Spontaneous pulmonary emphysema in mice lacking all three nitric oxide synthase isoforms

Area of Science:

• Pulmonary Medicine
• Molecular Biology
• Genetics

Background:

• The precise functions of endogenous nitric oxide (NO), produced by all nitric oxide synthases (NOSs), remain incompletely understood.
• Investigating the complete absence of NOS isoforms is crucial for elucidating NO's physiological roles.

Purpose of the Study:

• To investigate the in vivo consequences of deleting all three NOS isoforms (neuronal, inducible, and endothelial) on lung structure and function.
• To determine if complete NOS deficiency leads to spontaneous lung disease in mice.

Main Methods:

• Generation of triple n/i/eNOS knockout mice lacking all three NOS isoforms.
• Histological and micro-computed tomography analysis of lung tissue from knockout and wild-type mice.
• Cap analysis of gene expression (CAGE) to compare mRNA expression profiles in knockout and wild-type lungs.

Main Results:

• Triple n/i/eNOS knockout mice exhibited spontaneous pulmonary emphysema features, including increased alveolar size, destruction, and altered lung mechanics, evident by 4 weeks of age.
• Single and double NOS knockout mice did not display these emphysematous changes.
• Reduced expression of Wnt ligands and Wnt/β-catenin signaling components was observed in the lungs of triple knockout mice.

Conclusions:

• Complete disruption of all three NOS genes leads to spontaneous pulmonary emphysema in juvenile mice.
• The development of emphysema in n/i/eNOS knockout mice may be mediated by the down-regulation of the Wnt/β-catenin signaling pathway.
• These findings highlight a novel preventive role for the endogenous NO/NOS system in the pathogenesis of pulmonary emphysema.