Relation of Macrophage Migration Inhibitory Factor to Pulmonary Hemodynamics and Vascular Structure and Carbamyl-Phosphate Synthetase I Genetic Variations in Pediatric Patients with Congenital Cardiac Shunts.

Nair Y Maeda,Vera D Aiello,Luiz J Kajita,Sérgio P Bydlowski,Antonio Augusto Lopes,Paulo C Santos,Ana M Thomaz

doi:10.1155/2019/7305028

Abstract

Macrophage migration inhibitory factor (MIF) plays an important pathophysiological role in pulmonary hypertension (PHT). Previously, we demonstrated that serum MIF is increased in pediatric PHT associated with congenital heart disease (CHD). In the present study, we determined possible associations between MIF levels, hemodynamic and histological parameters, and mitochondrial carbamyl-phosphate synthetase I (CPSI) T1405N polymorphism in a similar population. The asparagine 1405 variant (related to A alleles in the C-to-A transversion) has been shown to be advantageous in pediatric PHT compared to the threonine 1405 variant (C alleles). Forty-one patients were enrolled (aged 2-36 months) and subsequently divided into 2 groups after diagnostic evaluation: the high-pulmonary blood flow (high PBF) group (pulmonary-to-systemic blood flow ratio 2.58 (2.21-3.01), geometric mean with 95% CI) and the high-pulmonary vascular resistance (high PVR) group (pulmonary vascular resistance 6.12 (4.78-7.89) Wood units × m2). Serum MIF was measured using a chemiluminescence assay. The CPSI polymorphism was analyzed by polymerase chain reaction followed by high-resolution melting analysis. Medial hypertrophy of pulmonary arteries was assessed by the histological examination of biopsy specimens. Serum MIF was elevated in patients compared to controls (p = 0.045), particularly in the high-PVR group (n = 16) (p = 0.022) and in subjects with the AC CPSI T1405N genotype (n = 16) compared to those with the CC genotype (n = 25) (p = 0.017). Patients with high-PVR/AC-genotype profile (n = 9) had the highest MIF levels (p = 0.030 compared with the high-PBF/CC-genotype subgroup, n = 18). In high-PVR/AC-genotype patients, the medial wall thickness of intra-acinar pulmonary arteries was directly related to MIF levels (p = 0.033). There were no patients with the relatively rare AA genotype in the study population. Thus, in the advantageous scenario of the asparagine 1405 variant (AC heterozygosity in this study), heightened pulmonary vascular resistance in CHD-PHT is associated with medial hypertrophy of pulmonary arteries where MIF chemokine very likely plays a biological role.

Highlights

Inflammation and immunity play a central role in the pathogenesis of pulmonary vascular disorders
Pulmonary-to-systemic blood flow ratio was 2.29 (1.99-2.64), and peripheral oxygen saturation was 94% (93%-96%)
The elevated serum levels of migration inhibitory factor (MIF) chemokine were observed in patients with congenital cardiac shunts and altered pulmonary hemodynamics compared to pediatric controls

Summary

Introduction

Inflammation and immunity play a central role in the pathogenesis of pulmonary vascular disorders. MIF is a noncanonical ligand of CXC chemokine receptors, leading to the activation of several signaling pathways that results in the inhibition of endothelial cell apoptosis and induction of smooth muscle cell proliferation It is associated with the exaggerated recruitment of peripheral blood mononuclear cells and proinflammatory endothelial cell behavior [1, 7,8,9]. In a recent study of ours involving pediatric patients with congenital cardiac communications, heightened serum MIF was observed in a specific subgroup of subjects with elevated pulmonary vascular resistance [10]. This finding suggests the possible involvement of this chemokine in the early development of pulmonary vasculopathy in congenital heart disease

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Conclusion