Abstract
The alveolar compartment, the fundamental gas exchange unit in the lung, is critical for tissue oxygenation and viability. We explored hepatocyte growth factor (HGF), a pleiotrophic cytokine that promotes epithelial proliferation, morphogenesis, migration, and resistance to apoptosis, as a candidate mediator of alveolar formation and regeneration. Mice deficient in the expression of the HGF receptor Met in lung epithelial cells demonstrated impaired airspace formation marked by a reduction in alveolar epithelial cell abundance and survival, truncation of the pulmonary vascular bed, and enhanced oxidative stress. Administration of recombinant HGF to tight-skin mice, an established genetic emphysema model, attenuated airspace enlargement and reduced oxidative stress. Repair in the TSK/+ mouse was punctuated by enhanced akt and stat3 activation. HGF treatment of an alveolar epithelial cell line not only induced proliferation and scattering of the cells but also conferred protection against staurosporine-induced apoptosis, properties critical for alveolar septation. HGF promoted cell survival was attenuated by akt inhibition. Primary alveolar epithelial cells treated with HGF showed improved survival and enhanced antioxidant production. In conclusion, using both loss-of-function and gain-of-function maneuvers, we show that HGF signaling is necessary for alveolar homeostasis in the developing lung and that augmentation of HGF signaling can improve airspace morphology in murine emphysema. Our studies converge on prosurvival signaling and antioxidant protection as critical pathways in HGF–mediated airspace maintenance or repair. These findings support the exploration of HGF signaling enhancement for diseases of the airspace.
Highlights
One approach to identifying mediators of alveolar formation and regeneration in the mammalian lung is to delineate the elemental events that attend airspace formation and systematically investigate candidate proteins that harbor a compatible signaling repertoire in animal or cellular model systems
We sought to determine whether hepatocyte growth factor, a cytokine with a functional armamentarium that subserves the critical events of alveolar formation, could be an important mediator of alveolar formation and airspace maintenance
Using an informative battery of mouse models and cell lines, we show that hepatocyte growth factor is a determinant of alveolar formation and that the enhancement of hepatocyte growth factor signaling can both protect and repair the airspace from pathologic airspace enlargement or emphysema
Summary
One approach to identifying mediators of alveolar formation and regeneration in the mammalian lung is to delineate the elemental events that attend airspace formation and systematically investigate candidate proteins that harbor a compatible signaling repertoire in animal or cellular model systems. The eruption of alveolar septae from a primordial saccule in early postnatal murine life requires localized epithelial proliferation, migration and resistance to apoptosis [1,2]. Epithelial morphogenesis must be accompanied by a microvasculature that permits efficient diffusion of gases from the airspace lumen to the systemic vascular bed. A candidate mediator of such events is hepatocyte growth factor (HGF). HGF is a pleiotrophic cytokine that promotes epithelial proliferation, morphogenesis, migration and survival [3,4]. HGF is known to induce angiogenesis and inhibit epithelial apoptosis. We sought to determine whether HGF is critical for alveolar formation and might have a therapeutic role in alveolar regeneration
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