Several factors contribute to the lack of repair following spinal cord injury, such as the lack of growth-promoting factors, poor intrinsic central nervous system regeneration abilities, and inhibition due to the glial scar1. The glial scar contains a class of inhibitory extracellular matrix molecules, chondroitin sulfate proteoglycans (CSPGs), which create a physical and chemical barrier to axon regeneration and sprouting. Previous studies showed that administration of an enzyme, chondroitinase ABC (ch'ase), can remove this inhibition

and promote functional and behavioral recovery in smaller animal models. To aid in translation to clinical trials, we examined whether ch'ase administration in a rhesus monkey model of spinal cord injury promoted such recovery. As of now, 9 of the 12 subjects were analyzed and we found a trend towards anatomical and behavioral recovery in ch'ase administered subjects. The trend toward increased corticospinal tract sprouting in ch’ase subjects may demonstrate that the success of ch’ase in smaller animal models is not unfounded. However, the behavioral recovery is not as distinct, and perhaps more optimization of ch’ase treatment is required in the monkey model before translation to clinical trials. Further conclusions can be drawn once the remaining 3 subjects have been analyzed and assessed. However, despite the incomplete dataset and low n, there are interesting trends in the data that may influence whether the ch’ase treatment will move on to clinical trials.

Pulmonary arterial hypertension (PAH) is a multifactorial disorder characterized by elevated right ventricle pressures (RVP) and pulmonary vascular resistance (PVR) thought to result from pulmonary vascular remodeling. Currently, there is no cure for PAH, but inflammatory mechanisms have been implicated in playing a role. Previously, members of our group measured elevated levels of interleukin-33 (IL-33) in Group 1 PAH patient serum. This alarmin, “danger” signal, is expressed by endothelial cells and its signaling can either repair the endothelial layer or, if the danger signals persist, contribute to uncontrolled proliferation. Thus, we hypothesized that pulmonary vascular remodeling in PAH is regulated by an IL-33-dependent pathway. To test this hypothesis, PAH was induced in adult C57BL/6J (wild-type, WT) mice, IL-33 receptor gene-ablated mice (ST2 -/-), in mice with a gene deletion of the upstream adaptor, MyD88 (MyD88 -/-), and in a strain with a conditional, endothelial-specific IL-33 gene-targeted inactivation using IL33 floxed and Tek-Cre transgenes [Tek-Cre (+/-)::IL33fl/fl]. Body weight, RVP, pulmonary vascular remodeling and endothelial cell proliferation were evaluated. PAH was induced using 10% hypoxia and weekly injections of the VEGF receptor antagonist, SU5416 (20 mg/kg) for three weeks (SuHx). The control condition was vehicle and room air, (DMSO/RA). RVP were measured by right heart catheterization in anesthetized mice. Pulmonary vascular wall thickness was morphometrically analyzed from paraffin-embedded H&E sections. Endothelial cell proliferation was analyzed by flow cytometry. Following SuHx conditions: all mice lost weight, except for MyD88 -/- mice, and RVP were increased in WT and Tek-Cre::IL33fl/fl mice, but attenuated in ST2 -/-, and MyD88 -/- mice. Pulmonary vascular wall thickening increased in WT-SuHx males and Tek-Cre::IL-33fl/fl males, but not in SuHx-female mice for any strain. SuHx-WT male mice demonstrated increased endothelial cell proliferation compared to WT-Control mice. These data suggest that the IL-33-receptor, ST2, and MyD88 signaling may play a role in the PAH vascular remodeling and disease progression. Further understanding of IL-33-mediated signaling that regulates endothelial cell proliferation, remodeling and cytokine activation may provide a better understanding of the disease and its advancement and allow the design of new treatment strategies for PAH.