Hypoxia, Receptor for Advanced Glycation End Products, and Cystic Fibrosis: A Pathway to Chronic Inflammation?

Abstract Background Identifying the factors that contribute to chronicity in inflamed colitic tissue is not trivial. However, in mouse models of colitis, we can investigate at preclinical timepoints. We sought to validate murine Trichuris muris infection as a model for identification of factors that promote development of chronic colitis. Methods We compared preclinical changes in mice with a resolving immune response to T. muris (resistant) vs mice that fail to expel the worms and develop chronic colitis (susceptible). Findings were then validated in healthy controls and patients with suspected or confirmed IBD. Results The receptor for advanced glycation end products (RAGE) was highly dysregulated between resistant and susceptible mice before the onset of any pathological signs. Increased soluble RAGE (sRAGE) in the serum and feces of resistant mice correlated with reduced colitis scores. Mouse model findings were validated in a preliminary clinical study: fecal sRAGE was differentially expressed in patients with active IBD compared with IBD in remission, patients with IBD excluded, or healthy controls. Conclusions Preclinical changes in mouse models can identify early pathways in the development of chronic inflammation that human studies cannot. We identified the decoy receptor sRAGE as a potential mechanism for protection against chronic inflammation in colitis in mice and humans. We propose that the RAGE pathway is clinically relevant in the onset of chronic colitis and that further study of sRAGE in IBD may provide a novel diagnostic and therapeutic target.

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Advanced glycation end products are elevated in cystic fibrosis-related diabetes and correlate with worse lung function

Journal of Cystic Fibrosis ◽

10.1016/j.jcf.2015.12.011 ◽

2016 ◽

Vol 15 (5) ◽

pp. 681-688 ◽

Cited By ~ 12

Author(s):

William R. Hunt ◽

Beth R. Helfman ◽

Nael A. McCarty ◽

Jason M. Hansen

Keyword(s):

Cystic Fibrosis ◽

Lung Function ◽

Advanced Glycation End Products ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products

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The Role of Advanced Glycation End-products in the Etiology of Insulin Resistance and Diabetes

US Endocrinology ◽

10.17925/use.2010.06.1.14 ◽

2010 ◽

Vol 06 (01) ◽

pp. 14 ◽

Cited By ~ 6

Author(s):

Helen Vlassara ◽

Gary E Striker ◽

◽

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Chronic Inflammation ◽

Advanced Glycation End Products ◽

Immune Defense ◽

Innate Immune ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products

Despite new and effective drug therapies, insulin resistance (IR) and type 2 diabetes and its complications remain major medical challenges. It is known that IR, often associated with overnutrition and obesity, results from elevated oxidant stress (OS) and chronic inflammation. Less widely known is that a major cause for this inflammation is excessive consumption of advanced glycation end-products (AGEs) by the citizens of developed countries. AGEs, which were largely thought as oxidative derivatives resulting from diabetic hyperglycemia, are increasingly seen as a potential risk factor for islet β-cell injury, peripheral IR, and diabetes. This article will discuss the relationships between exogenous AGEs, chronic inflammation, IR, and type 2 diabetes. We present new insights on the failure of innate immune defense mechanisms under chronic oxidant overload, which increase susceptibility to IR and type 2 diabetes and its complications. Finally, we describe evidence on AGE restriction, a new non-pharmacologic intervention, which effectively reduces persistent IR, restores innate immune functions, and, thus, optimizes current antidiabetic drug therapies.

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Defective Glyoxalase 1 Contributes to Pathogenic Inflammation in Cystic Fibrosis

Vaccines ◽

10.3390/vaccines9111311 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1311

Author(s):

Marilena Pariano ◽

Claudio Costantini ◽

Ilaria Santarelli ◽

Matteo Puccetti ◽

Stefano Giovagnoli ◽

...

Keyword(s):

Cystic Fibrosis ◽

Advanced Glycation End Products ◽

Interleukin 1 ◽

Autosomal Recessive Disorder ◽

Advanced Glycation ◽

Glyoxalase 1 ◽

Multiple Organs ◽

Glycation End Products ◽

End Products ◽

Inflammatory State

Cystic fibrosis (CF) is an autosomal recessive disorder that affects multiple organs, although a decline in respiratory function represents the major cause of morbidity and mortality. The airways of CF patients are characterized by a chronic inflammatory state to which the receptor for advanced glycation end-products greatly contributes. Glyoxalase 1 (GLO1) is the major enzyme metabolizing methylglyoxal, a potent precursor of advanced glycation end-products. Its role in CF has never been investigated. We herein resorted to murine and human preclinical models of CF to define the contribution of GLO1 to inflammatory pathology. We found that the expression and activity of GLO1, measured by real-time PCR and Western blot or a specific spectrophotometric assay, respectively, are defective in mice and human bronchial cells from CF patients exposed to Aspergillus fumigatus, a common pathogen in CF, but could be restored upon blockade of interleukin-1 receptor signaling by anakinra in mice. This study suggests that GLO1 contributes to pathology in CF and may be potentially targeted to mitigate inflammation.

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Differential expression of soluble receptor for advanced glycation end-products (sRAGE) in mice susceptible or resistant to chronic colitis

10.1101/719310 ◽

2019 ◽

Author(s):

Michael Bramhall ◽

Kevin Rich ◽

Ajanta Chakraborty ◽

Larisa Logunova ◽

Namshik Han ◽

...

Keyword(s):

Chronic Inflammation ◽

Mouse Models ◽

Advanced Glycation End Products ◽

Healthy Controls ◽

Advanced Glycation ◽

Chronic Colitis ◽

Trichuris Muris ◽

Soluble Rage ◽

Glycation End Products ◽

End Products

AbstractAimsIdentifying the factors that contribute to chronicity in inflamed colitic tissue is not trivial. However, in mouse models of colitis, we can investigate at preclinical timepoints. We sought to validate murine Trichuris muris infection as a model for identification of factors that promote development of chronic colitis.MethodsWe compared preclinical changes in mice with a resolving immune response to T. muris (resistant) versus mice that fail to expel the worms and develop chronic colitis (susceptible). Findings were then validated in healthy controls and patients with suspected or confirmed IBD.ResultsThe Receptor for Advanced Glycation End Products (Rage) was highly dysregulated between resistant and susceptible mice prior to the onset of any pathological signs. Increased soluble RAGE (sRAGE) in the serum and faeces of resistant mice correlated with reduced colitis scores. Mouse model findings were validated in a preliminary clinical study: faecal sRAGE was differentially expressed in patients with active IBD compared with IBD in remission, patients with IBD excluded or healthy controls.ConclusionPre-clinical changes in mouse models can identify early pathways in the development of chronic inflammation that human studies cannot. We identified the decoy receptor sRAGE as a potential mechanism for protection against chronic inflammation in colitis in mice and humans. We propose that the RAGE pathway is clinically relevant in the onset of chronic colitis, and that further study of sRAGE in IBD may provide a novel diagnostic and therapeutic target.

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