Developmental and Chronic Hypoxia-Induced Changes in Lung Pro-inflammatory Cytokines and Cyclooxygenase 2 (COX-2) Gene Expression. 1608

Abstract

Pro-inflammatory cytokines and prostaglandins have been implicated in the pathogenesis of adult Pulmonary Hypertension (PH), but their role in the neonatal form of the disease or the maintenance of a higher pulmonary vascular resistance (PVR) during fetal life is poorly understood. To address this issue, we evaluated fetal (3 days prior to term) and neonatal (3 days old) normal rabbits, as well as newborns subjected to 3 weeks of chronic hypoxia-induced PH and age-matched controls. Utilizing a semi-quantitative RT-PCR technique, lung tissue GAPDH normalized mRNA levels (units) for TNF-α, Interleukin-1β (IL-1β) and COX-2 were measured. PH was associated with an increase in TNF-α from 0.7±0.1 to 1.5±0.3 (P<0.01) and IL-1β from 1.6±0.2 to 2.7±0.3 (P<0.01), with no change in COX-2 (1.1±0.4 and 1.3±0.3). In contrast, significantly lower(P<0.01) mRNA levels of all three factors were measured in the fetus as compared to the newborn. The respective values were: TNF-α of 0.4±0.1 and 0.9±0.1; IL-1β of 0.3±0.04 and 0.8±0.1; COX-2 of 0.8±0.1 and 1.2±0.1. Our data suggest that pro-inflammatory cytokines may be involved in the pathogenesis of chronic hypoxia - induced PH in the neonate. The lower mRNA levels of these cytokines as well as COX-2 in the fetus suggest that a higher PVR is not the only determinant of up-regulation of these factors following PH. We speculate that pro-inflammatory cytokines may contribute to the pulmonary vascular remodeling and fibrotic lung changes secondary to PH in neonates.