Monocyte adhesive hyaluronan matrix induced by hyperglycemia in diabetic lung injuries.

Infiltrated pre-inflammatory monocytes and macrophages have important roles in the induction of diabetic lung injuries, but the mechanism mediating their infiltration is still unclear. Here, we showed that airway smooth muscle cells (SMCs) activated monocyte adhesion in response to hyperglycemic glucose (25.6 mM) by significantly increasing hyaluronan (HA) in the cell matrix, with concurrent 2- to 4-fold increases in adhesion of U937 monocytic-leukemic cells. The HA-based structures were attributed directly to the high-glucose and not to increased extracellular osmolality, and they required growth stimulation of SMCs by serum. Treatment of SMCs with heparin in high-glucose induces synthesis of a much larger HA matrix, consistent with our observations in the glomerular SMCs. Further, we observed increases in tumor necrosis factor-stimulated gene-6 (TSG-6) expression in high-glucose and high-glucose plus heparin cultures, and the heavy chain (HC)-modified HA structures existed on the monocyte-adhesive cable structures in high-glucose and in high-glucose plus heparin-treated SMC cultures. Interestingly, these HC-modified HA structures were unevenly distributed along the HA cables. Further, the in vitro assay with recombinant human TSG-6 and the HA14 oligo showed that heparin has no inhibitory activity on the TSG-6-induced HC-transfer to HA, consistent with the results from SMC cultures. These results support the hypothesis that hyperglycemia in airway smooth muscle induces the synthesis of a HA matrix that recruits inflammatory cells and establishes a chronic inflammatory process and fibrosis that lead to diabetic lung injuries.

Ginsenoside Rb1 reduces oxidative/carbonyl stress damage and ameliorates inflammation in the lung of streptozotocin-induced diabetic rats.

CONTEXT: Ginsenoside Rb1 (Rb1) is a biologically active component of ginseng [Panax ginseng C.A. Meyer (Araliaceae)]. OBJECTIVE: This study determined the underlying mechanisms of Rb1 treatment that acted on diabetes-injured lungs in diabetic rats. MATERIALS AND METHODS: Streptozotocin (STZ)-induced diabetic rat model was used. Male Sprague-Dawley (SD) rats were divided into four groups (n = 10): control, Rb1 (20 mg/kg), insulin (15 U/kg to attain the euglycaemic state) and diabetic (untreated). After treatment for six weeks, oxidative stress assay; histological and ultrastructure analyses; TNF-α, TGF-ß, IL-1 and IL-6 protein expression analyses; and the detection of apoptosis were performed. RESULTS: There was decreased activity of SOD (3.53-fold), CAT (2.55-fold) and GSH (1.63-fold) and increased levels of NO (4.47-fold) and MDA (3.86-fold) in the diabetic group from control. Rb1 treatment increased SOD (2.4-fold), CAT (1.9-fold) and GSH (1.29-fold) and decreased the levels of NO (1.76-fold) and MDA (1.51-fold) as compared with diabetic rats. The expression of IL-6 (5.13-fold), IL-1α (2.35-fold), TNF-α (2.35-fold) and TGF-ß (2.39-fold) was increased in diabetic rats from control. IL-6 (2.43-fold), IL-1α (2.27-fold), TNF-α (1.68-fold) and TGF-ß (2.3-fold) were decreased in the Rb1 treatment group. Diabetes increased the apoptosis rate (2.23-fold vs. control), and Rb1 treatment decreased the apoptosis rate (1.73-fold vs. the diabetic rats). Rb1 and insulin ameliorated lung tissue injury. DISCUSSION AND CONCLUSIONS: These findings indicate that Rb1 could be useful for mitigating oxidative damage and inflammatory infiltration in the diabetic lung.

Type 2 diabetes and reduced exercise tolerance: a review of the literature through an integrated physiology approach.

