Effect of hyperglycemia and angiopoietin-like-4 on pneumolysin-induced pulmonary barrier dysfunction

Pneumonia is the most common infectious disease worldwide with high lethality and Streptococcus pneumoniae is one of the main pathogens. Influence of the pathogen and/or an uncontrolled immune reaction can lead to alveolocapillary barrier failure and result in acute lung injury. Comorbidities, such as diabetes mellitus, are risk factors for pneumonia. Diabetes increases incidence and lethality of severe pneumonia, but contributing pathomechanisms are still unknown. The metabolic regulator angiopoietin-like-4 (Angptl-4) influences junctional proteins, Angptl-4 inhibition had a protective effect on pulmonary barrier function in murine influenza pneumonia, and Angptl-4 is increased in diabetes. The aim of our study is to characterize the influence of hyperglycemia on pneumonia-induced alveolocapillary barrier dysfunction, and investigate if Angptl-4 plays a causative role. We performed expression- and functional analyses on human and murine lung endothelial cells using qPCR and electrical cell-substrate impedance sensing. The effect of hyperglycemia or Angptl-4 on pneumolysin (PLY)-induced pulmonary hyperpermeability was investigated in isolated perfused and ventilated mouse lungs. We observed that an additional stimulation with high-glucose-buffer (HGB) or Angptl-4 significantly increased PLY-induced barrier failure in endothelial cells and in isolated mouse lungs. Angptl-4 expression was increased 4h after PLY stimulation, and further enhanced by combination of PLY with HGB. Our results suggest that hyperglycemia may increase susceptibility to pneumonia-induced barrier dysfunction. Further studies are warranted to investigate whether this effect is mediated by Angptl-4.