Background Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, smooth muscle activation and matrix degradation. This study tests the hypothesis that CD4+ T cell-produced IL-17 modulates inflammation and smooth muscle cell activation leading to the pathogenesis of AAA and that human mesenchymal stem cell (MSC) treatment can attenuate IL-17 production and AAA formation. Methods and Results Human aortic tissue demonstrated a significant increase in IL-17 and IL-23 expression in AAA patients compared to controls as analyzed by RT-PCR and ELISA. AAA formation was assessed in C57BL/6 (wild type; WT), IL-23−/− or IL-17−/− mice using an elastase-perfusion model. Heat-inactivated elastase was used as control. On days 3, 7 and 14 following perfusion, abdominal aorta diameter was measured by video micrometry, and aortic tissue was analyzed for cytokines, cell counts and IL-17-producing CD4+ T cells. Aortic diameter and cytokine production (MCP-1, RANTES, KC, TNF-α, MIP-1α and IFN-γ) was significantly attenuated in elastase-perfused IL-17−/− and IL-23−/− mice compared to WT mice on day 14. Cellular infiltration (especially IL-17-producing CD4+ T cells) was significantly attenuated in elastase-perfused IL-17−/− mice compared to WT mice on day 14. Primary aortic smooth muscle cells were significantly activated by elastase or IL-17 treatment. Furthermore, MSC treatment significantly attenuated AAA formation and IL-17 production in elastase-perfused WT mice. Conclusion These results demonstrate that CD4+ T cell-produced IL-17 plays a critical role in promoting inflammation during AAA formation and that immunomodulation of IL-17 by MSCs can offer protection against AAA formation.

Objectives Adenosine A2A receptor (A2AR) activation following lung transplantation attenuates ischemia-reperfusion (IR) injury by reducing inflammation. However, the effect of A2AR activation in donor lungs prior to transplant remains ill-defined. This study compares the efficacy of three different treatment strategies for A2AR agonist in a clinically relevant porcine lung transplantation model. Methods Mature porcine lungs underwent six hours cold ischemia prior to allotransplantation and four hours reperfusion. Five groups (n=6/group) were evaluated based upon treatment with ATL-1223, a selective A2AR agonist: Sham (thoracotomy alone), IR (transplant alone), ATL-D (donor pretreatment via ATL-1223 bolus), ATL-R (recipient treatment via ATL-1223 infusion), and ATL-D/R (combination of both ATL-1223 treatments). Lung function and injury were compared. Results Blood oxygenation was significantly higher among ATL-D, ATL-R, and ATL-D/R groups versus IR (392.0±52.5, 428.9±25.5, 509.4±25.1 vs. 77.2±17.0 mmHg, respectively, p<0.001). ATL-1223-treated groups had lower pulmonary artery pressures (ATL-D=30.5±1.8, ATL-R=30.2±3.3, ATL-D/R=29.3±4.5 vs. IR=45.2±2.1 mmHg, p<0.001) and lower mean airway pressures versus IR (ATL-D=9.1±0.8, ATL-R=9.1±2.6, ATL-D/R=9.6±1.3 vs. IR=21.1 mmHg, p<0.001). Similarly, ATL-1223-treated groups had significantly lower lung wet/dry weight, proinflammatory cytokine expression and lung injury scores by histology compared to IR. Importantly, all parameters of lung function and injury in ATL-1223-treated groups were similar to Sham (all p>0.05). Conclusions Pretreatment of donor lungs with ATL-1223 was as efficacious as other treatment strategies in protecting against IR injury. If necessary, supplemental treatment of recipients with ATL-1223 may provide additional protection. These results support the development of pharmacologic A2AR agonists for use in human clinical trials for lung transplantation.

