Advanced glycation end products in the skin are enhanced in COPD
Impact Factor: 6.159
Level of Evidence: V
Sample Size/Population: N= 395 (COPD: 202, Old Healthy: 83, Young Healthy: 110)
Protocol: Subject groups (COPD I-IV, Old Healthy, Young Healthy) performed a post-bronchodilator spirometry and body plethysmography in order to determine lung function and clinical characteristics. Skin autofluorescence (SAF) was also tested for using the AGE-Reader scanner. Three separate SAF measurements were recorded and expressed as the average of all three. Subject groups were compared between one another.
Statistical Analysis: Mann-Whitney U tests and Chi-square tests to compare baseline characteristics between groups. Linear regression analyses to observe associations between SAF and clinical characteristics as well as SAF and lung function.
Study Type: Cross-sectional study
Results: In terms of SAF values, there was a significant difference between COPD patients and healthy subjects, with COPD patients having higher SAF values. It was also noted that SAF values were significantly associated with lower lung function, regardless of age, gender, or pack-years in smokers. SAF levels were also observed to be similar between COPD groups I-IV. There was not a significant difference between healthy smokers and healthy non-smokers in each group, however.
Conclusion: AGE levels measured through SAF were significantly higher in individuals with COPD in comparison to healthy controls. However, given that SAF values were similar between COPD groups, it is indicated that the level of AGEs in the skin is not indicative of the level of disease in COPD. Researchers do suggest, however, that AGE formation may have a genetic component that contributes to onset of disease. This study was limited by the fact that it is a cross-sectional study and the possible broad overlap between groups. It is suggested that SAP values could be implemented as biomarkers for COPD in the clinic.
Hoonhorst SJ, Lo Tam Loi AT, Hartman JE, Telenga ED, van den Berge M, Koenderman L, Lammers JW, Boezen HM, Postma DS, Ten Hacken NH. Advanced glycation end products in the skin are enhanced in COPD. Metabolism. 2014 Sep;63(9):1149-56. doi: 10.1016/j.metabol.2014.06.006. Epub 2014 Jun 13. PMID: 25034386.
Dietary phenotype and advanced glycation end-products predict WTC-obstructive airways disease: a longitudinal observational study.
Impact Factor: 4.043
Level of Evidence: IV
Sample Size/Population: N= 4,015 (Ever WTC-OAD: 921, Never WTC-OAD: 3,094).
Protocol: Subjects assessed for risk of developing World Trade Center obstructive airways disease (WTC-OAD) in association with dietary quality and AGE content. REAP-S nutritional scores with AGE quantification from annual FDNY-HP visits compiled and assessed.
Statistical Analysis: Paired sample t-tests comparing clinical parameters at two separate time periods, student t-tests comparing groups, one-way ANOVA to analyze lung function and dietary quality.
Study Type: observational prospective study.
Results: Subjects with WTC-OAD were found to consume significantly more processed meats and sugary drinks and consume significantly less grains and vegetables. Also, those who regularly consume AGE-rich foods from a single category were not at increased risk of developing WTC-OAD. In contrast, those who regularly consume AGE-rich foods from two categories had a significantly increased risk of developing WTC-OAD and those who regularly consume AGE-rich foods in at least three categories are at a highly significant increased risk.
Conclusion: Subjects with AGE-rich diets were significantly more likely to develop WTC-OAD. This is most likely due to the fact that AGEs induce oxidative stress and inflammation in the body, especially lung tissue. This study mimicked similar findings in other studies comparing high intakes of processed meats with risk of developing COPD. Limitations to the study included self-reporting of dietary habits which is subject to participant bias.
Lam R, Kwon S, Riggs J, Sunseri M, Crowley G, Schwartz T, Zeig-Owens R, Colbeth H, Halpren A, Liu M, Prezant DJ, Nolan A. Dietary phenotype and advanced glycation end-products predict WTC-obstructive airways disease: a longitudinal observational study. Respir Res. 2021 Jan 18;22(1):19. doi: 10.1186/s12931-020-01596-6. PMID: 33461547; PMCID: PMC7812653.
Lung level of HMBG1 is elevated in response to advanced glycation end product-enriched food in vivo.
