Abstract
In diabetes mellitus (DM) patients, the morbidity of infectious disease is increased, and these infections can easily progress from local to systemic infection. Sepsis is a characteristic of organ failure related to microcirculation disorders resulting from endothelial cell injury, whose most frequent comorbidity in patients is DM. The aim of the present study was to evaluate the influence of infection on DM-induced microvascular damage on inflammation and pulmonary endothelial structure using an experimental endotoxemia model. Lipopolysaccharide (LPS; 15 mg/kg) was injected intraperitoneally into 10-week-old male C57BLKS/J Iar- + leprdb/leprdb (db/db) mice and into C57BLKS/J Iar–m + / + leprdb (db/ +) mice, which served as the littermate non-diabetic control. At 48 h after LPS administration, the survival rate of db/db mice (0%, 0/10) was markedly lower (P < 0.05) than that of the db/ + mice (75%, 18/24), whereas the survival rate was 100% in both groups 24 h after LPS administration. In control mice, CD11b-positive cells increased at 6 h after LPS administration; by comparison, the number of CD11b-positive cells increased gradually in db/db mice until 12 h after LPS injection. In the control group, the number of Iba-1-positive cells did not significantly increase before and at 6, 12, and 24 h after LPS injection. Conversely, Iba-1-positive cells continued to increase until 24 h after LPS administration, and this increase was significantly greater than that in the control mice. Expression of Ext1, Csgalnact1, and Vcan related to endothelial glycocalyx synthesis was significantly lower in db/db mice than in the control mice before LPS administration, indicating that endothelial glycocalyx synthesis is attenuated in db/db/mice. In addition, ultrastructural analysis revealed that endothelial glycocalyx was thinner in db/db mice before LPS injection. In conclusion, in db/db mice, the endothelial glycocalyx is already injured before LPS administration, and migration of inflammatory cells is both delayed and expanded. This extended inflammation may be involved in endothelial glycocalyx damage due to the attenuation of endothelial glycocalyx synthesis.
Highlights
Endothelial disorder in patients with non-insulin-dependent diabetes mellitus, which accounts for 90–95% of DM cases, is caused by chronic micro-inflammation from the early stages of diabetes (Ross, 1999)
After LPS administration, the levels of neutrophil infiltration and pulmonary edema increased compared with pre-LPS injection levels. db/db mice showed a significant increase in neutrophil infiltration and pulmonary edema compared with the control mice. These results suggest that inflammation was aggravated in db/db mice compared with the control mice
After LPS injection, intensity score is lower in both the control and db/db mice compared with before LPS injection, and especially, it was lower in db/db mice than in the control mice. These results suggest that injury to endothelial glycocalyx in pulmonary capillaries was aggravated in db/db mice
Summary
Endothelial disorder in patients with non-insulin-dependent diabetes mellitus (type 2 DM), which accounts for 90–95% of DM cases, is caused by chronic micro-inflammation from the early stages of diabetes (Ross, 1999). In patients with type 2 DM, the morbidity of infectious disease is increased, and these infections can progress from local infection to systemic infection (Muller et al, 2005). Poor glycemic control in patients with type 2 DM can complicate the infection (Koh et al, 2012). Glycemic control is aggravated by infection, further increasing the severity of infection. One factor accounting for the easy contraction of infectious diseases by DM patients is endothelial disorder (Koh et al, 2012). The most frequent comorbidity in patients with sepsis is DM (Abe et al, 2018; Kushimoto et al, 2020)
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