Disrupted Pulmonary Vasculature and Decreased Vascular Endothelial Growth Factor, Flt-1, and TIE-2 in Human Infants Dying with Bronchopulmonary Dysplasia

Abstract

An abnormal pulmonary vasculature may be an important component of bronchopulmonary dysplasia (BPD). We examined human infant lung for the endothelial cell marker PECAM-1 and for angiogenic factors and their receptors. Lung specimens were collected prospectively at approximately 6 h after death. The right middle lobe was inflation fixed and part of the right lower lobe was flash frozen. We compared lungs from infants dying with BPD (n = 5) with lungs from infants dying from nonpulmonary causes (n = 5). The BPD group was significantly more premature and had more days of ventilator and supplemental oxygen support, but died at a postconceptional age similar to control infants. PECAM-1 protein and mRNA were decreased in the BPD group. PECAM-1 immunohistochemistry showed the BPD group had decreased staining intensity and abnormal distribution of alveolar capillaries. The dysmorphic capillaries were frequently in the interior of thickened alveolar septa. The BPD group had decreased vascular endothelial growth factor (VEGF) mRNA and decreased VEGF immunostaining, compared with infants without BPD. Messages for the angiogenic receptors Flt-1 and TIE-2 were decreased in the BPD group. We conclude that infants dying with BPD have abnormal alveolar microvessels and that disordered expression of angiogenic growth factors and their receptors may contribute to these abnormalities.

Pentoxifylline and prevention of hyperoxia-induced lung ­injury in neonatal rats

“…Inhibition of angiogenesis reduces alveolarization (25) and VEGF expression is decreased in infants dying of BPD (26). As previously reported (27), we found suppression of VEGF expression in newborn rat lungs during hyperoxia.…”

Hypoxia and chronic lung disease

“…RDS predisposes to BPD, whose pathogenesis resembles, to some extent, that of retinopathy of prematurity, in which high oxygen levels lead to disruption of VEGF-maintenance of blood vessels and endothelial cell apoptosis, resulting in organ damage. In fact, the expression of HIF-1α, HIF-2α, and downstream angiogenic growth factors (VEGF, PECAM-1, Flt-1, and Tie-2) are decreased in animal models of RDS or BPD [24][25][26][27]. Several of adolescent and adult BPD patients exhibit an emphysematous phenotype, potentially related to disruption of alveolar maintenance (see emphysema, below).…”

Inhaled nitric oxide in infants >1500 g and <34 weeks gestation with severe respiratory failure

“…4 Until recently, the effects of iNO on vascular tone and ventilation perfusion matching were assumed to be responsible for its benefit, 5 but recent animal model investigation has shown that deficient endogenous NO disrupts pulmonary parenchymal and vascular development and that exogenous NO may benefit the developing lung by its effects on vascular remodeling, inflammation and pulmonary edema, lung mechanics, lung growth, angiogenesis and airway smooth muscle. [6][7][8][9][10][11][12][13][14][15][16][17] Despite these intriguing animal model findings, the benefit of iNO in premature infants has not been consistently demonstrated in randomized clinical trials. Several small trials demonstrated an increase in oxygenation with iNO therapy, but no significant impact on the primary endpoints of death and/or BPD was demonstrated.…”