Impact Factor: 4.653
Level of Evidence: II
Sample Size/Population: N=18 (control: 6, bread crust: 6, coffee extract: 6, young adult: 9, senescent: 9)
Protocol: High mobiity group box protein 1 (HMBG1) are copounts that are used for normal regulation of transcription in somatic cells. In order to determine the impact of food-derived AGEs and age-related AGEs on lung tissue in regards to HMBG1, five separate rat animal model groups were formed. Food-derived AGEs were studied via a control mouse group, a group fed with bread crumbs, and a group fed with coffee extract. Level of AGEs were measured and observed after a notable feeding time period of 15 days. Age-derived AGEs were studied via an adult rat group and a senescent rat group. Level of AGEs were compared between the two groups in order to determine the effects of age.
Statistical Analysis: Groups compared using a student’s t-test and one-way ANOVA. A two-sided test was used to perform a linear regression in order to determine the significance of the data.
Study Type: Animal model control trial.
Results: Overall, feeding rats AGE-rich foods resulted in increased AGEs in lung tissue after the 15 day feeding period. This was true for both the bread crumb feeding group and the coffee extract feeding group in comparison to the control group. The same effects were not as pronounced in the age-dependent models, however, which suggests that dietary AGEs may play a larger role in determining AGE levels within lung tissue. In addition, when looking at the effects of AGE-rich foods it was shown that long term consumption resulted in decreased levels of HMGB1 in the lungs.
Conclusion: Given that AGE-rich foods presented with a large difference in AGE amounts between the groups, it is presumed that dietary AGEs play a big part in determining overall AGE levels in the lungs. This is especially true regarding regulation of HMGB1 in the lungs. This same phenomenon was not observed with aging ,however. This indicates that dietary AGE consumption is a better prediction of HMGB1 expression, an overall lung function, better than age-related AGE levels.
Bartling B, Fuchs C, Somoza V, Niemann B, Silber RE, Simm A. Lung level of HMBG1 is elevated in response to advanced glycation end product-enriched food in vivo. Mol Nutr Food Res. 2007 Apr;51(4):479-87. doi: 10.1002/mnfr.200600223. PMID: 17357979.
Advanced glycation end-products and receptor for advanced glycation end-products expression in patients with idiopathic pulmonary fibrosis and NSIP.
Impact Factor: 1.706
Level of Evidence: II
Sample Size/Population: N = 30 (Control: 10, IPF: 10, NSIP: 10)
Protocol: Lung samples from patients with non-specific interstitial pneumonia (NSIP), idiopathic pulmonary fibrosis (IPF), and a control group were analyzed using immunofluorescence assay, Western blot, and ELISA. Immunofluorescence assay was performed in order to determine the AGE and RAGE composition of the lung tissue. Results were compared between groups.
Statistical Analysis: This study used Tukey’s test to determine differences between groups as well as a one-way analysis of variance in order to determine specific differences. All of the data values were also expressed as means with standard deviations.
Study Type: Observational study.
Results: Despite the IPF and NSIP patients exhibiting decreased pulmonary function, there appeared to be no correlation between AGE levels and clinical parameters. With that being said, however, there was a significant difference between AGE and RAGE levels in patients with IPF compared to NSIP and control patients. No significant difference between NSIP and control or IPF subjects was observed. The Western blot demonstrated that patients with IPF not only have increased expression of AGEs, but also higher circulating levels of AGEs. The ELISA test revealed that these increased levels in IPF patients was significant.
Conclusion: The study confirmed previous evidence that AGE levels are significantly higher in patients with IPF in comparison to those with NSIP and controls. No significant difference in AGE expression was observed in patients with NSIP. In addition to the increased expression of AGE in IPF patients, circulating levels of AGE were also increased in these patients. Researchers indicated that this may mean that there is a connection between circulating AGE levels and the pathogenesis of IPF.
Kyung SY, Byun KH, Yoon JY, Kim YJ, Lee SP, Park JW, Lee BH, Park JS, Jang AS, Park CS, Jeong SH. Advanced glycation end-products and receptor for advanced glycation end-products expression in patients with idiopathic pulmonary fibrosis and NSIP. Int J Clin Exp Pathol. 2013 Dec 15;7(1):221-8. PMID: 24427342; PMCID: PMC3885476.
Immunohistochemical localisation of advanced glycation end products in pulmonary fibrosis.
Impact Factor: 2.460
Level of Evidence: II
Sample Size/Population: N = 17 (IPF: 7, Diffuse alveolar damage: 3, control: 7).
