Background Ischemia/reperfusion injury (IRI) is common in general surgery and organ transplantation, and in the case of liver it triggers pro-inflammatory innate immune cascade and hepatic necrosis, leading to increased incidence of early and late organ rejection. IL-22, an inducible cytokine of T-cell origin and a member of the IL-10 superfamily, acts on target tissues via IL-22 receptor (IL-22R1). Methods Partial hepatic warm ischemia was induced in C57Bl/6 wild-type (WT) and type-1 IFN receptor (IFNAR)-deficient (KO) mice for 90 min followed by 6-24 h of reperfusion. WT mice were treated at 30 min prior to the ischemia insult with recombinant IL-22 (rIL-22) or anti-IL-22 neutralizing antibody (IL-22 Ab); PBS and IgG served as respective controls. Results IL-22 was detected at 24 h but not 6 h of liver IRI. The expression of IL-22R1 was increased by 6 h of reperfusion in WT but not IFNAR KO mice that were protected from IRI. Treatment of WT mice with rIL-22 decreased sAST levels, ameliorated cardinal histological features of IR damage (Suzuki’s score) and diminished leukocyte sequestration, along with the expression of IL-22R1 and pro-inflammatory cytokines. IL-22 Ab did not appreciably affect IRI but increased IL-22R1 transcription in the liver. Administration of IL-22 protein exerted hepatoprotection via STAT3 activation. Conclusions This is the first report investigating immune modulation by T cell-derived IL-22 in liver injury due to warm ischemia and reperfusion. Treatment with IL-22 protein may represent a novel therapeutic strategy to prevent liver IRI in transplant recipients.

Objective Management of type 2 endoleaks after endovascular aneurysm repair has been controversial. Some advocate for conservative management, while others believe that intervention is indicated. This study investigated the natural history of type 2 endoleaks in order to derive direction in management. Methods Patients who had endovascular aneurysm repair at the Veterans Affairs Long Beach were retrospectively identified and computerized tomographic angiography was independently reviewed by a radiologist and a vascular surgeon. Type 2 endoleaks were analyzed for the following outcomes: rupture, duration of endoleak, spontaneous resolution, changes in the size of the aneurysm sac, and reintervention rates. Results Of the 160 patients who had completed required follow-up to date (mean 3 years) after endovascular aneurysm repair, 39 (24.4%) patients were identified as having a type 2 endoleak on computerized tomographic angiography imaging. 6 (15.4%) of these 39 patients required repair due to aneurysm sac growth >1 cm. 2 (5.13%) were repaired with an open procedure and 4 (10.3%) with an endovascular approach. Of these 6 aneurysm leaks requiring repair, 4 (66.7%) had a simultaneous endoleak (types 1 or 3) in addition to the identified type 2 endoleak. Spontaneous resolution of type 2 endoleaks occurred in 16 (41.0%) patients. 4 patients (10.3%) had delayed type 2 endoleaks that presented 4, 9, 12, and 23 months after their 30 day post op computed tomography was normal. None of the 4 patients with delayed type 2 endoleaks required reintervention and none had aneurysm sac growth greater than 5 mm. Conclusions Overall, we found that 85% of patients who had type 2 endoleaks did not require intervention after a mean follow-up time of 3 years. The association of a type 1 or 3 endoleak with a type 2 endoleak was more likely to require correction due to aneurysm expansion >1 cm, thus type 2 endoleaks associated with another type of endoleak require more aggressive management.

AIM: Bone morphogenetic protein-2 (BMP-2) is an FDA approved, osteoinductive growth factor for bone regeneration. However, increasing awareness of the side effects of BMP-2, including inflammation, bone resorption and fat formation, require the development of animal surgical models that replicate these adverse events. MATERIAL AND METHODS:We devised a mouse femoral uni-cortical defect (UCD) model to study the clinical side effects of BMP-2. UCDs (3×1×1 mm) were drilled in one femur of mice and filled with poly(D,L-lactide-co-glycolide) (PLGA) scaffolding coated with PBS or rhBMP-2 (0.3mg/ml or 0.6mg/ml). Post mortem analyses were performed at four weeks post-surgery. RESULTS: 100% successful surgery was achieved in mouse femoral UCD without surgical complication. Micro-CT analyses of the high dose rhBMP-2 group revealed bone cyst formation with ~2.5 fold increase in bone volume and more than 50% decrease in bone mineral density and trabecular number compared to PBS control. Tartrate-resistant acid phosphatase (TRAP) staining revealed a significant increase in osteoclast number, while immunostaining for fatty acid binding protein 4 (FABP4) and peroxisome proliferatoractivated receptor gamma (PPAR-γ) confirmed significant increases in adipocyte formation with rhBMP-2 in a dose dependent manner. Lastly, rhBMP-2 treatment caused significant increases in inflammation, as determined by immunostaining for tumor necrosis factor-α (TNF-α) and interleukin 6 (IL6). CONCLUSION: Here, we established a mouse UCD model that faithfully replicates the clinically reported side effects of rhBMP-2. This model may facilitate future studies to improve upon current efforts in rhBMP-2 based bone repair.

Osteoporosis is the most common metabolic disease of bone, resulting in significant worldwide morbidity. Currently, there are insufficient imaging modalities available to evaluate osteoporotic bones in small animal models. Here, we demonstrate the feasibility of using high resolution X-ray imaging as a comparable measure of bone degeneration to dual-energy X-ray absorptiometry (DXA) in an osteoporosis rodent model. At week 0, animals underwent either an ovariectomy (OVX) or sham procedure (SHAM). DXA analysis was performed weekly to confirm and compare the bone degenerative changes induced by OVX. A comparison using high resolution X-ray imaging (Faxitron®) was then performed postmortem due to need of soft tissue removal. Two regions of interest (ROIs) were utilized: the distal third of the femur and the lumbar spine (L4/L5). It was observed that SHAM animals maintained a relatively constant bone mineral density (BMD), in comparison to OVX animals, whereby a significant decrease in BMD was appreciated. Post mortem X-ray scans were performed and converted to 8-bit color and quantified. A high level of agreement with DXA quantifications was observed with X-ray quantifications, and a significant correlation between the radiopacity, visualized by color distributions, and the DXA BMD values between animal groups was evident. Our study demonstrates the applicability of high resolution X-ray imaging both qualitatively and quantitatively as a reliable approach for quantifying osteoporosis in rodent osteoporotic models. With DXA being a highly user dependent modality, our technique is a unique secondary methodology to verify DXA findings and minimize inter-observer variability.