The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) is well established. Early in the course of the diabetic disease, some degree of impaired exercise capacity (a powerful marker of health status with prognostic value) can be frequently highlighted in otherwise asymptomatic T2DM subjects. However, the literature is quite heterogeneous, and the underlying pathophysiologic mechanisms are far from clear. Imaging-cardiopulmonary exercise testing (CPET) is a non-invasive, provocative test providing a multi-variable assessment of pulmonary, cardiovascular, muscular, and cellular oxidative systems during exercise, capable of offering unique integrated pathophysiological information. With this review we aimed at defying the cardiorespiratory alterations revealed through imaging-CPET that appear specific of T2DM subjects without overt cardiovascular or pulmonary disease. In synthesis, there is compelling evidence indicating a reduction of peak workload, peak oxygen assumption, oxygen pulse, as well as ventilatory efficiency. On the contrary, evidence remains inconclusive about reduced peripheral oxygen extraction, impaired heart rate adjustment, and lower anaerobic threshold, compared to non-diabetic subjects. Based on the multiparametric evaluation provided by imaging-CPET, a dissection and a hierarchy of the underlying mechanisms can be obtained. Here we propose four possible integrated pathophysiological mechanisms, namely myocardiogenic, myogenic, vasculogenic and neurogenic. While each hypothesis alone can potentially explain the majority of the CPET alterations observed, seemingly different combinations exist in any given subject. Finally, a discussion on the effects -and on the physiological mechanisms-of physical activity and exercise training on oxygen uptake in T2DM subjects is also offered. The understanding of the early alterations in the cardiopulmonary response that are specific of T2DM would allow the early identification of those at a higher risk of developing HF and possibly help to understand the pathophysiological link between T2DM and HF.

The Jiangtang Tongmai Prescription Inhibits Inflammation and Fibrosis of Lung Fibroblast Autophagy Induced by Hyperglycemia by Regulating CAV1 Expression.

OBJECTIVE: The lung is one of the target organs of diabetes. This study aimed to probe the protective mechanism of Jiangtang Tongmai Prescription (JTTMP) against diabetic lung injury. METHODS: JTTMP-containing serum was collected, and a high glucose and high-fat diabetic cell model was established. The cells were treated with a drug-containing serum or a CAV1-associated vector. Transfection efficiency was measured by qRT-PCR and western blot, the cell proliferative capacity was tested by CCK-8 assay, and the expression of autophagosome marker LC3B was measured by immunophluorescence assay. Expression levels of the autophagy markers LC3B, p62, and Beclin-1, and the expression levels of the fibrosis markers α-SMA, FN-1, and TGF-ß1 were determined by western blot, and the levels of inflammatory factors TNF-α and IL-1ß in the supernatants were assessed by ELISA. RESULTS: In high glucose and high fat-induced MRC-5 cells, JTTMP-containing serum impeded the abnormal cell proliferation and the expression levels of autophagy markers, fibrosis markers, as well as inflammatory factors. CAV1 expression was decreased in MRC-5 cells treated with JTTMP-containing serum. In MRC-5 cells upon transfection with the CAV1 overexpression vector and treatment with JTTMP-containing serum, increased cell proliferation, increased LC3B, p62, Beclin-1, α-SMA, FN-1, and TGF-ß1, TNF-α, and IL-1ß levels were found compared with cells treated with JTTMP-containing serum alone. CONCLUSION: This study suggests that JTTMP suppresses CAV1 expression to attenuate diabetic lung injury by reducing abnormal proliferation and autophagy, and reducing levels of fibrosis and inflammation.

Ameliorative effects of the Coptis inflorescence extract against lung injury in diabetic mice by regulating AMPK/NEU1 signaling.