Protocol: A monoclonal mouse anti-AGE antibody (6D12) was produced in order to determine the level of AGEs in lung tissue. The 6D12 antibody was used since it reacts with the main AGE structure and would therefore cover a wide variety of AGEs. Immunochemistry was performed in order to evaluate the composition of AGEs found in the lung tissue of the three groups contained within the research study. Immunochemistry specifically for AGE on macrophages was performed.
Statistical Analysis: This study used a Mann-Whitney U test to compare the levels of immunoreactivity between groups of lung tissue. Probability levels were set at a significance level of 0.05. In order to compare level of immunoreactivity between groups, a semiquantitative scale was developed to use for evaluation.
Study Type: Observational case study.
Results: From immunochemistry analysis researchers found that five out of the seven control patients were negative for 6D12. However, all seven of the IDP patients exhibited 6D12 on immunohistochemistry. In addition, some of the cases with diffuse alveolar damage also exhibited 6D12 on immunohistochemistry. These results show that patients with idiopathic pulmonary fibrosis and diffuse alveolar damage exhibit advanced glycation end products in their lung tissue.
Conclusion: This study found that AGEs were detected in lung tissue samples from patients with idiopathic pulmonary fibrosis and diffuse alveolar damage. This was not found in the majority of the control group. Given that macrophages are thought to play a major role in the pathogenesis of pulmonary diseases such as IPF, researchers from this study suggest that AGEs, more specifically AGE modified proteins, may be a useful biomarker in determining oxidative stress of pulmonary tissue. The researchers also suggest that AGE may be a useful biomarker in the pathogenesis of pulmonary fibrosis.
da Silva LF, Skupien EC, Lazzari TK, Holler SR, de Almeida EGC, Zampieri LR, Coutinho SE, Andrades M, Silva DR. Advanced glycation end products (AGE) and receptor for AGE (RAGE) in patients with active tuberculosis, and their relationship between food intake and nutritional status. PLoS One. 2019 Mar 14;14(3):e0213991. doi: 10.1371/journal.pone.0213991. PMID: 30870511; PMCID: PMC6417785.
Emphysema requires the receptor for advanced glycation end-products triggering on structural cells.
Impact Factor: 5.373
Level of Evidence: Level VII
Sample Size/Population: RAGE-/- and RAGE+/+ mice.
Protocol: RAGE-/- and RAGE+/+ mice were generated to study the role of RAGE in the development of emphysema.
Statistical Analysis: The groups were compared using a one-way ANOVA and the Tukey-Kramer test to compare multiple groups.
Study Type: Randomized controlled trial/animal research study.
Results: In terms of the RAGE-/- mice, they were found to be less susceptible to porcine pancreatic elastase (PPE) induced emphysema compared to RAGE+/+ mice. For RAGE+/+ mice, there was an increase in proinflammatory cytokine and RAGE ligand that led to an increase in recruitment of inflammatory cells such as neutrophils and macrophages to the lungs. In regards to both groups, the number of RAGE positive cells in the lungs was not significantly different between the groups. Finally, RAGE expression in the lungs was found to be spontaneous and not affected by PPE treatment.
Conclusion: Currently the role of RAGE in pulmonary emphysema is not fully understood. Based on the study, RAGE is involved in increased neutrophil-related cytokines and chemokines as a result of PPE-induced acute phase neutrophilic inflammation and emphysematous change in the lungs. As a result, it was concluded that RAGE could be targeted in emphysema cases for an improved clinical outcome.
Waseda K, Miyahara N, Taniguchi A, Kurimoto E, Ikeda G, Koga H, Fujii U, Yamamoto Y, Gelfand EW, Yamamoto H, Tanimoto M, Kanehiro A. Emphysema requires the receptor for advanced glycation end-products triggering on structural cells. Am J Respir Cell Mol Biol. 2015 Apr;52(4):482-91. doi: 10.1165/rcmb.2014-0027OC. PMID: 25188021.
The receptor for advanced glycation end products is a central mediator of asthma pathogenesis.
Impact Factor: 3.491 (The American Journal of Pathology)
Level of Evidence: Level III
Sample Size/Population: Wild-type and RAGE knockout mice.
