A Polymorphism in the Macrophage Migration Inhibitory Factor Promoter Is Associated With Bronchopulmonary Dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is a common adverse outcome of prematurity, causing severe morbidity and mortality. The cytokine macrophage migration inhibitory factor (MIF) has been recently shown to favor murine fetal lung development. In this prospective study, we evaluate the expression of MIF in the lung and in the serum of preterm infants (n ϭ 50) and investigate whether the Ϫ173 G/C MIF promoter polymorphism is associated with the risk of BPD (n ϭ 103). MIF was highly expressed in lung tissue from preterm infants. Serum MIF levels were measured by ELISA at d 1 after birth. MIF levels were increased [median (interquartile range), 71.01 (44.9 -162.3) ng/mL], particularly in those infants with 2) ng/mL] compared with healthy adults [2.4 (1.2-5.0) ng/mL], (p Ͻ 0.001). The MIF Ϫ173*C allele, which predisposes to higher MIF production, was associated with a lower incidence of BPD (OR, 0.2; 95% CI, 0.04 -0.93), independently from mechanical ventilation and oxygen exposure (p ϭ 0.03). In conclusion, these data show that MIF expression is increased in lung and serum of preterm infants and suggest that the high producing MIF Ϫ173*C allele may be a protective factor for BPD. (Pediatr Res 69: 142-147, 2011) R DS and bronchopulmonary dysplasia (BPD) are major causes of morbidity and mortality in preterm neonates. RDS is an acute condition that appears in the first hours of life and is caused by the lack of pulmonary surfactant, with progressive atelectasis and respiratory insufficiency. BPD is a chronic condition, which appears later in life and is characterized by an initial inflammatory component, followed by alveolar edema and fibrosis, resulting in impaired development of the immature lung (1,2). Prematurity, RDS, mechanical ventilation, lung disruption, and oxygen (O 2 ) toxicity play a major role in BPD pathogenesis (3). The contribution of inflammation remains controversial (4). Chorioamnionitis and cytokine exposure in utero seem to protect from RDS, suggesting that inflammatory mediators and cytokines may promote lung maturation (5,6). Conversely, there is evidence that a postnatal exaggerated and/or prolonged inflammatory response may amplify lung damage, resulting in tissue autoinjury, structural changes, and ultimately BPD (7). In addition to environmental factors, heritability studies demonstrated that genetic factors also contribute to the susceptibility to BPD (8), and potential candidate genes have been identified (9 -15).Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine, which plays a critical role in immune and inflammatory responses. MIF induces macrophage production of cytokines and promotes T lymphocytes proliferation (16). It has been implicated in the pathogenesis of immune and inflammatory diseases, including sepsis, asthma, allergic neuritis, and rheumatoid arthritis (17,18). MIF has also been reported to be involved in angiogenesis (19,20). In lungs, MIF is expressed in alveolar macrophages, bronchial epithelial cells, and alveolar endothelium (21,22).Anima...

Plasma Levels of Macrophage Migration Inhibitory Factor and d-Dopachrome Tautomerase Show a Highly Specific Profile in Early Life

“…While carriage of high expression MIF alleles was generally associated with more severe complications and poor outcome, it has also been associated with survival in patients with community-acquired pneumonia (17, 65, 66). Our findings of higher MIF levels in infants who did not develop BPD or LOS are consistent with a previous study showing an association between carriage of a high expression MIF allele and a lower incidence of BPD in preterm newborns (30). We did not determine the MIF genotype of the very preterm newborns because genetic material was unavailable and because such a study would be strongly underpowered considering MIF allele frequencies and patient number (14, 16, 17).…”

“…We report lower expression of MIF and DDT on postnatal day 6 in the circulation of very preterm newborns who subsequently developed BPD and/or LOS, two major complications of preterm birth. This is in line with the observation that MIF levels in tracheal aspirates obtained within the first 2 days of life are reduced in preterm infants who develop BPD (27, 30). Studies on the role of DDT have been limited to adults in humans and animals so far (34–36, 45, 60–62), and we do not known to which extend DDT impacts, like MIF, on lung development and innate immune responses in early life.…”

“…In humans, MIF is present in the amniotic fluid and is expressed in the fetal membranes of the placenta and in the fetal and neonatal lungs (28–31). Interestingly, circulating levels of MIF are at least 10-fold higher in healthy term newborns than in adults (30, 32, 33). We recently reported that high expression levels of MIF sustain innate immune responses of newborn monocytes and counter-regulate the activity of adenosine and prostaglandin E2, two immunosuppressive mediators produced at high levels by the placenta (33).…”

Macrophage Migration Inhibitory Factor Is a Novel Determinant of Cigarette Smoke–Induced Lung Damage

“…These three transcription factors are critical regulators of cell fate in the context of environmental stimuli (i.e., hypoxia, DNA damage, and increased reactive oxygen species, respectively), and thus are critical determinants of homeostatic responses to intracellular or extracellular stressors. Animal models of ischemic cardiac injury, bronchopulmonary dysplasia, and radiation-induced lung injury (19)(20)(21) demonstrate that loss of MIF is associated with increased tissue damage. We have identified MIF as a modulator of the sensitivity of CS-induced human lung EC apoptosis in vitro (22) antagonizing p53-dependent activation of the mitochondrial apoptotic pathway.…”

The Role of Genetic Polymorphisms in Antioxidant Enzymes and Potential Antioxidant Therapies in Neonatal Lung Disease

“…The TLR5 (1174C > T) variant resulted in association with the risk of severe BPD, and SNP (2054C > T) of the toll-IL-1 domain containing adaptor protein, which is involved in the TLR4 signaling pathway, also resulted in association with the risk of BPD (143); moreover, TLR6 rs5743827 SNP was recently proved to reduce the risk of BPD (188). Among the factors regulating inflammatory cells' recruitment, the SNP -173C of macrophage migration inhibitory factor, which was associated with increased expression, resulted in an independent protective factor for BPD (120); while L-selectine Ser213 allele was associated with an increased risk of BPD (39). MMP are key regulators of the extracellular matrix remodeling process, which is of primary importance for a proper alveolarization of the preterm lung (78).…”