br The role of apelin in

The role of apelin in respiratory diseases At present, several scientific studies have suggested that the apelin/APJ system may play an important role in the development of pulmonary diseases (Table 4). For example, in an experiment on rats suffering from acute lung injury, apelin-13 decreases the levels of inflammatory cytokines and reduces the lung tissue level, but it should be emphasized that treatment by (Ala)-apelin-13 produces an opposite effect [50]. The authors also noticed an increase in the expression of apelin in plasma and lung tissue during acute lung injury [50]. Also, in rats with pulmonary hypertension, an increased level of apelin and a decreased level of APJ in lung tissue are observed [51]. Next, Chen et al. [52] studied the effect of swimming exercise on the expression of apelin and its receptor in pulmonary tissues of rats with hypoxic pulmonary hypertension. This study has shown that in comparison with the hypoxia group, in animals from the swimming group, higher APJ and lower apelin expression is observed. The authors suggested that by regulation of the pulmonary apelin/APJ system, hypoxic pulmonary hypertension could be mediated [52]. In turn, in neonatal rats with hyperoxia-induced lung injury, apelin improves alveolarization and angiogenesis, increases lung cyclic guanosine 3′,5′-monophosphate levels, and reduces pulmonary fibrin deposition, inflammation, septum thickness, arteriolar wall thickness, and right ventricular hypertrophy [53].
The role of apelin in gastrointestinal diseases In a newly published study, it was shown that apelin expression is positively correlated with the advent of inflammation in the body. For example, in patients suffering from Crohn's disease, an increase in apelin expression in the mesenteric adipose tissue and colon tissues is observed (Table 5) [54]. In an experiment on Il-10−/− mice with established colitis, the i.p. injection of apelin-13 decreases mucosal inflammation, improves the infiltration of inflammatory herpes simplex virus 2 and decreases the expressions of Tnf-α, Il-1β and Il-6 mRNA in the colonic tissue. Exogenous apelin also increases the colonic epithelial cell proliferation, thus accelerating the intestinal epithelium repair [55]. In turn, Han et al. [56] showed that apelin reduces the level of inflammatory mediators in mice suffering from chronic pancreatitis. Such an effect is related to activation of pancreatic nuclear factor (NF)-κB and inhibition of the up-regulation of pancreatic TNF-α, macrophage inflammatory protein-1 α/β, and IL-1β expression. Moreover, apelin exposure reduces the pancreatic membrane levels of phosphorylated protein kinase C-δ and increases the replenishment of pancreatic IκB proteins [56]. Apelin also can serve as a regulatory protein involved in the healing mechanism of stress-induced gastric damage. In an experiment on rats suffering from gastric lesion healing acquired as a result of stress, the overexpression of apelin in the first days of the disease and gradual reduction in the days following the stress exposure have been found. The blockage of apelin receptor APJ using apelin receptor antagonist (F13A) leads to a decrease in mucosal blood flow, prostaglandin E2 production and vascular endothelial growth factor expression in rats [57]. Therefore, taking the above-presented data into account, it can be concluded that apelin may play a protective role against gastric diseases.
Relationship between apelin and inflammatory factors Pro-inflammatory factors can influence apelin expression and, the other way around, apelin can influence pro-inflammatory factor expression. For example, it has been discovered that TNF-α up-regulates apelin mRNA expression in isolated human and mouse adipocytes, and intraperitoneal injection of TNF-α increases apelin expression in cells and plasma in mice [58]. Heinonen et al. [59] in an experiment on patients with metabolic syndrome found that apelin in vivo correlates with TNF-α and MAP expression. Moreover, apelin influences the activity of macrophages. In an in vitro experiment conducted on RAW264.7 cells in both normal and hypoxic conditions, it was noticed that apelin decreases the levels of monocyte chemotactic protein 1 (MCP1), monocyte chemotactic protein 3 (MCP3), macrophage inflammatory protein 1 (MIP1α, MIP1β), vascular endothelial growth factor A (VEGFA), angiopoietin 2 (Ang2) and TNF-α. Furthermore, apelin suppresses caspase 9/3 expression in RAW264.7, thus protecting macrophages from apoptosis [60]. Incubation of primary rat peritoneal macrophages with (Pyr1)-apelin-13 decreases the expression of pro-inflammatory cytokines (TNF-α, IL-6) and decreases phagocytose and chemotaxis activity. Also, treatment of peritoneal macrophages with (Pyr1)-apelin-13 plus the APJ antagonist F13A prevents the decrease in the production of pro-inflammatory cytokine expression and at the same time underlines the role of apelin as a mediator influencing macrophage functions [61]. However, there is also evidence that apelin can act as a stimulator of inflammatory cytokine expression. In the experiment on microglial BV2 cells, apelin increased the expression of TNF-α, IL-1β, MCP-1 and MIP-1α and decreased the level of IL-10 [62].