RAGE and tobacco smoke: insights into modeling chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by chronic airway inflammation and airspace remodeling, leading to airflow limitation that is not completely reversible. Smoking is the leading risk factor for compromised lung function stemming from COPD pathogenesis. First- and second-hand cigarette smoke contain thousands of constituents, including several carcinogens and cytotoxic chemicals that orchestrate chronic lung inflammation and destructive alveolar remodeling. Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors primarily expressed by diverse lung cells. RAGE expression increases following cigarette smoke exposure and expression is elevated in the lungs of patients with COPD. RAGE is responsible in part for inducing pro-inflammatory signaling pathways that culminate in expression and secretion of several cytokines, chemokines, enzymes, and other mediators. In the current review, new transgenic mouse models that conditionally over-express RAGE in pulmonary epithelium are discussed. When RAGE is over-expressed throughout embryogenesis, apoptosis in the peripheral lung causes severe lung hypoplasia. Interestingly, apoptosis in RAGE transgenic mice occurs via conserved apoptotic pathways also known to function in advanced stages of COPD. RAGE over-expression in the adult lung models features of COPD including pronounced inflammation and loss of parenchymal tissue. Understanding the biological contributions of RAGE during cigarette smoke-induced inflammation may provide critically important insight into the pathology of COPD.

Association of Polymorphisms of the Receptor for Advanced Glycation End Products Gene with COPD in the Chinese Population

“…An analysis of RAGE in bronchial biopsies by immunohistology demonstrated its abundance in the bronchial epithelia of patients with COPD. The conditional upregulation of RAGE expression in the bitransgenic adult mouse lung leads to the manifestation of key features of COPD, including pronounced inflammation and loss of parenchymal tissue (Robinson et al, 2012a). RAGE-deficient mice under hyperoxic conditions survived longer than wild-type controls.…”

“…The prevailing mechanisms underlying the pathogenesis of COPD include chronic inflammation, imbalances involving proteases/antiproteases, oxidative stress, and elevated apoptosis mediated by RAGE (Robinson et al, 2012a). Inflammation is produced predominantly by neutrophil infiltrates, which are found in abundance in the bronchoalveolar lavage and sputum of COPD patients.…”

Acute secondhand smoke-induced pulmonary inflammation is diminished in RAGE knockout mice

“…Following organogenesis, however, RAGE expression persists at the basolateral membrane of differentiated alveolar epithelial cells, where it influences interactions with the extracellular matrix and may contribute to structural and apoptotic changes associated with alveolar epithelial cell maintenance (8,38). RAGE also has inflammatory roles in cardiovascular and lung diseases including pulmonary fibrosis, asthma, pneumonia, and acute lung injury, among others (7,10,33). Of interest to the current investigation, RAGE expression is prominently detected in the alveolar compartments of smokers with COPD (48).…”

Effect of Hospital Use of Oral Nutritional Supplementation on Length of Stay, Hospital Cost, and 30-Day Readmissions Among Medicare Patients With COPD

“…In 2010, for example, the cost of COPD in the United States was estimated at nearly $50 billion annually. 2,11 Because of its typical onset later in life and its progressive nature, 2 COPD imposes particularly large costs on Medicare. Compared with age-and sex-matched counterparts without COPD, Medicare patients with COPD incurred approximately $20,500 (26.0%) more in healthcare costs in 2004.…”