ROCK2 is involved in accelerated fetal lung development induced by in vivo lung distension.
Lung development is strongly influenced by its state of distension. For instance, increasing distension induced by fetal tracheal occlusion (TO) stimulates lung development. In contrast, oligohydramnios (OH) reduces lung distending forces and results in lung hypoplasia. We hypothesize that Rho/Rho-associated kinase (ROCK) pathway plays an important role as mechanosensor in vivo acting either directly or indirectly in the translation of increased distension into acceleration of lung growth. TO was done in fetal mice sacrificed either 3 or 24 hr later; in a subset of dam, fasudil, a specific ROCK inhibitor, or vehicle was injected intra-peritoneally. OH was done by puncture of the amniotic sac. ROCK2 protein levels were assessed by Western blot and immunohistochemistry (IHC); lung development was assessed by measuring the generation of distal respiratory airway. Significant differences were found in ROCK2 protein levels between TO and Sham-TO at 3 and 24 hr, but not for ROCK1. Indeed, IHC revealed that ROCK2 staining was sparse and restricted to a few mesenchymal cells in Sham-TO, whereas it was strong in acini of TO lungs. OH lungs expressed lower levels of ROCK2 in the acini when compared to untouched controls. In fasudil-treated animals, the degree of lung development following TO was significantly lower than in the group injected with vehicle. At the dose regimen used, fasudil did not affect normal lung development, as observed in the untouched animals. In summary, ROCK2 protein levels was affected by the degree of lung expansion and blunting ROCK activity abolished the response to increased lung distension, suggesting that ROCK is a key regulator in TO-induced accelerated lung development.
Cloutier
Marc
M
Unité de Recherche en Pédiatrie, Centre de Recherche du Centre Hospitalier de l'Université Laval, Québec, QC, Canada.
Tremblay
Monique
M
Piedboeuf
Bruno
B
D000818:Animals; D008168:Lung / Q000254:growth & development* / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000378:metabolism*
C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases