Surfactant Gene Expression Recovered after Inhibition of Nitric Oxide

George Leikauf
University of Cincinnati
R01ES10562 and P30ES06096

Background: Although one of the simplest biological molecules in nature, nitric oxide (NO) has found its way into nearly every phase of biology and medicine ranging from its role as a critical endogenous regulator of blood flow and thrombosis to a principal neurotransmitter mediating erectile function to a major pathophysiological mediator of inflammation and host defense. These major discoveries have stimulated intense and extensive research into a vast array of fields including chemistry, molecular biology, and gene therapy.

NO has been proposed as a therapeutic agent for acute lung injury. The administration of low levels of NO preferentially dilate vessels in the lung to improve oxygenation of the blood. However, the role of NO in acute lung injury remains controversial because overall mortality is not reduced in adults. NO formation in the lungs may be detrimental to recovery. This is illustrated by clinical studies where inhibitors of the NO synthase enzyme restored pulmonary function. These investigators explored the function of NO in mice with nickel-induced acute lung injury.

Advance: Nickel exposed mice with acute lung injury were given either a saline control treatment or a NO synthase inhibitor (NG-nitro-L-arginine methyl ester; L-NAME). The saline treated mice exhibited multiple endpoints of acute lung injury while those that received the inhibitor had better survival, lower NO synthase activity, and lower levels of cytokine release, an indicator of inflammation. Surfactant protein gene expression initially decreased in both groups but recovered in the inhibitor group.

Implication: This work builds upon previous studies of acute lung injury that indicated inhibition of NO synthesis restores pulmonary function. These findings suggest inhibiting NO formation during acute lung injury may be protective possibly my limiting NO synthase-mediated vascular permeability, cytokine production, and causing later restoration of proper surfactant production.

Citation: McDowell SA, Gammon K, Zingarelli B, Bachurski CJ, Aronow BJ, Prows DR, Leikauf GD. Inhibition of nitric oxide restores surfactant gene expression following nickel-induced acute lung injury. Am J Respir Cell Mol Biol. 2003 Feb;28(2):188-98.