NOS2 mediates lung structure and function changes in the SP-D model of emphysema without improving surfactant homeostasis

Abstract

The collectin Surfactant protein D (SP-D) is an innate host defense protein with well-established immuno-modulatory properties. Mice deficient in SP-D (SP-D−/−) spontaneously develop typical emphysematous and inflammatory alterations: a significant decrease in alveolar number, accumulation of enlarged alveolar macrophages overproduction of the inducible nitric oxide synthase (iNOS), hypertrophy and hyperplasia of alveolar type II cells and disturbances of surfactant homoeostasis. Using design-based stereology, wild type, iNOS(−/−), SP-D(−/−) and double knockout (DiNOS) mice at 12 weeks of age were measured for a series of structural parameters. Lung resistance and elastance as functions of frequency at positive end-expiratory pressures in the range of 0–9 cm H2O were measured using Flexivent. The additional ablation of the iNOS gene improved emphysematous alterations in the SP-D(−/−) mouse resulting in a significant increase in alveolar number and a reduction in mean alveolar volume. DiNOS mice exhibited reduced amount of enlarged alveolar macrophages and altered their inflammatory phenotype relative to SP-D(−/−) mice. Neither disturbances of intracellular surfactant homeostasis nor the hyperplasia or hypertrophy of alveolar type II cells were corrected by iNOS ablation. However, despite a lack of effect on surfactant homeostasis, iNOS ablation did normalize lung function. The increased iNOS-activity in SP-D(−/−) mice is critical to the development of inflammation and consequent emphysema but is not important in altered surfactant homeostasis, implying that emphysema and alterations of type II cells are mediated via different pathways. The structural remodeling appears to dominate in terms of lung function.