**3. Endothelial dysfunction and the formation of the functional status of the intestinal mucosal barrier in newborns with a low birth weight prone to perinatal hypoxia**

Endothelial dysfunction against the background of hypoxia and ischemia is accompanied by central nervous system lesions as well as dysfunctions of peripheral organs and systems [24, 25]. Visceral hypoperfusion is accompanied by the activation of indigenous microflora, damaging the immature intestinal barrier. Loss of the intestinal barrier can lead, due to the resorption of endotoxins, bacteria, and other substances, to systemic inflammatory reaction syndrome, remote organ damage, and multiple organ failure [26]. Considering the above, the purpose of this study was to determine the effect of endothelial dysfunction on the levels of markers, reflecting the functional state of the digestive system in newborns with a low birth weight with perinatal hypoxia.

Neurons and glial cells, whose need for energy supply is higher than that of all other cells of the body, are the first to suffer under conditions of oxygen deficiency. In this study, the biochemical marker of the destruction of nerve cells and the permeability of the blood–brain barrier in newborns of Group 1 and 2 significantly exceeded the indicators of the Control group on days 1–3 and 7–10 of life (**Figure 3**). The highest values of this marker are typical for newborns prone to acute birth asphyxia. Degradation of NMDA receptors as a result of neurotoxicity, assessed by the level of antibodies to NR2, in newborns of Group 1 significantly differed from the indicators of the Control group

#### **Figure 3.**

*The blood concentrations of NR2 (A, ng/ml), NSE (B, ng/ml), NO (C, ng/ml), and ET-1 (D, ng/ml) in infants with hypoxic–ischemic encephalopathy in 1–3 and 7–10 days of life (DOL). \*Significance of difference in comparison with control infants; significance of difference in comparison with second group.*

for both the first and second measurements, although a significant difference between Groups 1 and 2 was not found. This may be due, on the one hand, to the peculiarities of the immune response of immature newborns, which significantly predominate in the group subject to acute birth asphyxia. On the other hand, a longer period of time is required for the formation of ischemia foci and the accumulation of antibodies to glutamate receptors. The dynamics of the content of vasoregulatory markers in the peripheral blood in the studied groups are also shown in **Figure 3**. Both Group 1 and 2 were characterized by high concentrations of NO, while a significant difference in relation to this indicator was found between Group 1 and the Control group. Despite the level of endothelin-1 being initially high in both groups subject to chronic intrauterine hypoxia, in the group of newborns with acute asphyxia, the content of this marker sharply decreased toward the end of the perinatal period.

Violation of the vasoregulatory function of the vascular endothelium, manifested by a low level of endothelin-1 against the background of a high concentration of NO, in chronic intrauterine hypoxia complicated by acute birth asphyxia, being a causative factor in reducing blood pressure, leads to tissue ischemia. Visceral hypoperfusion in children with perinatal asphyxia is the leading cause of abdominal complications. Ischemia triggers a vicious circle of damage to the gastrointestinal mucosa and serves as a trigger for the formation of multiple organ failure [27]. The level of the intestinal ischemia marker I-FABP in newborns of Group 1 and 2 did not significantly exceed that of the Control group in the first days of life; however, it almost doubled in dynamics and differed significantly from the level of healthy infants (**Figure 4**).

Due to damage to the intestinal mucosa, failure of defense mechanisms, and overgrowth of Gram-negative intestinal flora, colonizing bacteria penetrate the mesenteric lymph nodes and systemic circulation (bacterial translocation) [28]. Violation of the intestinal barrier function, even in the absence of bacteremia, leads to portal and systemic endotoxemia, which serves as a trigger for a hypermetabolic and immunoinflammatory response [29]. The level of plasma L-FABP in newborns subject to asphyxia was 1.5 times lower than that in newborns of Group 2 and did not differ from that in the Control group. In general, on days 1–3 and 7–10, no significant differences in relation to this indicator were found between the studied groups. Despite chronic hypoxia and weakness of autoregulation in the GIT and liver compared to other vascular pools, the liver, due to its blood supply being from two sources, is better protected from hypoxia and ischemia. As can be seen in **Figure 4**, in newborns of Group 2, ischemia of the intestinal wall was accompanied by a high concentration of the marker of antiendotoxin immunity. In children in Group 1, the level of LBP was significantly lower than that in Group 2, indicating the failure of immune defense mechanisms in acute asphyxia that developed against the background of chronic intrauterine hypoxia.

Juli M. Richter et al. indicated an improvement in the processes of regeneration of the intestinal epithelium susceptible to LPS attack after intraperitoneal administration of LBP at high concentrations [14]. The physiological increase in the level of this marker in newborns of the Control group was due to intestinal colonization, contact with bacteria, colostrum components, or postpartum maturation of the liver [30]. The concentration of ITF, which stabilizes intestinal mucus and attenuates damage to the intestinal barrier, in newborns of Group 1 exceeded that of healthy newborns and infants in Group 2 (**Figure 5**). This difference was significant only for the Control group. Despite the decrease in this marker in dynamics, its content continued to exceed the indicators of the other two groups. According to Nancy A. Louis, HIF1 expression under hypoxic conditions and early reperfusion after ischemia trigger a

*Endothelial Dysfunction and Intestinal Barrier Injury in Preterm Infants with Perinatal Asphyxia DOI: http://dx.doi.org/10.5772/intechopen.110352*

#### **Figure 4.**

*The blood concentrations of IFABP (A, ng/ml), LFABP (B, ng/ml), and LBP (C, ng/ml) in infants with hypoxic–ischemic encephalopathy in 1–3 and 7–10 days of life (DOL). \*Significance of difference in comparison with control infants; significance of difference in comparison with group 1.*

physiological response characterized by the activation of functional mucus proteins, such as trefoil factor and P glycoprotein, aimed at preventing inflammatory processes in the intestine [23, 31]. At the same time, the level of secreted mucin does not increase in response to hypoxia. On the contrary, in this study, in newborns exposed to acute hypoxia, the level of MUC2, although not significantly, was somewhat lower than that of the other two groups.

Thus, newborns with a low birth weight subject to acute birth asphyxia are characterized by a high detection rate of organ and systemic disorders of posthypoxic origin. The results obtained showed that perinatal hypoxia initiated processes leading to an increase in the permeability of cell membranes, neuron death due to necrosis and/or apoptosis, disruption of the integrity of the blood–brain barrier structure, and entry of brain antigens into the systemic circulation, stimulating the immune system to produce antibrain antibodies. Involvement in the pathological process of the GIT is a logical outcome of severe hypoxic injury. The cause of damage to the digestive system is hemodynamic disturbances as a result of endothelial dysfunction, including

**Figure 5.**

*The blood concentrations of ITF (A, ng/ml) and MUC-2 (B, ng/ml) in infants with hypoxic–ischemic encephalopathy in 1–3 and 7–10 days of life (DOL). \*Significance of difference in comparison with control infants.*

regional dysfunction with a decrease in blood circulation in the mesenteric arteries in the first minutes of life in newborns who have experienced asphyxia. Disorders of the systemic and peripheral circulation as well as disorders of oxygen uptake and delivery to tissues accompanying perinatal asphyxia result in the development of a number of pathophysiological and pathobiochemical cascades, leading to secondary damage to the GIT.

*Endothelial Dysfunction and Intestinal Barrier Injury in Preterm Infants with Perinatal Asphyxia DOI: http://dx.doi.org/10.5772/intechopen.110352*
