Up-Regulation of Receptors for Advanced Glycation End-Products by Alveolar Epithelium Influences Cytodifferentiation and Causes Severe Lung Hypoplasia

Reynolds, Paul; Stogsdill, Jeffrey A.; Stogsdill, Megan P.; Heimann, Nicholas B.

doi:10.1165/rcmb.2011-0170oc

Cited by 42 publications

(53 citation statements)

References 49 publications

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“…Two transgenic lines of mice were generated and mated to create conditional doxycycline (dox)-inducible mice that overexpress RAGE (CCSP-RAGE TG) [24]. One mouse line specifically included a tetracycline-inducible RAGE construct and another utilized the club cell (Clara) secretory protein (CCSP) promoter successfully used to specifically target proximal airway epithelium [25].…”

Section: Methodsmentioning

confidence: 99%

Conditionally induced RAGE expression by proximal airway epithelial cells in transgenic mice causes lung inflammation

et al. 2014

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BackgroundReceptors for advanced glycation end-products (RAGE) are multiligand cell-surface receptors expressed abundantly by distal pulmonary epithelium. Our lab has discovered RAGE-mediated effects in the orchestration of lung inflammation induced by tobacco smoke and environmental pollutants; however, the specific contribution of RAGE to the progression of proximal airway inflammation is still inadequately characterized.Methods and resultsWe generated a Tet-inducible transgenic mouse that conditionally overexpressed RAGE using the club cell (Clara) secretory protein (CCSP) promoter expressed by club (Clara) cells localized to the proximal airway. RAGE was induced for 40 days from weaning (20 days of age) until sacrifice date at 60 days. Immunohistochemistry, immunoblotting, and qPCR revealed significant RAGE up-regulation when compared to non-transgenic controls; however, H&E staining revealed no detectible morphological abnormalities and apoptosis was not enhanced during the 40 days of augmentation. Freshly procured bronchoalveolar lavage fluid (BALF) from CCSP-RAGE TG mice had significantly more total leukocytes and PMNs compared to age-matched control littermates. Furthermore, CCSP-RAGE TG mice expressed significantly more tumor necrosis factor alpha (TNF-α), interleukin 7 (IL-7), and interleukin 14 (IL-14) in whole lung homogenates compared to controls.ConclusionsThese data support the concept that RAGE up-regulation specifically in lung airways may function in the progression of proximal airway inflammation.

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Section: Methodsmentioning

confidence: 99%

Conditionally induced RAGE expression by proximal airway epithelial cells in transgenic mice causes lung inflammation

et al. 2014

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“…RAGE expression is highly associated with lung development and increases during the alveolarization (29,40). High RAGE expression prior to the alveolarization period has adverse effects associated with a severe pulmonary dysplasia (16,41). A reduced alveolar expression of RAGE is related to pathophysiological changes of the lung tissue, such as carcinoma (3), fibrosis (34, 37), and chronic obstructive pulmonary disease (COPD) (34).…”

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confidence: 99%

The receptor for advanced glycation end-products supports lung tissue biomechanics

Al‐Robaiy

Weber

Simm

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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The receptor for advanced glycation end-products (RAGE) and its soluble forms are predominantly expressed in lung but its physiological importance in this organ is not yet fully understood. Since RAGE acts as a cell adhesion molecule, we postulated its physiological importance in the respiratory mechanics. Respiratory function in a buffer-perfused isolated lung system and biochemical parameters of the lung were studied in young, adult, and old RAGE knockout (RAGE-KO) mice and wild-type (WT) mice. Lungs from RAGE-KO mice showed a significant increase in the dynamic lung compliance and a decrease in the maximal expiratory air flow independent of age-related changes. We also determined lower mRNA and protein levels of elastin in lung tissue of RAGE-KO mice. RAGE deficiency did not influence the collagen protein level, lung capillary permeability, and inflammatory parameters (TNF-␣, high-mobility group box protein 1) in lung. Overexpressing RAGE as well as soluble RAGE in lung fibroblasts or cocultured lung epithelial cells increased the mRNA expression of elastin. Moreover, immunoprecipitation studies indicated a trans interaction of RAGE in lung epithelial cells. Our findings suggest the physiological importance of RAGE and its soluble forms in supporting the respiratory mechanics in which RAGE trans interactions and the influence on elastin expression might play an important role.receptor for advanced glycation end-products; aging; biomechanics; elastin; mouse THE RECEPTOR FOR ADVANCED glycation end-products (RAGE) is a pattern recognition receptor of the immunoglobulin superfamily (32). RAGE is predominantly expressed in lung, particularly in the type I alveolar epithelial (ATI) cells (12,15,46). This specific localization suggests its important physiological function in the alveolar epithelium. In other cell types and tissues, the expression of RAGE is activated in response to pathophysiological conditions, such as the accumulation of advanced glycation end-products (AGEs) and inflammation (1). RAGE expression is highly associated with lung development and increases during the alveolarization (29,40). High RAGE expression prior to the alveolarization period has adverse effects associated with a severe pulmonary dysplasia (16,41). A reduced alveolar expression of RAGE is related to pathophysiological changes of the lung tissue, such as carcinoma (3), fibrosis (34, 37), and chronic obstructive pulmonary disease (COPD) (34). In addition to the membrane-bound receptor, soluble RAGE (sRAGE) forms exist as the result of either alternative splicing (22) or protein shedding by metalloproteinases (39, 52). sRAGE normally exists in the bronchoalveolar lavage (BAL) at a high level (53), but it is deficient in neutrophilic asthma and COPD (47, 49).The physiological importance of RAGE in lung is not yet fully understood because mice lacking RAGE do not show obvious pulmonary alterations (5, 9). Only intervention studies indicated an adverse effect of RAGE in the development of lung fibrosis (14, 19) and acute lung injury (4...

