The Involvement Of Diabetes Type I And High Glucose In Hypoxia-induced Lung Injury And Pulmonary Epithelial Cancer Cell Proliferation

Diabetes is an abnormal metabolic syndrome which is caused by the interaction ofthe genetic and enviromental factors. The global incidence of diabetes increases by years.It has become serious threat to human health followed by tumor and cardiovascular andcerebrovascular diseases due to the aging population, improvement of living standard,changes of dietary structure, nervous life rhythm and lack of exercise. Diabetes mellitusleads to metabolic disorders, decreases host defense ability, and easy concurrence ofsevere infection has becomethe main characteristics of clinical chronic (long-term) highblood sugar. Recently, Klein et al showed that adults with diabetes mellitus have lowerforced vital capacity (FVC) and forced expiratory volume in one second (FEV1), withreductions in FVC more consistent than FEV1and lower diffusion capacity (DLCO)compared with their non-diabetic counterparts. The reduced lung function in patients withdiabetes is inversely related to blood glucose levels, duration of diabetes and its severityand is independent of smoking or obesity. However, the mechanism involved in theeffects of diabetes and high glucose on lung function needs to be further elucidated.Accumulating evidence has demonstrated that diabetes mellitus plays critical rolesin cancer cell proliferation and differentiation in a cell and tissue-specific manner.Recently, Ferguson et al showed that hyperinsulinemia in a mouse model promoted breastcancer metastasis to the lung. However, whether diabetes and high glucose promoteprimary lung cancer cell proliferation and metastasis remains unknown.Thus, in the present study, we carried out the following two parts of work:1. Theeffects of Diabetes type I on hypoxia-induced lung injury;2. The mechanisms involved inthe pro-proliferative effects of high glucose on lung epithelial cancer cell line A549.Main Results:1. In contrast to hypoxic control mice, hypoxic diabetic mice showed more widenalveolar septa, distruction of alveolar, congestion and abruption of alveolar wall vessels,edema, and inflammatory cell and red blood cells infiltration and suffer more severe lunginjury.2. In contrast to hypoxic control mice, MDA contents and MPO activity in lungtissues of hypoxic diabetic mice.3. Inflammatory cytokines IL-6and IL-1βin lung tissue of hypoxic diabetic miceincreased significantly compared to hypoxic control mice. 4. Results of Real-time PCR and Western blot analysis showed that mRNA andprotein expression of TLR4, FOXO1and FOXO3a in lung tissue of diabetic mice weresignificantly increased in contrast to control mice.5. The mRNA expression of target genes of FOXOs, p21and GADD45, wereincreased in lung tissues of diabetic mice in contrast to control mice.6. High glucose evidently promotes the proliferation and inhibit the apoptosis ofA549cells in a dose-dependent manner.7. High glucose inhibits the expression of p53and its target gene p21in A549cellsin a dose-dependent manner.8. High glucose promotes the protein expression of SIRT1, FOXO1and FOXO3a inA549cells in a dose-dependent manner.9. The promoting effects of high glucose on cells proliferation is partially blockedby anti-oxidant resveratrol and almost completely blocked by JNK inhibitor. Theinhibitory effect of high glucose on p53expression is also completely blocked by JNKinhibitor.10. High glucose decreased the expression of IL-8mRNA in a dose-dependentmanner. SIRT1agonist and especially the inhibitor of JNK can reverse this effect.Conclusion:(1) The present study demonstrates for the first time that the lung injury of hypoxicdiabetic mice is obviously severer than those in hypoxic control mice. The upregulationof TLR4and FOXOs expression may be key mechanisms involved in this process.(2) High glucose significantly promotes A549proliferation, meanwhile increasesSIRT1and FOXOs expressions，inhibits cell apoptosis and p53、p21、IL-8expression;JNK inhibitor completely blocks the pro-proliferative effects of high glucose on A549cells, meanwhile thoroughly reverses the inhibitory effects of high glucose on p53expression. These results suggest that JNK-dependent p53reduction may play importantroles in the pro-proliferation process of high glucose.