Protocol: Wild type mice and RAGE knockout mice were exposed to house dust mites (HDM) via three different methods. After exposure they were sacrificed and their tissues were studied via qRT-PCR, immunoblotting, immunofluorescence microscopy, H&E and PAS staining, histologic scoring, and an ELISA for a smattering of different immune compounds including IgE and IL-4.
Statistical Analysis: Significance was determined by two-way variance analysis and in some cases an unpaired Student’s t-test with a P value <0.05.
Study Type: In-vivo mouse model.
Results: There was no statistically significant difference in overall RAGE when the whole wild type mouse lung was examined. Immunofluorescence microscopy also showed no change in bronchial or vascular RAGE in the treated wild type mice lung. The wild type mice did show eosinophilia, goblet cell hyperplasia, and elevated mucin expression during histologic evaluation. The RAGE knockout mice showed none of these histologic changes. The ELISA showed little differences between wild type, knockout, and controls. The only significant difference was RAGE knockout mice had higher baseline levels of IL-17 than the wild type. Interestingly, wild type mice showed induction of IL-17 after HDM exposure while the knockout mice did not. IL-17 was examined due to its connection to asthma in previous studies. Administration of soluble RAGE (sRAGE), which is potentially thought to decrease inflammatory responses, did show a decrease in bronchovascular inflammation. Overall, an asthmatic response is not initiated in RAGE knockout mice based on the pulmonary function parameters, histology, and cytokine profiling.
Conclusion: The seemingly protective effect that treatment with sRAGE had on lung tissue suggests that this kind of therapy could be beneficial in treatment of asthma. The absence of expression of IL-17 in the RAGE knockout mice treated with HDM extract implies that RAGE plays a role in IL-17 synthesis. Considering that IL-17 is known to contribute to the symptoms of asthma, this would mean that RAGE plays a role in the development of asthma, through its connection to IL-17. Also, the heightened baseline IL-17 levels in the RAGE knockout mice in the absence of the antigen suggests that some other process is upregulating to compensate for the lack of IL-17. More specifically, IL-17 is thought to contribute to neutrophilic asthma and also negatively regulating established allergic asthma. This means that the elevated baseline in the knockout mice may actually be inhibiting a primary asthmatic response. This also may be contributing to the subtle, unexpected differences in the other tests completed on these mice.
Overall, an asthmatic response is not initiated in RAGE knockout mice. This clearly is not straightforward, but there is some connection between RAGE and the development of asthma that should be further explored
Milutinovic PS, Alcorn JF, Englert JM, Crum LT, Oury TD. The receptor for advanced glycation end products is a central mediator of asthma pathogenesis. Am J Pathol. 2012 Oct;181(4):1215-25. doi: 10.1016/j.ajpath.2012.06.031. Epub 2012 Aug 11. PMID: 22889845; PMCID: PMC3463633.
The role of receptor for advanced glycation end products in airway inflammation in CF and CF related diabetes.
Impact Factor: 3.998 (Scientific Reports)
Level of Evidence: Level IV
Sample Size/Population: The study consisted of 10 healthy individuals, 5 cystic fibrosis patients (CF), 5 cystic fibrosis patients with associated diabetes (CFRD), and 7 diabetic patients.
Protocol: Five patients from each of the groups were selected sequentially to provide sputum samples. The following experiments considered both membrane bound RAGE (mRAGE) and free, soluble RAGE (sRAGE). Levels of mRAGE and sRAGE were stained for in sputum samples and quantified via independent observers. PCR was also used to quantify the amount of mRAGE and sRAGE mRNA in blood leukocytes and sputum. ELISA was also used to determine concentrations of RAGE in both blood and sputum samples.
Statistical Analysis: This group used ANOVA followed by Tukey’s test to examine differences between group means. The P value was <0.05.
Study Type: Case-control study.
Results: According to the PCR analysis of RAGE mRNA, CF individuals had higher RAGE mRNA than the healthy individuals and diabetics. Diabetic individuals had decreased amounts of RAGE mRNA. CFRD patients also had increased RAGE mRNA, but to a lesser extent than CF patients.
During immunocytochemistry, diabetic individuals had significantly higher mRAGE levels than healthy individuals. Also, CF patients had significantly more mRAGE than the healthy, CFRD, and diabetic groups.
