A critical role for fibroblast growth factor-7 during early alveolar formation in the neonatal rat.

Mesenchymal cell-derived FGF-7 (fibroblast growth factor-7) induces proliferation in both epithelial and endothelial cells. We found FGF-7 to be expressed in the lungs of neonatal rats from birth to d 14 of age. A role for FGF-7 in early postnatal lung growth and alveolar formation, by an action on type II pneumocytes, has been excluded by the work of others. However, a role through an action of FGF-7 on other cell types has not been excluded. We used intraperitoneal injections of neutralizing antibodies on d 3, 4, and 5 of life to inhibit binding of FGF-7 to its receptors, and assessed alveolar formation on d 6 of life. This intervention inhibited DNA synthesis in, and number of, alveoli-forming secondary crests, resulting in a significantly reduced alveolar number. This failure of alveolar formation was associated with a reduction in the number of small blood vessels in the lung periphery. We conclude that FGF-7, most likely through its effect on the vascular bed, is required for normal early postnatal alveolar formation from secondary crests.

Hepatocyte growth factor is required for alveologenesis in the neonatal rat.

RATIONALE: Our core hypothesis is that growth factors that have dysregulated expression during experimental neonatal lung injury are likely to be involved in normal postnatal lung growth and alveologenesis. OBJECTIVES: To determine if hepatocyte growth factor (HGF) is upregulated in neonatal lung injury and is essential for postnatal alveologenesis. METHODS: A neonatal lung injury, in which there were patchy areas of interstitial thickening with a relative increase in the proportion of epithelial cells, was induced in newborn rats by exposing them to 60% oxygen for 14 days. Air-exposed pups had binding of endogenous HGF to its natural receptor, c-Met, inhibited by the intraperitoneal injection of either neutralizing antibody to HGF, or a truncated soluble c-Met receptor. MEASUREMENTS AND MAIN RESULTS: The 60% oxygen-mediated lung injury was associated with increased lung mRNAs for hepatocyte growth factor and c-Met, relative to air-exposed control lungs, at Day 7 after birth. After exposure to 60% oxygen, immunoreactive HGF was increased at Days 4 and 7, and immunoreactive c-Met was increased at Day 14. In air-exposed pups, intraperitoneal injections of neutralizing antibody to HGF inhibited DNA synthesis in alveoli-forming secondary crests, and reduced the number of alveoli in 6-day-old pups. Intraperitoneal injections of a truncated soluble c-Met receptor inhibited DNA synthesis in secondary crests in 4-day-old air-exposed rat pups. CONCLUSIONS: HGF and its c-Met receptor are required for normal postnatal alveolar formation from secondary crests, and are upregulated during 60% oxygen-induced neonatal lung injury.