Congenital heart disease (CHD) is a common congenital developmental malformation in pediatrics. Cardiopulmonary bypass (CPB) is a representative technique of cardiac surgery, and it has been increasingly improved and widely popularized in recent years. However, CPB is an invasive treatment, whose postoperative complications, such as postoperative infection, low cardiac output syndrome, heart failure, arrhythmia and bleeding, should be paid enough attention to. The surgical trauma, low temperature, ischemia reperfusion and the contact with the surface of artificial materials, such as the artificial tube during CPB, can activate the immune system in the body, lead to activation of inflammatory cells, coagulation system, complement system, white blood cells (WBCs) and platelets, and release inflammatory factors (1–3). Lipoxin A₄ (LXA₄), as an important endogenous anti-inflammatory mediator, can reduce the production of inflammatory factors and inhibit the activation and chemotaxis of neutrophils (4). This study compared the LXA₄ levels between child patients with CHD and non-CHD children, observed the dynamic changes of LXA₄ in the perioperative period of CPB, and analyzed its correlation with blood routine indexes, high-sensitivity C-reactive protein (hs-CRP) and other clinical indexes, so as to find the correlation between LXA₄ and the inflammatory response of CHD.

There were no significant differences in age and sex between CPB and control group, and the plasma LXA₄ level in CPB group was significantly lower at Tc compared to that in the control group (P<0.01) (Table II). LXA₄ showed an increasing trend after operation, which was significantly increased at T1 compared to that at Tc (P<0.01), continued to show an upward trend, and was still significantly increased at T3 and T7 compared to that at Tc (P<0.01) (Fig. 1A). WBC was increased significantly at T1 and T3 (P<0.05) for a short time, and dropped at T7 near the level at Tc (Fig. 1B). The proportion of neutrophils (N%) was obviously and rapidly increased at T0 compared to that at Tc (P<0.01), for a long time, and was still remarkably increased at T7 compared to that at Tc (P<0.01) (Fig. 1C). The dynamic changes in hs-CRP were similar to those of WBC. hs-CRP level was significantly increased at T1 and T3 compared to that at Tc (P<0.01) and dropped at T7 near the level at Tc (Fig. 1D).

According to Pearson's linear correlation analysis, the CPB time and aortic clamping time were positively correlated with the time in the PICU, application time of ventilator and hs-CRP level at T0 (Table III). LXA₄ had no correlations with age, weight, CPB time and aortic clamping time. No correlation was found between LXA₄ and WBC, N% and hs-CRP at the corresponding time-points.

LXA₄, as the metabolite of arachidonic acid, is the first endogenous lipid mediator found with extensive functions of anti-inflammation and promotion of inflammatory resolution, and is hailed as the ‘braking signal’ of inflammatory response (5). LXA₄ is the metabolite produced by arachidonic acid through the lipoxygenase (LOX) pathway in the inflammatory process, as well as an endogenous antagonist of leukotrienes, and its major function is to inhibit the chemotaxis of neutrophils and adhere to endothelial cells, which is related to the inflammatory resolution (6). LX can also stimulate endothelial cells to produce prostacyclin and nitric oxide, help dilate blood vessels and improve blood flow (7). Under the influence of inflammation or disease and the stimulus of inflammatory factors, different LOXs will sequentially catalyze arachidonic acid to promote LX synthesis, in which interactions between cells, such as that between leukocytes, between leukocytes and platelets and between leukocytes and epithelial cells, are needed. If something is wrong in these interactions, the LX synthesis will be affected (8,9). There have been no studies on the correlations of LXA₄ with CHD and CPB. Reina-Couto et al have found that the severity of chronic heart failure (CHF) is negatively related to the plasma LXA₄ level, and LXA₄ can be considered as a valuable marker for the risk stratification of CHF, which may be related to the defects in pro-inflammatory and anti-inflammatory mechanisms of CHF (10). Child patients with CHD are often accompanied with cardiac insufficiency in different degrees, and it has been found that the LXA₄ level declines in child patients with CHD compared to that in normal children, in consistency with the research results of Reina-Couto et al. Moreover, child patients with CHD are prone to concurrent infection, and some studies have found that they often suffer from immunodeficiency in different degrees, such as the lower chemotaxis and phagocytosis of neutrophils, complement function and secretion of IgA than normal subjects (11). The immunodeficiency in child patients with CHD may be related to the low content of LXA₄, which needs to be confirmed via further experiments.

In the present study, it was found that LXA₄ showed a gradually increasing trend after CPB, and its average level at T7 was still significantly different from that in control group. The contact with a large number of artificial materials, surgical trauma and pulmonary ischemia-reperfusion injury during CPB can lead to activation of the monocyte/macrophage and the release of a large number of inflammatory factors in the body in order to resist stress and promote repair (1). Serhan et al (12) were the first to find that inflammation resolution is a highly-ordered active process closely regulated by a large number of lipid mediators produced by unsaturated fatty acid via enzymatic catalysis. LXA₄ can bind to its coupled receptor to downregulate the expression of inflammatory factors in tissues through a variety of signaling pathways. Moreover, LXA₄ can inhibit the chemotaxis of leukocytes towards the inflammatory site and promote macrophages to phagocytose apoptotic granulocytes and other damaged cells, thereby inhibiting the inflammatory process, promoting the inflammation resolution, and exerting specific anti-infection and anti-inflammatory effects in inflammatory infection-related diseases (13). Therefore, it is speculated that the inflammatory response after CPB increases the synthesis of LXA₄ with a strong anti-inflammatory effect.

In this study, it was also found that WBC, N% and hs-CRP were transiently increased at T0 and were most significantly increased at T1, which is consistent with the results of a number of experiments (14,15). CRP is an acute-phase reactive protein and an important inflammatory marker, which will obviously increase in the case of acute inflammation and trauma in the body (16). With the application of anti-inflammatory and anti-infective drugs after operation and inflammation control, CRP gradually declines, and the body temperature also gradually drops to normal. We also found that the CPB time and aortic clamping time were positively correlated with the time in the PICU, application time of ventilator and hs-CRP level at T0. CPB time and aortic clamping time are often related to the complexity of operation and general condition of patients. The longer the surgical exposure is, the higher the probability of infection will be. Therefore, from the perspective of postoperative complications and recovery, the CPB time and aortic clamping time should be reduced as soon as possible during operation, so as to promote postoperative recovery.

In conclusion, the LXA₄ level in child patients with CHD is lower than that in normal children, but it has dynamic changes and gradually increases during CPB under the influence of inflammatory response. However, changes in LXA₄ have no correlation with inflammation and infection indexes, such as WBC, N% and hs-CRP, so it cannot be used as a sensitive index for monitoring inflammation, but can be used to evaluate the recovery of the disease.