BACKGROUND: In diabetic patients, complications are the leading cause of death and disability, while diabetic lung damage has received little research. The Coptis inflorescence extract (CE) has hypoglycemic properties, but the mechanism of its protective role on diabetic lung injury is understood. PURPOSE: This study aims to explore the protective actions and molecular mechanism of CE and its active ingredients in diabetic lung disease. METHOD: Twenty-nine metabolites were identified in the metabolomic profile of CE using HPLC-ESI/MS, and high-content substances of berberine (BBR) and linarin (LIN) were isolated from CE using column chromatography. The potential targets and molecular mechanisms of CE against diabetic lung damage were systematically investigated by network pharmacology and in vitro experimental validation. RESULTS: CE significantly improved lung function and pathology. CE (360 mg/kg) or metformin treatment significantly improved lipid metabolism disorders, including decreased HDL-C and elevated serum TG, TC, and LDL-C levels. Furthermore, CE's chemical composition was determined using the HPLC-QTOF-MS method. CE identified five compounds as candidate active compounds (Berberine, Linarin, Palmatine, Worenine, and Coptisine). Network pharmacology analysis predicted CE contained five active compounds and target proteins, that AMPK, TGFß1, and Smad might be the key targets in treating diabetic lung injury. Then we investigated the therapeutic effect of bioactive compounds of CE on diabetic lung damage through in vivo and in vitro experiments. Intragastric administration with BBR (50 mg/kg) or LIN (20 mg/kg) suppressed weight loss, hyperglycemia, and dyslipidemia, significantly alleviating lung inflammation in diabetic mice. Further mechanism research revealed that LIN or BBR inhibited alveolar epithelial-mesenchymal transition induced by high glucose by regulating AMPK/NEU-mediated signaling pathway. CONCLUSION: In conclusion, the administration of CE can effectively alleviate diabetic lung damage, providing a scientific basis for lowering blood sugar to moisturize lung function. BBR and LIN, the main components of CE, can effectively alleviate diabetic lung damage by regulating AMPK/NEU1 Signaling and inhibiting the TGF-ß1 level, which may be a critical mechanism of its effects.

Protective effect of quercetin on pulmonary dysfunction in streptozotocin-induced diabetic rats via inhibition of NLRP3 signaling pathway.

Diabetes mellitus (DM) is a dysmetabolic disease characterized by chronic hyperglycemia. In the developed countries, DM is the commonest life style disease that affects both old and young age. Nod-like receptor protein-3 (NLRP3)-mediated pyroptosis may in fact aid in the development of diabetic complications. Quercetin is a natural flavonoid, can be present in natural foods and plants. Many studies have reported the antioxidant role of quercetin on different tissues, but its effects on NLRP3-mediated pyroptosis in diabetic lung are unclear. The current study aimed to assess quercetin's protective effects on lung function, oxidative stress, and NLRP3-mediated pyroptosis in Wister rats exposed to streptozotocin (STZ)-induced DM. Forty male Wister rats were randomly allocated into four equal groups. The groups of rats were as follows: group 1 (G1) was kept under normal control conditions; G2 was injected I/P quercetin at a dose of 30 mg/kg b.wt., daily for 30 days; G3 and G4 were injected with a single dose of streptozotocin (STZ) 50 mg/kg b.wt. I/P to induce DM. After 72-h post diabetes induction, the rats of G4 were treated with quercetin as a manner in the second group. The results showed that quercetin ameliorates the pulmonary dysfunctions caused by DM through restoring the levels of glucose, insulin, and arterial blood gases, as well as the oxidative markers. Also, NLRP3-pyroptosis-mediated IL1ß was inhibited. Quercetin also reduces the effect of DM on the lung by decreasing the pathological changes in the lung. In conclusion, NLRP3 inflammasome-induced pyroptosis may aggravate lung injury in diabetic rats. Quercetin has the potential to ameliorate diabetes induced pulmonary dysfunction by targeting NLRP3.

Jiangtang Tongmai Prescription Reduced Diabetic Lung Injury Through SnoN and TGF-ß1/Smads Signaling Pathway.

By establishing a rat diabetes model in rats with intervening treatment by Jiangtang Tongmai Prescription (JTTMP), this study explored the restorative pairing effect of JTTMP on diabetic lung injury. The model of type II diabetes model was used to establish the rat diabetes model, using a high-fat diet and streptozotocin (STZ) induction. Different doses of JTTMP and metformin were administered as a therapeutic to intervene, and blood was collected to assess the blood glucose level of each group of rats. HE (Hematoxylin and eosin (H&E) staining was performed to detect the morphological changes in rat lung tissue and enzyme-linked immunoassay ELISA was used to detect and quantify the expression of interleukin (IL)-6, TNF tumor necrosis factor-ɑa, and IL-1ß in serum and the lung tissue of each group of rats. The level expression of TGF-ß1 [transforming growth factor (TGF)-ß1), SnoN (transcriptional co-repressor Ski-N terminal (SnoN)], Smad2, Smad3, Smad7, and other signaling pathway proteins were assessed by Western blot. In comparison with the normal control (NC) group, rats in the diabetes model (DM) group lost weight and showed significantly increased blood sugar levels. The levels of TGF-ß1 and Smad2/3 were increased in the DM group but Smad7 decreased. After 8 weeks of JTTMP intervention, the level of TGF-ß1 and Smad2/3 decreased but Smad7 increased, blood sugar decreased significantly and the expression of inflammatory factors in lung tissue decreased. Therefore, JTTMP may activate SnoN and the downstream TGF-ß1/Smads signaling pathway to repair diabetic lung injury, which suggests its application has potential for future clinical treatment of diabetes with lung injury.

