Respiratory adaptations to lung morphological defects in adult mice lacking Hoxa5 gene function.

The Hoxa5 mutation is associated with a high perinatal mortality rate caused by a severe obstruction of the laryngotracheal airways, pulmonary dysmorphogenesis, and a decreased production of surfactant proteins. Surviving Hoxa5(-/-) mutant mice also display lung anomalies with deficient alveolar septation and areas of collapsed tissue, thus demonstrating the importance of Hoxa5 throughout lung development and maturation. Here, we address the functional consequences of the Hoxa5 mutation on respiration and chemoreflexes by comparing the breathing pattern of Hoxa5(-/-) mice to that of wild-type animals under resting conditions and during exposure to moderate ventilatory stimuli such as hypoxia and hypercapnia. Resting Hoxa5(-/-) mice present a higher breathing frequency and overall minute ventilation that likely compensate for their reduced lung alveolar surface available for gas exchange and their increased upper airway resistance. When exposed to ventilatory stimuli, Hoxa5(-/-) mice maintain the higher minute ventilation by adapting the tidal volume and/or the breathing frequency. The minute ventilation increase seen during hypoxia was similar for both groups of mice; however, the dynamics of the frequency response was genotype-dependent. The hypercapnic ventilatory response did not differ between genotypes. These findings reveal the strategies allowing survival of Hoxa5(-/-) mice facing morphologic anomalies leading to a significant deficit in gas exchange capacity.