Receptors for Advanced Glycation End-Products Targeting Protect against Hyperoxia-Induced Lung Injury in Mice

Department of Internal Medicine, Pulmonary Division, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 06/2009; 42(5):545-51. DOI: 10.1165/rcmb.2008-0265OC
Source: PubMed


Patients with acute lung injury almost always require supplemental oxygen during treatment; however, elevated oxygen itself is toxic. Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors predominantly localized to alveolar type I cells that influence development and cigarette smoke-induced inflammation, but studies that address the role of RAGE in acute lung injury are insufficient. In the present investigation, we test the hypothesis that RAGE signaling functions in hyperoxia-induced inflammation. RAGE-null mice exposed to hyperoxia survived 3 days longer than age-matched wild-type mice. After 4 days in hyperoxia, RAGE-null mice had less total cell infiltration into the airway, decreased total protein leak, diminished alveolar damage in hematoxylin and eosin-stained lung sections, and a lower lung wet-to-dry weight ratio. An inflammatory cytokine antibody array revealed decreased secretion of several proinflammatory molecules in lavage fluid obtained from RAGE knockout mice when compared with wild-type control animals. Real-time RT-PCR and immunoblotting revealed that hyperoxia induced RAGE expression in primary alveolar epithelial cells, and immunohistochemistry identified increased RAGE expression in the lungs of mice after exposure to hyperoxia. These data reveal that RAGE targeting leads to a diminished hyperoxia-induced pulmonary inflammatory response. Further research into the role of RAGE signaling in the lung should identify novel targets likely to be important in the therapeutic alleviation of lung injury and associated persistent inflammation.

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Available from: Paul R Reynolds, Oct 08, 2015
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    • "Apoptosis is an important mechanism for hyperoxic lung epithelial injury (50). Reynolds et al. demonstrated that adult RAGE-null mice survived longer and had diminished inflammation and inflammatory signals after 4 days in 75% FiO2 (51), implicating the RAGE receptor in pathways leading to hyperoxic pulmonary injury. "
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    ABSTRACT: The alveolar surface is covered by large flat Type I cells (alveolar epithelial cells 1, AEC1). The normal physiological function of AEC1s involves gas exchange, based on their location in approximation to the capillary endothelium and their thinness, and in ion and water flux, as shown by the presence of solute active transport proteins, water channels, and impermeable tight junctions between cells. With the recent ability to produce relatively pure cultures of AEC1 cells, new functions have been described. These may be relevant to lung injury, repair, and the abnormal development that characterizes bronchopulmonary dysplasia (BPD). To hypothesize a potential role for AEC1 in the development of lung injury and abnormal repair/development in premature lungs, evidence is presented for their presence in the developing lung, how their source may not be the Type II cell (AEC2) as has been assumed for 40 years, and how the cell can be damaged by same type of stressors as those which lead to BPD. Recent work shows that the cells are part of the innate immune response, capable of producing pro-inflammatory mediators, which could contribute to the increase in inflammation seen in early BPD. One of the receptors found exclusively on AEC1 cells in the lung, called RAGE, may also have a role in increased inflammation and alveolar simplification. While the current evidence for AEC1 involvement in BPD is circumstantial and limited at present, the accumulating data supports several hypotheses and questions regarding potential differences in the behavior of AEC1 cells from newborn and premature lung compared with the adult lung.
    Frontiers in Pediatrics 05/2014; 2:45. DOI:10.3389/fped.2014.00045
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    • "Next, we studied whether RAGE and ICAM-1 are linked to the anti-inflammatory PC pathway in more disease relevant mouse models: LPS-induced acute lung injury (LPS-ALI) [34, 35] and LPS-induced lethal endotoxemia [36]. Based on our results during LPS-induced ALI, RAGE and ICAM-1 play a crucial role in leukocyte recruitment during lung inflammation, a finding that has been described in earlier studies [30, 32, 37, 38]. Since PC treatment had no effect on bronchoalveolar neutrophil emigration in RAGE−/− mice but insignificantly reduced the number of neutrophils in BAL of Icam-1−/− mice, we suggest that RAGE, which is abundantly expressed in the lung [31, 39], plays a dominant role for mediating anti-inflammatory effects of PC during acute lung inflammation. "
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    ABSTRACT: By binding β 2-integrins both ICAM-1 and the receptor for advanced glycation end products (RAGE) mediate leukocyte recruitment in a stimulus-dependent manner. Using different inflammatory mouse models we investigated how RAGE and ICAM-1 are involved in anti-inflammatory functions of protein C (PC; Ceprotin, 100 U/kg). We found that, depending on the stimulus, RAGE and ICAM-1 are cooperatively involved in PC-induced inhibition of leukocyte recruitment in cremaster models of inflammation. During short-term proinflammatory stimulation (trauma, fMLP, and CXCL1), ICAM-1 is more important for mediation of anti-inflammatory effects of PC, whereas RAGE plays a major role after longer proinflammatory stimulation (TNF α ). In contrast to WT and Icam-1(-/-) mice, PC had no effect on bronchoalveolar neutrophil emigration in RAGE(-/-) mice during LPS-induced acute lung injury, suggesting that RAGE critically mediates PC effects during acute lung inflammation. In parallel, PC treatment effectively blocked leukocyte recruitment and improved survival of WT mice and Icam-1-deficient mice in LPS-induced endotoxemia, but failed to do so in RAGE-deficient mice. Exploring underlying mechanisms, we found that PC is capable of downregulating intracellular RAGE and extracellular ICAM-1 in endothelial cells. Taken together, our data show that RAGE and ICAM-1 are required for the anti-inflammatory functions of PC.
    Mediators of Inflammation 05/2014; 2014(9):743678. DOI:10.1155/2014/743678 · 3.24 Impact Factor
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    • "RAGE has been implicated in lung injury induced by hyperoxia [27] or bleomycin [28]. In addition, in pneumonia caused by Streptococcus pneumoniae, rage−/− mice have shown mitigated lung injury and neutrophil migration [29]. "
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    ABSTRACT: Staphylococcus (S.) aureus has emerged as an important cause of necrotizing pneumonia. Lung injury during S. aureus pneumonia may be enhanced by local release of damage associated molecular patterns such as high-mobility group box 1 (HMGB1). In the current study we sought to determine the functional role of HMGB1 and its receptors, toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE), in the injurious host response to S. aureus pneumonia. Pneumonia was induced in wild type (Wt), TLR4 deficient (tlr4-/-) and RAGE deficient (rage-/-) mice by intranasal inoculation of 1 x 107 colony-forming units (CFU) of a USA300 S. aureus. In a separate set of experiments, Wt mice were injected intraperitoneally with a monoclonal anti-HMGB1 antibody or an isotype matched control antibody immediately before and every 24 hours after intranasal infection of S. aureus. Mice were sacrificed at 6, 24, 48 or 72 hours after infection for harvesting of blood and organs. S. aureus pneumonia was associated with HMGB1 release in the bronchoalveolar compartment peaking after 24 hours. Anti-HMGB1 attenuated lung pathology and protein leak and reduced interleukin-1beta release 6 hours after infection, but not at later time points. RAGE deficiency more modestly attenuated lung pathology without influencing protein leak, while TLR4 deficiency did not impact on lung injury. These data suggest that HMGB1 and RAGE, but not TLR4, contribute to lung injury accompanying the early phase of S. aureus pneumonia.
    Critical care (London, England) 12/2013; 17(6):R296. DOI:10.1186/cc13162 · 4.48 Impact Factor
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