Acute Hyperglycemic Exacerbation of Lung Ischemia–Reperfusion Injury Is Mediated by Receptor for Advanced Glycation End-Products Signaling

Abstract

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...

Targeting advanced glycation endproducts and mitochondrial dysfunction in cardiovascular disease

“…Here mitochondrial ATP levels are depleted amongst a milieu of inflammation, cell death and fibrosis. Previous studies in mice have identified that RAGE is a key modulator of myocardial ischaemic injury [35] leading to oxidative injury in mitochondria which has been confirmed in other contexts [36]. There is also suggestion that RAGE ligands such as S100 calgranulins [37] and AGEs [38] can influence mitochondrial function in the context of ischaemic-reperfusion injury.…”

Ischemia-induced hyperglycemia: Consequences, neuroendocrine regulation, and a role for RAGE

“…When combined with the marked inflammatory milieu associated with an ischemic injury to the CNS it seems likely that this effect would be of an even greater magnitude. Very recently, Lapar and colleagues reported that hyperglycemia exacerbated lung injury in WT but not RAGE knockout mice though the transgenic animals were relatively protected from injury even under normoglycemic conditions (Lapar et al, 2011). Taken together it seems likely that activation of RAGE signaling by both rapidly induced AGEs and other inflammatory ligands like members of the S100 family and HMGB1 that are induced by hyperglycemia mediates at least part of the deleterious effects of injury induced hyperglycemia.…”

Hyperglycemia and Liver Ischemia Reperfusion Injury: A Role for the Advanced Glycation Endproduct and Its Receptor Pathway

“…What remains to be determined is the mechanism of how diabetes/hyperglycemia regulates the inflammatory immune response. Advanced glycation endproducts (AGEs) and their receptor (RAGE) have been shown to be accumulated and activated in tissues/cells of diabetic hosts, which may exert potent immune regulatory functions in disease pathogenesis, including ischemia reperfusion injury (IRI) (10)(11)(12)(13)(14)(15).…”