IMPACT OF DIABETES ON ACUTE LUNG INJURY: UNRAVELLING MECHANISMS TO IMPROVE OUTCOMES

Abstract

Diabetes mellitus (DM) is a common comorbidity in acute lung injury (ALI) patients. Despite its well-established prevalence and known complications affecting many organs, our understanding of the lung as a target organ in DM remains limited, relying heavily on inconsistent findings from observational data. This thesis aims to investigate the effects of DM on lung health and ALI development and outcomes using a combinatorial approach incorporating clinical, cellular, and pre-clinical data. The Fluids and Catheters Treatment Trial (FACTT) dataset and plasma samples were analyzed to assess the impact of pre-existing diabetes on ALI patients. Additionally, the molecular effects of advanced glycation end-products (AGEs) were examined in human microvascular lung endothelial (HMLE) and epithelial (A549) cells, while the influence of DM on lung health and ALI severity was evaluated in 12-week-old type 1 DM mice with or without sepsis. Clinically, we found that ARDS patients with DM had lower survival rates and longer hospital and ICU stays compared to those without DM. Mechanistically, AGE treatment (50 µg/ml) modulated tight junction proteins and impaired barrier function. AGE exposure also activated key inflammatory pathways (AKT and P38 MAPK) and elevated the expression of inflammatory cytokines (TNF-α, IL-1β, IL-10, and IL-6). Experimentally, mouse DM lungs exhibited significant inflammation and edema compared to non-DM lungs. RNA sequencing identified genes involved in inflammation and endothelial barrier dysfunction, supporting the link between DM and lung injury. Furthermore, DM increased the risk of worsening ALI in sepsis mice compared to on-DM sepsis. Overall, our findings indicate that DM is a risk factor for lung inflammation and worsened ALI progression. This study highlights the potential for improving ALI outcomes by targeting diabetes-associated inflammatory and metabolic pathways, offering new insights for therapeutic interventions in diabetic patients at risk for ALI.