Abstract

The receptor for advanced glycation end-products (RAGE) is a transmembrane cell surface protein of the immunoglobulin superfamily that acts as part of both the innate and adaptive immune system. RAGE is highly expressed in lung tissue and is therefore of interest in the pulmonary immune response. Specifically, RAGE mediates several cell-signaling responses such as inflammation and apoptosis. This work sought to elucidate the role of RAGE in the setting of chronic pulmonary irritation such as that found in long-term exposure to secondhand smoke (SHS). This irritation has several shared characteristics with lung diseases such as chronic obstructive pulmonary disease (COPD) and is therefore of value in discovering potential mechanistic targets for future therapeutic treatments for exacerbations of the disease. We validated the extracellular signal-regulated kinase (ERK) pathway as a downstream RAGE cascade to activate the cellular transcription factor NF-B and excluded the protein kinase B (AKT) pathway in chronic pulmonary inflammation. We also identified several proinflammatory cytokines mediated by RAGE in long-term SHS exposure; these included increased expression of TNF-, MIP-1, IL-13, and IFN, among others. Furthermore, we identified semisynthetic glycosaminoglycan ethers (SAGEs) as effective RAGE inhibitors in acute pulmonary inflammation and the improvement of lung function. RAGE is also implicated in many other diseases such as type II diabetes mellitus, Alzheimer’s disease, atherosclerosis, and obstetric complications. We investigated its postnatal expression in pups that experienced SHS-induced intrauterine growth restriction (IUGR) antenatally. Increased expression of RAGE correlated with concomitant decreased heart and kidney weights at 4 weeks of age. By 12 weeks of age, weights had improved to age-expected measurements, and detected RAGE protein levels had decreased. These results implicate a potential role for RAGE in disease pathologies of adults who experienced antenatal IUGR due to maternal SHS exposure during pregnancy. In addition to the RAGE signaling pathways, we also investigated the Gas6/AXL pathway in the lungs of pregnant preeclamptic rodents. Gas6 is a ligand for the transmembrane AXL receptor and has been found in increased levels in the serum of pregnant women with preeclampsia (PE). Previous studies in our lab demonstrated a rodent Gas6 model of PE. Using this model, we established that the maternal lung from Gas6-induced preeclamptic rats experienced increased AXL mRNA as well as higher total cell counts, protein, and inflammatory cytokines in bronchoalveolar lavage fluid (BALF). These findings established a connection between lung inflammation and the development of preeclampsia that was previously unknown.

Degree

PhD

College and Department

Life Sciences

Rights

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