Sputum samples showed a decreased amount of sRAGE in CF and CFRD patients than the healthy group. Sputum of CFRD patients also showed an increased ratio of mRAGE, which is proinflammatory, to sRAGE, which is said to be protective against inflammation. This was compared to other fluid samples from the body and suggests that there is localization of inflammation in the airways for this group of people. Overall, CF patients had low sRAGE and AGE levels. CFRD patients had increases in all variables measured.
Conclusion: CFRD patients have faster lung function decline than those with CF. The group hypothesized that this could be due to the increased RAGE and AGE levels in the body associated with diabetes leading to increased lung inflammation. CF patients showed downregulation of protective sRAGE and upregulation of mRAGE. CFRD patients had less mRAGE and even less sRAGE than the CF patients. Most importantly, the CFRD group had a much larger mRAGE/sRAGE ratio than any other group. This means that the tissue has more pro-inflammatory receptors and less protective receptors in the lung tissue. This is significant because lung function deteriorates when there is inflammation present. Serum RAGE levels were not increased in CF or CFRD patients which was unexpected considering results found in other studies on chronic lung diseases and suggests this point be examined more in further studies on chronic lung disease. Examining each piece of the RAGE system proved to be difficult and complex to monitor. All of the components were looked at simultaneously which also made the data much more difficult to present and decipher. Data may be better viewed as ratios with considerations of different parts of the system, such as the mRAGE/sRAGE ratio. It also would be beneficial to view these ratios over time to compare an individual’s healthy state to their unwell state.
Mulrennan S, Baltic S, Aggarwal S, Wood J, Miranda A, Frost F, Kaye J, Thompson PJ. The role of receptor for advanced glycation end products in airway inflammation in CF and CF related diabetes. Sci Rep. 2015 Mar 10;5:8931. doi: 10.1038/srep08931. PMID: 25754382; PMCID: PMC4354142.
Receptor for advanced glycation end products is protective during murine tuberculosis.
Impact Factor: 3.641
Sample Size/Population: 12-16 wild type (Wt) mice C57Bl/6 and 12-16 RAGE−/− mice.
Protocol: Both Wt and RAGE−/− mice were infected intranasally with M. tuberculosis. 7-8 mice from each group were then sacrificed at 3 weeks and again at 6 weeks after infection. The remaining mice were sacrificed at 28 weeks after infection. Lungs and livers were removed from the mice used to obtain the several parameters of infection compared in this study. The lungs were immunostained for RAGE and analysed by a pathologist unaware of the sample's genotype. To score inflammation and damage, each sample was screened for interstitial inflammation, alveolar inflammation, vasculitis, bronchitis, edema, and pleuritis. Each parameter was graded on a scale of 0-4 (0 being absent, 4 being severe) and the “total lung inflammation score” was then expressed as a sum of the parameter scores for each sample (max = 24). Lung sample infiltrates were characterized by immunostaining for cell surface molecules using directly labeled antibodies against CD3, CD4, CD8, or GR-1. Percentage of polymorphonuclear cells (PMNs), macrophages, and lymphocytes were determined by detection of these antibody types. Cytokine measurements were taken from lung homogenates as well. Interferon (IFN)-, interleukin (IL)-4, TNF-, IL-10, IL-1, IL-6, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein 2 (MIP-2) were measured via an ELISA using matched antibody pairs.
Statistical Analysis: Values were expressed as mean ± SE. Mann-Whitney U- test analyzed differences between the two groups, log rank test compared survival curves, two way ANOVA was used to compare the two groups at multiple time points, bacterial counts were transformed to log values before further statistical comparison, and statistical significance was considered P<0.05.
Study Type: Case-Control study.
Results: M. Tuberculosis pneumonia results in enhanced RAGE expression in the lungs, as indicated by predominant RAGE immunostaining in the interalveolar septae of infected mice. The RAGE-/- mice demonstrated enhanced pulmonary inflammation as indicated by higher mean total histology score, heavier weighing lungs (indicative of inflammation and edema), and higher amount of leukocytes (profoundly neutrophils and lymphocytes). RAGE -/- mice also demonstrated elevated levels of proinflammatory cytokines and chemokines compared to the Wt mice. Additionally, the RAGE -/- mice displayed a “transiently enhanced” outgrowth of M. tuberculosis. At 3 weeks it was observed that the M. tuberculosis counts were 2-4 fold higher in the RAGE-/- mice, but at 6 weeks the bacterial counts between the two groups were similar. So to observe the semination of M. tuberculosis to distant organs, bacterial load was determined from the sample’s livers as well. No statistical difference was observed in the bacterial counts obtained from the liver at either 3 or 6 weeks. Finally, RAGE -/- mice demonstrated enhanced lethality after M. tuberculosis infection. RAGE -/- mortality was 58% while the Wt mortality was 12%.
