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Congenital heart defects (CHDs) are one of the most common congenital malformations and often require heart surgery with cardiopulmonary bypass (CPB). Children undergoing cardiac surgery with CPB are especially at greater risk of post-operative complications due to a systemic inflammatory response caused by innate inflammatory mediators. However, the pathophysiological response is not fully understood and warrants further investigation. Therefore, we investigated the inflammatory response in macrophages initiated by peri-operative serum samples obtained from patients with CHD undergoing CPB cardiac surgery. Human differentiated THP-1 macrophages were pretreated with Stattic, a STAT3 (Tyr705) inhibitor, before stimulation with serum samples. STAT3 and NF-κB activation were investigated via a Western blot, IL-1β, TNFα, IL-10, mediators for vascular permeability (VEGF-A, ICAM), and SOCS3 gene expressions via RT-qPCR. CPB induced an inflammatory response in macrophages via the activation of the STAT3 but not NF-κB signaling pathway. Longer duration on the CPB correlated with increased cytokine, VEGF, and ICAM expressions, relative to individual pre-operation levels. Patients that did not require CPB showed no significant immune response. Pretreatment with Stattic significantly attenuated all inflammatory mediators investigated except for TNFα in the macrophages. CPB induces an increased expression of cytokines and mediators of vascular permeability via the activation of STAT3 by IL-6 and IL-8 in the serum samples. Stattic attenuates all mediators investigated but promotes TNFα expression. [ABSTRACT FROM AUTHOR]