Published ahead of print on June 30, 2005, doi:10.1164/rccm.200504-567OC
© 2005 American Thoracic Society doi: 10.1164/rccm.200504-567OC
Hepatocyte Growth Factor Is Required for Alveologenesis in the Neonatal RatCanadian Institutes of Health Research Group in Lung Development; Lung Biology Programme, Hospital for Sick Children Research Institute; Clinical Integrative Biology, Sunnybrook and Women's Research Institute; and the Departments of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada Correspondence and requests for reprints should be addressed to Dr. A. Keith Tanswell, M.B., Division of Neonatology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. E-mail: keith.tanswell{at}sickkids.ca 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.
Key Words: bronchopulmonary dysplasia • lung growth • lung injury • morphometry • soluble receptors This article has been cited by other articles:
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