Conclusion: RAGE deficiency resulted in enhanced inflammatory response in the lungs of mice infected with M. tuberculosis. This is reflected by the accelerated weight loss and increased mortality observed in the RAGE-/- group. The authors showed that healthy Wt mice abundantly express RAGE and that RAGE expression is also upgradulared in healthy Wt lung tissue inoculated with M. tuberculosis. Uniquely, the data collected in this study demonstrates enhanced, rather than diminished, leukocyte recruitment in RAGE -/- mice. The high accounts of neutrophils and lymphocytes can most likely be attributed to a combination of the RAGE receptors cell migration capabilities and the unbalanced immune response observed in the RAGE -/- mice. The higher bacterial counts observed in the RAGE -/- mice could also possibly be attributed to the less controlled inflammatory reaction. The findings in the study suggest that RAGE is important for a balanced inflammatory reaction in lungs infected with M. tuberculosis.
van Zoelen MA, Wieland CW, van der Windt GJ, Florquin S, Nawroth PP, Bierhaus A, van der Poll T. Receptor for advanced glycation end products is protective during murine tuberculosis. Mol Immunol. 2012 Oct;52(3-4):183-9. doi: 10.1016/j.molimm.2012.05.014. Epub 2012 Jun 13. PMID: 22698798.
Relationship between advanced glycation end-product accumulation in the skin and pulmonary function.
Impact Factor: 3.691
Level of Evidence: Level III
Sample Size/Population: 272 patient that went through a medical checkup at Ginza Hospital.
Protocol: Subjects went through the Anti-Aging Dock and then were divided into categories of >65 and <65 years old. The subjects measurements for AGEs (Advanced Glycation End products), pulmonary function, and blood parameters were recorded. Skin autofluorescence (SAF) was assessed using an AGE Reader to determine AGE accumulation in the skin. A spirometer was used to assess forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and percent predicted FEV1 (%FEV1). A medical history was also taken for each subject and all the data was then statistically analyzed.
Statistical Analysis: Unpaired Student’s t-test, Fisher’s exact test, Spearman’s rank correlation coefficient, and multiple linear regression analysis using the backward-selection method. P<0.05 was considered statistically significant. All analyses were performed using SPSS 19.0 for Windows.
Study Type: Cross sectional study.
Results: SAF was found to be an independent factor that is negatively associated with FEV1/FVC in elderly people with normal spirometry results, but not in younger people. Pack years of smoking was significantly associated with decreased FEV1/FVC in the elderly group which was accelerated by AGE accumulation. Between the elderly and younger groups, there were no significant differences in gender ratio, BMI, HDL-C, LDL-C, TG, HbA1c, WBC, DL, lipid-lowering and other drugs, drinking status, smoking status, %FVC, and %FEV1.
Conclusion: Pulmonary function was shown to potentially be maintained by preventing AGE accumulation in the body. In elderly people with normal spirometry results, AGE accumulation that was assessed through SAF was found to be an independent factor negatively associated with FEV1/FVC.
Kubo A, Kato M, Sugioka Y, Mitsui R, Fukuhara N, Nihei F, Takeda Y. Relationship between advanced glycation end-product accumulation in the skin and pulmonary function. J Phys Ther Sci. 2018 Mar;30(3):413-418. doi: 10.1589/jpts.30.413. Epub 2018 Mar 2. PMID: 29581662; PMCID: PMC5857449.
Plasma advanced glycation end-products and skin autofluorescence are increased in COPD.
Impact Factor: 12.339 (European Respiratory Journal)
Level of Evidence: Level IV
Sample Size/Population: This study involved 114 stable COPD patients, and 61 healthy individuals who are not current smokers. In the end, 6 controls and 26 COPD patients were excluded due to poor data collection.
