Abstract 387 Developmental Pharmacology: Drug Effects on Neonatal Angiogenesis and Vascular Function Platform, Monday, 5/3

Normal lung growth and development involves multiple and interactive signals that coordinate growth between airways and vessels. In the rat, alveolarization occurs primarily during the first 3 weeks of postnatal life. Past studies have demonstrated that adverse stimuli, such as hypoxia, hyperoxia, and dexamethasone treatment, can disrupt lung growth during this critical period, causing lung hypoplasia with reduced alveolarization. Normal lung vascular growth during this time period occurs primarily by angiogenesis, concomitant with alveolar development. However, mechanisms that link vascular development with alveolarization are unclear. To determine if angiogenesis is necessary for normal alveolarization, we hypothesized that inhibition of angiogenesis would disrupt normal lung growth and alveolarization. To test this hypothesis, we studied the effects of 2 anti-angiogenic agents, fumagillin and thalidomide, on alveolarization in infant rats. Newborn Sprague-Dawley rats were treated with daily injections of fumagillin (2 mg/kg; subcutaneous), thalidomide (10 mg/kg; intraperitoneal), or vehicle (control; DMSO). Injections were initiated on day 1 and continued for 13 days. Rats were sacrificed on day 14 for study. Lungs were formalin fixed at constant pressure (10 cm H2O), paraffin-embedded, sectioned and stained for histology and morphometric analysis. Tissue analysis was performed after masking of the treatment group from the observer. Alveolarization was assessed by radial alveolar counts (RAC); vessel density was expressed as the number of vessels per high powered field. We found that fumagillin and thalidomide treatment reduced RAC in comparison with vehicle controls. Vessel density was reduced in the fumagillin-treated group but not in the thalidomide-treated rats. (see table; * signifies p<0.05 versus vehicle control group).

Table 1 No caption available
Full size table

We conclude that fumagillin and thalidomide treatment during a critical period of lung growth reduced alveolarization in infant rats. We speculate that anti-angiogenesis agents may disrupt lung growth, but whether the inhibitory effects of these drugs on lung growth is specifically through decreased angiogenesis is uncertain.