The effects of acute hyperglycemia on lung ischemia-reperfusion (IR) injury and the role of receptor for advanced glycation endproducts (RAGE) signaling in this process are unknown. The objective of this study was twofold: (1) evaluate the impact of acute hyperglycemia on lung IR injury; and (2) determine if RAGE signaling is a mechanism of hyperglycemia-enhanced IR injury. We hypothesized that acute hyperglycemia worsens lung IR injury through a RAGE signaling mechanism. C57BL/6 wild-type (WT) and RAGE knockout (RAGE 2/2 ) mice underwent sham thoracotomy or lung IR (1-h left hilar occlusion and 2-h reperfusion). Acute hyperglycemia was established by dextrose injection 30 minutes before ischemia. Lung injury was assessed by measuring lung function, cytokine expression in bronchoalveolar lavage fluid, leukocyte infiltration, and microvascular permeability via Evans blue dye. Mean blood glucose levels doubled in hyperglycemic mice 30 minutes after dextrose injection. Compared with IR in normoglycemic mice, IR in hyperglycemic mice significantly enhanced lung dysfunction, cytokine expression (TNF-a, keratinocyte chemoattractant, IL-6, monocyte chemotactic protein-1, regulated upon activation, normal T cell expressed and secreted), leukocyte infiltration, and microvascular permeability. Lung injury and dysfunction after IR were attenuated in normoglycemic RAGE 2/2 mice, and hyperglycemia failed to exacerbate IR injury in RAGE 2/2 mice. Thus, this study demonstrates that acute hyperglycemia exacerbates lung IR injury, whereas RAGE deficiency attenuates IR injury and also prevents exacerbation of IR injury in an acute hyperglycemic setting. These results suggest that hyperglycemia-enhanced lung IR injury is mediated, at least in part, by RAGE signaling, and identifies RAGE as a potential, novel therapeutic target to prevent post-transplant lung IR injury.Keywords: lung transplant; receptor for advanced glycation end-products; hyperglycemia; inflammation Ischemia-reperfusion (IR) injury remains a leading cause of morbidity and mortality among patients undergoing lung transplantation. IR injury entails a rapid inflammatory response upon transplantation resulting in activation of the innate immune system, expression of proinflammatory cytokines, leukocyte infiltration, and edema, all of which contribute to subsequent acute graft failure. With a reported incidence of 25-30%, IR injury results in increased resource utilization, including prolonged mechanical ventilation, intensive care unit duration, and overall hospital lengths of stay (1, 2). Moreover, IR injury has also been identified as an important clinical risk factor for the development of chronic graft rejection in the form of bronchiolitis obliterans (3). As a result, studies aimed toward the development of therapeutic strategies to combat this complication hold tremendous clinical value.The receptor for advanced glycation end-products (RAGE) is a ubiquitous, multiligand receptor implicated in a variety of pathological conditions, such as diabetes and its compli...

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Objective The impact of leukotriene production by the 5-Lipoxygenase (5-LO) pathway in the pathophysiology of Abdominal Aortic Aneurysms (AAA) has been debated. Moreover, a clear mechanism through which 5-LO influences AAA remains unclear. Approach and Results Aneurysm formation was attenuated in 5-LO−/− mice, and in lethally irradiated WT mice reconstituted with 5-LO−/− bone marrow in an elastase perfusion model. Pharmacologic inhibition of 5-LO attenuated aneurysm formation in both aortic elastase perfused WT and angiotensin II treated LDLr−/− mice, with resultant preservation of elastin and fewer 5-LO and MMP9 producing cells. Separately, analysis of WT mice 7 days after elastase perfusion showed that 5-LO inhibition was associated with reduced polymorphonuclear leukocyte infiltration to the aortic wall. Importantly, 5-LO inhibition initiated 3 days after elastase perfusion in WT mice arrested progression of small AAA. Human AAA and control aorta corroborated these elastin and 5-LO expression patterns. Conclusions Inhibition of 5-LO by pharmacologic or genetic approaches attenuates aneurysm formation and prevents fragmentation of the medial layer in two unique AAA models. Administration of 5-LO inhibitor in small AAA slows progression of AAA. Targeted interruption of the 5-LO pathway is a potential treatment strategy in AAA.

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