Hepatocyte Growth Factor, a Determinant of Airspace Homeostasis in the Murine Lung

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.

Thirty Years of Research on Met Receptor to Move a Biomarker from Bench to Bedside

“…In the last few years, conditional Met knockout provided additional information about its role in the formation of individual structures. Thus, Met invalidation in lung severely impairs formation of airspaces (12), and its extinction in central nervous system induces loss of motor neurons innervating pectoral muscles ( Fig. 1C and D; ref.…”

“…Conditional extinction of Met in nervous system prevents survival of a motoneurons subgroup innervating the pectoralis minor muscle, leading to motor defects (13). D, Met invalidation in lung severely impairs airspaces formation (12) ubiquitinylation. Met receptor is then internalized and degraded (19).…”

Biological roles of hepatocyte growth factor‑Met signaling from genetically modified animals (Review)

“…The cKO (Met -/-) lung displayed impaired saccular development and enlarged distal airspaces with few primary septae. Furthermore, to analyze the postnatal phenotype of these cKO mice using doxycycline, tri-transgenic mice were generated (51). The cKO mice exhibited markedly impaired airspace formation due to a reduction in AEC abundance and survival, truncation of the pulmonary vascular bed and enhanced oxidative stress in AECIIs (51).…”

“…Furthermore, to analyze the postnatal phenotype of these cKO mice using doxycycline, tri-transgenic mice were generated (51). The cKO mice exhibited markedly impaired airspace formation due to a reduction in AEC abundance and survival, truncation of the pulmonary vascular bed and enhanced oxidative stress in AECIIs (51). The HGF-Met signaling pathway therefore performs essential functions in lung development, particularly in septum formation.…”

Le récepteur Met fête ses 30 ans

“…À partir des années 2000, l'extinction conditionnelle de Met a permis de détailler son rôle dans la mise en place de structures individuelles. Ainsi, son invalidation dans les poumons inhibe significativement le développement alvéolaire [13] ; dans le système nerveux central, elle induit la perte de sous-groupes de motoneurones [14] (Figure 2). …”