The Diabetic Lung: Insights into Pulmonary Changes in Children and Adolescents with Type 1 Diabetes.

Historically, the lung was not listed and recognized as a major target organ of diabetic injury. The first evidence of diabetic lung involvement was published fifty years ago, with a study conducted in a population of young adults affected by type 1 diabetes (T1D). In recent years, there has been mounting evidence showing that the lung is a target organ of diabetic injury since the beginning of the disease-at the pediatric age. The deeply branched vascularization of the lungs and the abundance of connective tissue, indeed, make them vulnerable to the effects of hyperglycemia, in a way similar to other organs affected by microvascular complications. In this review, we focus on pulmonary function impairment in children and adolescents affected by T1D. We also cover controversial aspects regarding available studies and future perspectives in this field.

Hypertension Is Associated with Increased Risk of Diabetic Lung.

Lung function is often impaired in diabetic patients, especially in a restrictive pattern, which has recently been described as the diabetic lung. Since hypertension (HTN) is common in diabetic patients, our study investigated whether HTN acts as an aggravating factor in diabetic lung. Within the cross-sectional study from the 6th Korean National Health and Nutrition Examination Survey (KNHANES), fasting plasma glucose (FPG), blood pressure (BP), pulmonary function, and laboratory data were examined in 4644 subjects aged between 40 and 79 years. A multivariate regression model was used to investigate the relationship between BP, FPG, and pulmonary function. Lung function was significantly reduced in the HTN (p = 0.001), impaired fasting glucose (IFG) (p < 0.001), and diabetes mellitus (DM) (p < 0.001) groups. Next, a multivariate logistic regression model was used to derive the odds ratio (OR) of reduced lung function based on the presence of IFG, DM, and HTN. The OR of reduced forced vital capacity (FVCp < 80%) was 3.30 (p < 0.001) in the HTN-DM group and 2.30 (p < 0.001) in the normal BP-DM group, when compared with the normal BP-normal FPG group. The combination of HTN and DM had the strongest negative effect on FVC. The results presented in this study indicate that diabetes and hypertension have a synergistic association with impaired lung function.

Circadian Clock and Sirtuins in Diabetic Lung: A Mechanistic Perspective.

Diabetes-induced tissue injuries in target organs such as the kidney, heart, eye, liver, skin, and nervous system contribute significantly to the morbidity and mortality of diabetes. However, whether the lung should be considered a diabetic target organ has been discussed for decades. Accumulating evidence shows that both pulmonary histological changes and functional abnormalities have been observed in diabetic patients, suggesting that the lung is a diabetic target organ. Mechanisms underlying diabetic lung are unclear, however, oxidative stress, systemic inflammation, and premature aging convincingly contribute to them. Circadian system and Sirtuins have been well-documented to play important roles in above mechanisms. Circadian rhythms are intrinsic mammalian biological oscillations with a period of near 24 h driven by the circadian clock system. This system plays an important role in the regulation of energy metabolism, oxidative stress, inflammation, cellular proliferation and senescence, thus impacting metabolism-related diseases, chronic airway diseases and cancers. Sirtuins, a family of adenine dinucleotide (NAD+)-dependent histone deacetylases, have been demonstrated to regulate a series of physiological processes and affect diseases such as obesity, insulin resistance, type 2 diabetes (T2DM), heart disease, cancer, and aging. In this review, we summarize recent advances in the understanding of the roles of the circadian clock and Sirtuins in regulating cellular processes and highlight the potential interactions of the circadian clock and Sirtuins in the context of diabetic lung.

lncRNA ZEB1-AS1 is downregulated in diabetic lung and regulates lung cell apoptosis.

