Endothelial Glycocalyx Disorders May Be Associated With Extended Inflammation During Endotoxemia in a Diabetic Mouse Model

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.

Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging

“…The glycocalyx on the luminal surface of BECs obstructs macromolecule extravasation and leukocyte adhesion and prevents BECs from sensing proinflammatory changes. Hypoxia, inflammation, and TNF-α have been known as disrupting the glycocalyx for some time ( 115 ); it is only recently that studies on the impact of systemic inflammation on endothelial glycocalyx damage have been conducted ( 116 ). In an experimental endotoxemia mouse model of T2D, LPS administration induced pulmonary edema and serum syndecan-1 elevation (the endothelial glycocalyx injury marker) ( 116 ).…”

“…Hypoxia, inflammation, and TNF-α have been known as disrupting the glycocalyx for some time ( 115 ); it is only recently that studies on the impact of systemic inflammation on endothelial glycocalyx damage have been conducted ( 116 ). In an experimental endotoxemia mouse model of T2D, LPS administration induced pulmonary edema and serum syndecan-1 elevation (the endothelial glycocalyx injury marker) ( 116 ). Nevertheless, acute death of the experimental mice within 48 h may not highlight the natural process of SCI.…”

Tetramethylpyrazine Alleviates Endothelial Glycocalyx Degradation and Promotes Glycocalyx Restoration via TLR4/NF-κB/HPSE1 Signaling Pathway During Inflammation

“…A lot of factors cause glycocalyx damage, such as lipopolysaccharide (LPS) (Sampei et al, 2021), hypernatremia, oxidized low-density lipoprotein (LDL), and reduced vascular wall shear stress (Yamaoka-Tojo, 2020). These stimuli systemically induce shedding of vascular endothelial glycocalyx, cause the glycocalyx layer thinning, and lead to endothelial damage.…”

Clotting Dysfunction in Sepsis: A Role for ROS and Potential for Therapeutic Intervention

“…Injury to the glycocalyx is known to be accentuated by increased levels of inflammatory molecules such as IL-1b. Diabetes likely further increases the associated risk; to this end, a recent study undertaken in mice demonstrated that diabetes limits glycocalyx synthesis, which is further damaged by endotoxemia [ 37 ]. Importantly, patients with diabetes have higher hospital admission rates when compared with non-diabetics [ 38 ].…”