Hyperglycemia-Mediated Oxidative Stress Increases Pulmonary Vascular Permeability

Abstract

Objective: Hyperglycemia in diabetes mellitus is associated with endothelial dysfunction as evidenced by increased oxidative stress and vascular permeability. Whether impaired glucose control in metabolic syndrome impacts pulmonary vascular permeability is unknown. We hypothesized that in metabolic syndrome, hyperglycemia increases lung vascular permeability through superoxide.

Methods: Lung capillary Kf and vascular superoxide were measured in the isolated lungs of LZ and OZ rats. OZ were subjected to 4 weeks of metformin treatment (300 mg/kg/day orally) to improve insulin sensitivity. In a separate experiment, lung vascular permeability and vascular superoxide were measured in LZ exposed to acute hyperglycemia (30 mM).

Results: As compared to LZ, OZ had impaired glucose and insulin tolerance and elevated vascular superoxide which was associated with an elevated lung Kf. Chronic metformin treatment in OZ improved glucose control and insulin sensitivity which was associated with decreased vascular oxidative stress and lung Kf. Acute hyperglycemia in isolated lungs from LZ increased lung Kf, which was blocked with the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin (3 mM). Apocynin also decreased baseline Kf in OZ.

Conclusions: These data suggest that hyperglycemia in metabolic syndrome exacerbates lung vascular permeability through increases in vascular superoxide, possibly through NADPH oxidase.

Keywords: hyperglycemia; lung permeability; metabolic syndrome.

Figure 1

Effects of metformin treatment in OZ. A) Body weights at 9 to 13 weeks of age for OZ and OZ treated with metformin. (#P < 0.05 vs. OZ; n = 8 for each group). B) Plasma glucose after oral glucose tolerance test (3g/kg). (+P < 0.05 OZ vs. LZ; #P < 0.05 OZ vs. OZ + Metformin; n = 6–8 for each group). C) Plasma glucose after insulin tolerance test (1U insulin/kg body weight) (+P < 0.05 LZ vs. OZ; #P < 0.05 OZ vs. OZ + Metformin; n = 7–8 for each group).

Figure 2

A) Pulmonary Kf and B) vascular resistance for LZ, OZ, OZ acutely treated with apocynin (Apo), and OZ chronically treated with metformin (+P < 0.05 OZ vs. LZ; #P < 0.05 vs. OZ; n = 6–9 for each group except OZ + Apo, n=5).

Figure 3

A) DHE fluorescent images in aortic segments from LZ, OZ, OZ treated with metformin, and LZ treated with glucose (30 mM), and LZ treated with glucose and apocynin (3 mM). B) Percent DHE fluorescence from aortic segments from OZ, OZ treated with metformin, and LZ treated with glucose relative to LZ control (LZ control = 100%). (*P < 0.05 vs LZ control; #P < 0.05 vs. OZ; + P < 0.05 vs. LZ + Glucose; n = 6–8 for each group except LZ + Glucose + Apo, n=4).

Figure 4

The effect of acute hyperglycemia on A) pulmonary Kf and B) vascular resistance for LZ and OZ. Isolated lungs were perfused with either control solution, mannitol solution (30 mM), or glucose solution (30 mM). Additionally, LZ lungs perfused with control and glucose solutions were also treated with apocynin (*P < 0.05 vs LZ; #P < 0.05 LZ + Glucose vs LZ + Mannitol; n = 8–10 for all groups except LZ + Apo, n = 4).