic wall dilatation, increased aortic wall deposition and protected the aortic wall elastica from fragmentation. Similar results were noted in IL-33 transgenic mice. Exogenous CD4⁺Foxp3⁺ regulatory T-cell (Treg) numbers contained in the blood and spleens of CaPO₄-induced AAA mice increased following IL-33 treatment. These observations were mirrored in IL-33 transgenic mice when compared with non-transgenic (NTG) mice. This IL-33 Treg expansion was detected only in wild type, but not ST2-deficient ST2^−/− mice, indicating that the protective effects of IL-33 occur due to proliferation of Tregs which is, in turn, mediated by ST2. Tregs isolated from IL-33 mice enhanced ability to inhibit smooth muscle cell expression of MCP-1 and IL-6, in addition to reducing expression of MMP-2 and MMP-9. Tregs from this group were also found to increase M2 macrophage polarization than controls. Next, the authors demonstrated that IL-33 did not prevent AAA formation in CaPO₄-treated mice after depletion of Tregs through a reduced ability to suppress aortic wall elastic fragmentation and promotion of collagen deposition.

The porcine pancreatic elastase model produced similar results including the ability for IL-33 to reduce aortic diameter size and aortic wall elastic fragmentation and to increase collagen deposition. In addition, treatment with IL-33 reduced intra-lesional infiltration of T-lymphocytes and macrophages, inflammatory cytokine production, MMP-2 and MMP-9 production and lesion cell apoptosis.

Based on the findings outlined above, the authors propose recombinant IL-33 therapy and overexpression of endogenous IL-33 as a means of stemming the growth of AAA or indeed preventing it altogether. These suggestions, may however, be considered overly ambitious for a variety of reasons. First, small sample sizes were utilized in each study group with a maximum number of 15 mice employed. As such, one could consider the drawing of such conclusions to be both unfounded and premature. In the human setting, sample sizes this low would not be accepted outside of a pilot study. While the findings described here may well be reproducible, further validation work is undoubtedly required prior to translation into humans.

Next, the implications of exogenous IL-33 therapy or upregulation of this interleukin in the human setting have yet to be elucidated. Li et al. (1), performed histological analysis which did not show adverse effects on lung, liver, kidney or heart following IL-33 administration or overexpression. Despite this, extensive safety profiling will be required before this therapy could be considered to be either safe or efficacious for use in human studies. While the authors of this work should be commended for undertaking extensive research into the potential role of IL-33 in AAA, their findings may merely represent the groundwork on which further studies can be built.