Inhibition of A_2B Adenosine Receptor Attenuates Intestinal Injury in a Rat Model of Necrotizing Enterocolitis

Abstract

<jats:p>Necrotizing enterocolitis (NEC) is a lethal gastrointestinal tract disease that occurs in premature infants. Adenosine receptor A<jats:sub>2B</jats:sub> (A<jats:sub>2B</jats:sub>R) regulates the inflammation cytokine secretion and immune cell infiltration in the colonic pathophysiology conditions. In the present study, we aim to determine the roles of A<jats:sub>2B</jats:sub>R in the development of NEC. A NEC rat model was established and treated with A<jats:sub>2B</jats:sub>R agonist-BAY60-6583 or A<jats:sub>2B</jats:sub>R antagonist-PSB1115. Animals in the control group were free from any interventions. Our results showed that the inhibition of A<jats:sub>2B</jats:sub>R PSB1115 improved intestinal injury and inflammation in newborn NEC rats. The expression levels of caspase-3 and the ratio of apoptotic cells were upregulated in NEC rats, and these indices were downregulated after treating with PSB1115 but further upregulated by BAY60-6583. Meanwhile, a similar trend was also witnessed in the changes of MPO activities and proinflammatory cytokines including IL-6, IFN-<jats:italic>γ</jats:italic>, and TNF-<jats:italic>α</jats:italic>. However, the anti-inflammatory cytokine IL-10 in the NECP group was significantly higher than that in the NEC and NECB groups (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>p</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.05</mml:mn></mml:math>, respectively). Moreover, the expression of Ki67 was significantly increased in the NECP group as compared with those of the NEC and the NECB groups (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>p</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.05</mml:mn></mml:math>, respectively). Collectively, our study suggested that the inhibition of A<jats:sub>2B</jats:sub>R attenuates NEC in the neonatal rat, at least partially through the modulation of inflammation and the induction of epithelial cell proliferation.</jats:p>

Reduced Incidence of Necrotizing Enterocolitis due to the Anti-Inflammatory Effects of CXCL14 in Intestinal Tissue

“…Intriguingly, some researchers confirm that CXCL14 could prevent macrophages from polarizing in the direction of M1 [ 34 ]. Macrophage is a critical member of the immune cells in the intestinal tract equipped with a potent function of releasing cytokines [ 35 , 36 ].…”

Purinergic receptors modulators: An emerging pharmacological tool for disease management

“…Overexpression of these receptors has been reported in IBDs, intestinal ischemia, or perfusion injury. Hence, this overexpression of A 2B receptors as a deleterious consequence may be a target for the treatment of IBD 45–48 . However, in a recent study, a specific A 2B receptors intestinal epithelial signaling also protect the intestine for IBD by elevating mucosal barrier responses 49 …”

Adenosine and Inflammation: Here, There and Everywhere

“…The detrimental role of this receptor subtype was further corroborated by the fact that A 2B AR genetic deletion attenuated colonic inflammation induced by DSS or TNBS [ 137 ]. Moreover, a recent study demonstrated that the inhibition of A 2B AR with the antagonist PSB1115 attenuated intestinal injury in a neonatal rat model of necrotizing enterocolitis [ 138 ]. By contrast, an opposite effect was reported in the DSS colitis model, where both the administration of PSB1115 and the genetic deletion of A 2B AR resulted in an increase in the severity of colitis [ 139 ].…”