Protocol: The main focus of this study was examining the amount of AGEs in the body via a skin autofluorescence reader (AFR) which can identify AGEs due to their yellow-brown fluorescence coloring. This fluorescence was examined on the palmar side of the dominant forearm of each participant. This data was collected via spectrometry as a ratio of the light administered to the skin compared to the light emitted back from the skin. Spirometry was also used to assess lung function. Plasma was collected to assess levels of CML, pentosidine, and CEL, some of the better studied AGEs. Oxidative damage of plasma protein was determined via examination of carbonyls in the plasma collected. Other factors such as high-density lipoproteins (HDL), triglycerides, glucose, c-reactive protein (CRP), and creatine were also measured in the blood.
Statistical Analysis: Comparison of characteristics between groups was done by t-test for continuous data and Chi-squared test for categorical data. Multiple linear regression analysis was used in examining if COPD and lung function were correlated to AGE levels. A linear regression model was used to investigate the correlation of AFR reported AGE levels and plasma AGE levels. Both of these last two methods were adjusted for the secondary data collected such as age, BMI, and CRP levels.
Study Type: Case-control trial.
Results: The following variables were shown to have no difference between groups: BMI, HDL cholesterol, triglycerides, glucose, plasma creatine, and oxidative stress markers. CRP was increased in COPD patients compared to controls. COPD patients had smoked more pack-years than controls. Plasma levels of CML were lower in COPD patients than controls, while plasma CEL levels were increased in COPD patients. Plasma pentosidine showed no difference between the two groups. AFR was higher in the COPD patients than the controls. Both plasma and AFR levels did not differ between the never- and ex- smokers in the control group. Interestingly, plasma and AFR levels of AGEs also did not differ between ex-smoker controls and currently smoking COPD patients. Increased levels of CEL and CML were associated with higher AFR readings, while increased pentosidine was not.
Conclusion: When all the data is said and done, CML was shown to be a negative determinant of disease state and CEL and AFR were positive determinants of disease state. However, it is unclear how these compounds and findings are implicated in the disease state. More work should be done to investigate the mechanisms of AGEs, specifically CEL, in the lungs and how it may contribute to COPD.
Gopal P, Reynaert NL, Scheijen JL, Engelen L, Schalkwijk CG, Franssen FM, Wouters EF, Rutten EP. Plasma advanced glycation end-products and skin autofluorescence are increased in COPD. Eur Respir J. 2014 Feb;43(2):430-8. doi: 10.1183/09031936.00135312. Epub 2013 May 3. PMID: 23645408.
Effect of high advanced glycation end-product diet on pulmonary inflammatory response and pulmonary function following gastric aspiration.
Impact Factor: 3.203
Level of Evidence: Level VII
Sample Size/Population: Male, specific-pathogen-free CD-1 mice.
Protocol: Mice were separated into two groups: one group was fed a high AGE (HAGE) diet and the other a low AGE (LAGE) diet for four weeks. After the four weeks, the mice were further separated into 1.- LAGE uninjured controls; 2. HAGE uninjured controls; 3. LAGE + gastric aspiration injury; and 4. HAGE + gastric aspiration injury. The mice lung tissue was then assessed for resistance, plasma AGE concentrations, whole lung myeloperoxidase activity, albumin concentrations, cytokines and chemokines, and histopathology.
Statistical Analysis: GraphPad Prism 5® was used for all of the analysis. A two-way ANOVA was done then Prism performed the post test Bonferroni’s correction. Comparisons were considered significantly different for p <0.05.
Study Type: Randomized controlled study.
Results: Elevated number of PMNs in BAL and whole lung homogenate MPO enzymatic activity and increased expression of TNFsRII showed that increased blood AGE levels were associated with more intense pulmonary inflammatory responses.
Conclusion: High circulatory AGEs levels secondary to diet exacerbate acute lung injury following gastric aspiration. This implies an important pathogenic interaction between AGEs and the acute inflammatory response in the lung following gastric aspiration. Thus, this study supports further research in the role of RAGE in the lung and the benefits of restricting AGEs in the diets of patients with lung injury after gastric aspiration.
Guo WA, Davidson BA, Ottosen J, Ohtake PJ, Raghavendran K, Mullan BA, Dayton MT, Knight PR 3rd. Effect of high advanced glycation end-product diet on pulmonary inflammatory response and pulmonary function following gastric aspiration. Shock. 2012 Dec;38(6):677-84. doi: 10.1097/SHK.0b013e318273982e. PMID: 23143059; PMCID: PMC3532929.