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“…Briefly, one line of mice was generated in our laboratory that harbored a single transgene that contained the Cldn6 cDNA sequence downstream of seven concatomerized Tet-on response elements [34]. These mice were mated to mice of a second transgenic line that express a reverse tetracycline transactivator (rtTA) downstream of the human surfactant protein C (SP-C) promoter [35]. Male double transgenic SPC-rtTA/TetO-Cldn6 mice (Cldn6 TG) were weaned and genotyped at PN20 [36] and dox (625 mg/kg; Harlan Teklad, Madison, WI, USA) was continuously available until euthanasia on PN90.…”

Section: Methodsmentioning

confidence: 99%

Up-Regulation of Claudin-6 in the Distal Lung Impacts Secondhand Smoke-Induced Inflammation

Lewis

Milner

Lewis

et al. 2016

IJERPH

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It has long been understood that increased epithelial permeability contributes to inflammation observed in many respiratory diseases. Recently, evidence has revealed that environmental exposure to noxious material such as cigarette smoke reduces tight junction barrier integrity, thus enhancing inflammatory conditions. Claudin-6 (Cldn6) is a tetraspanin transmembrane protein found within the tight junctional complex and is implicated in maintaining lung epithelial barriers. To test the hypothesis that increased Cldn6 ameliorates inflammation at the respiratory barrier, we utilized the Tet-On inducible transgenic system to conditionally over-express Clnd6 in the distal lung. Cldn6 transgenic (TG) and control mice were continuously provided doxycycline from postnatal day (PN) 30 until euthanasia date at PN90. A subset of Cldn6 TG and control mice were also subjected to daily secondhand tobacco smoke (SHS) via a nose only inhalation system from PN30-90 and compared to room air (RA) controls. Animals were euthanized on PN90 and lungs were harvested for histological and molecular characterization. Bronchoalveolar lavage fluid (BALF) was procured for the assessment of inflammatory cells and molecules. Quantitative RT-PCR and immunoblotting revealed increased Cldn6 expression in TG vs. control animals and SHS decreased Cldn6 expression regardless of genetic up-regulation. Histological evaluations revealed no adverse pulmonary remodeling via Hematoxylin and Eosin (H&E) staining or any qualitative alterations in the abundance of type II pneumocytes or proximal non-ciliated epithelial cells via staining for cell specific propeptide of Surfactant Protein-C (proSP-C) or Club Cell Secretory Protein (CCSP), respectively. Immunoblotting and qRT-PCR confirmed the differential expression of Cldn6 and the pro-inflammatory cytokines TNF-α and IL-1β. As a general theme, inflammation induced by SHS exposure was influenced by the availability of Cldn6. These data reveal captivating information suggesting a role for Cldn6 in lungs exposed to tobacco smoke. Further research is critically necessary in order to fully explain roles for tight junctional components such as Cldn6 and other related molecules in lungs coping with exposure.

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Up-Regulation of Receptors for Advanced Glycation End-Products by Alveolar Epithelium Influences Cytodifferentiation and Causes Severe Lung Hypoplasia

Cited by 42 publications

References 49 publications

Conditionally induced RAGE expression by proximal airway epithelial cells in transgenic mice causes lung inflammation

Conditionally induced RAGE expression by proximal airway epithelial cells in transgenic mice causes lung inflammation

The receptor for advanced glycation end-products supports lung tissue biomechanics

Up-Regulation of Claudin-6 in the Distal Lung Impacts Secondhand Smoke-Induced Inflammation

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