The present study aimed to investigate the role of ZEB1-antisense RNA 1 (AS1) in diabetic lung (pneumonia with excluded causes other than diabetes). In the present study, the expression of ZEB1-AS1 in plasma was detected by performing reverse transcription-quantitative PCR. A receiver operating characteristic curve was used for diagnostic analysis. Lung cell apoptosis under the treatment of high glucose was analyzed by a cell apoptosis assay. p53 expression in lung cells was detected by performing western blotting. The present data demonstrated that ZEB1-AS1 was downregulated in the plasma of patients with diabetic lung (DL) compared with diabetic patients without complications (~1.6-fold) and healthy controls (~2.4-fold), and downregulation of ZEB1-AS1 distinguished patients with DL from healthy controls. ZEB1-AS1 in lung cells was downregulated by high glucose treatment, and overexpression of ZEB1-AS1 resulted in inhibited lung cancer cell apoptosis and downregulated p53. p53 overexpression attenuated the effects of ZEB1-AS1 overexpression on lung cell apoptosis. In conclusion, the present study demonstrated that ZEB1-AS1 was downregulated in patients with DL and regulates lung cancer cell apoptosis by downregulating p53.

Effectiveness of Adjuvant Yoga Therapy in Diabetic Lung: A Randomized Control Trial.

CONTEXT: Recent studies provide ample evidence of the benefits of yoga in various chronic disorders. Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia and Sandler coined the term "Diabetic Lung" for the abnormal pulmonary function detected in diabetic patients due underlying pulmonary dysfunction. Yoga therapy may help in achieving better pulmonary function along with enhanced glycaemic control and overall health benefits. AIM: To study the effect of adjuvant yoga therapy in diabetic lung through spirometry. SETTINGS AND DESIGN: Randomized control trial was made as interdisciplinary collaborative work between departments of Yoga Therapy, Pulmonary Medicine and Endocrinology, of MGMC & RI, Sri Balaji Vidyapeeth Puducherry. MATERIALS AND METHODS: 72 patients of diabetic lung as confirmed by spirometry (<70% of expected) were randomized into control group (n=36) who received only standard medical treatment and yoga group (n=36) who received yoga training thrice weekly for 4 months along with standard medical management. Yoga therapy protocol included yogic counseling, preparatory practices, Asanas or static postures, Pranayama or breathing techniques and relaxation techniques. Hathenas of the Gitananda Yoga tradition were the main practices used. Spirometry was done at the end of the study period. Data was analyzed by Student's paired and unpaired 't' test as it passed normality. RESULTS: There was a statistically significant (P < 0.05) reduction in weight, and BMI along with a significant (P < 0.01) improvement in pulmonary function (FEV1, FVC) in yoga group as compared to control group where parameters worsened over study period. CONCLUSION: It is concluded from the present RCT that yoga has a definite role as an adjuvant therapy as it enhances standard medical care and hence is even more significant in routine clinical management of diabetes, improving physical condition and pulmonary function.

Potential Biochemical Mechanisms of Lung Injury in Diabetes.

Accumulating evidence has shown that the lung is one of the target organs for microangiopathy in patients with either type 1 or type 2 diabetes mellitus (DM). Diabetes is associated with physiological and structural abnormalities in the diabetic lung concurrent with attenuated lung function. Despite intensive investigations in recent years, the pathogenic mechanisms of diabetic lung injury remain largely elusive. In this review, we summarize currently postulated mechanisms of diabetic lung injury. We mainly focus on the pathogenesis of diabetic lung injury that implicates key pathways, including oxidative stress, non-enzymatic protein glycosylation, polyol pathway, NF-κB pathway, and protein kinase c pathway. We also highlight that while numerous studies have mainly focused on tissue or cell damage in the lung, studies focusing on mitochondrial dysfunction in the diabetic lung have remained sketchy. Hence, further understanding of mitochondrial mechanisms of diabetic lung injury should provide invaluable insights into future therapeutic approaches for diabetic lung injury.