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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    • "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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    • "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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    • "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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