Antenatal N-acetylcysteine antioxidant therapy relieves lung oxidative stress and related perinatal lethality in HRas/NRas double-null mutant mice

Author:

Fuentes-Mateos Rocío1,García-Navas Rósula1,Calzada Nuria,Santos Eugenio2ORCID,Fernández-Medarde Alberto1ORCID

Affiliation:

1. Centro de Investigación del Cáncer-Instituto de Biología Molecular y Celular del Cáncer (CSIC)-Universidad de Salamanca and CIBERONC

2. Centro de Investigación del Cáncer - IBMCC (CSIC-USAL) and CIBERONC, Universidad de Salamanca

Abstract

Abstract We reported previously that concomitant HRas/NRas ablation causes very high rates of mortality in mice at birth (P0) due to severe respiratory distress and defective lung maturation which was linked to significant ceramide accumulation and delayed alveolar differentiation in this respiratory organ. Antenatal treatment with dexamethasone (DEX), a glucocorticoid known to boost lung maturation, reverted the lung immaturity of our HRas/NRas double-null mutant (DKO) animals but failed to rescue their elevated perinatal lethality. Our search for mechanistic clues to these deleterious phenotypes uncovered significantly increased levels of intracellular oxidative stress, altered mitochondrial electron transport and respiratory function (Oxygen Consumption Rate, OCR), and elevated neutrophil infiltration in the lungs of our HRas/NRas-DKO mice. We also evaluated the functional effects of antenatal antioxidant therapy using N-acetylcysteine (NAC) on postnatal survival and the defective lung phenotypes of our double-KO mice. In contrast to DEX treatment, we observed that antenatal NAC treatment resulted in normal lung development and the survival to adulthood of more than 50% of the newborn HRas/NRas-DKO pups. We also observed that the redox imbalance of our double-KO newborn pups was fully corrected upon NAC antioxidant treatment, but only partially by dexamethasone, indicating that the lung oxidative stress played a major role in the lethality of the DKO mice. Our observations provide a direct mechanistic link between the absence of HRas and NRas and the control of lung intracellular oxidative stress, the perinatal maturation of specific pulmonary cellular lineages, and the subsequent survival of the newborn pups.

Publisher

Research Square Platform LLC

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