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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 5, May, 2001 621-626

Nitric Oxide Deficiency Contributes to Impairment of Airway Relaxation in Cystic Fibrosis Mice

Maroun J. Mhanna, Tom Ferkol,* Richard J. Martin, Ismail A. Dreshaj, Anna M. van Heeckeren, Tom J. Kelley, and Musa A. Haxhiu

Departments of Pediatrics, Rainbow Babies and Childrens Hospital and MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio

The pulmonary disease of cystic fibrosis (CF) is characterized by persistent airway obstruction, which has been attributed to chronic endobronchial infection and inflammation. The levels of exhaled nitric oxide (NO) are reduced in CF patients, which could contribute to bronchial obstruction through dysregulated constriction of airway smooth muscle. Because airway epithelium from CF mice has been shown to have reduced expression of inducible NO synthase, we examined airway responsiveness and relaxation in isolated tracheas of CF mice. Airway relaxation as measured by percent relaxation of precontracted tracheal segments to electrical field stimulation (EFS) and substance P, a nonadrenergic, noncholinergic substance, was significantly impaired in CF mice. The airway relaxation in response to prostaglandin E2 was similar in CF and non-CF animals. Treatment with the NO synthase inhibitor NG-nitro-L-arginine methylester reduced tracheal relaxation induced by EFS in wild-type animals but had virtually no effect in the CF mice. Conversely, exogenous NO and L-arginine, a NO substrate, reversed the relaxation defect in CF airway. We conclude that the relative absence of NO compromises airways relaxation in CF, and may contribute to the bronchial obstruction seen in the disease.

*  Current address: Dept. of Pediatrics, Washington University School of Medicine, St. Louis, MO.
Abbreviations: analysis of variance, ANOVA; cystic fibrosis, CF; CF transmembrane conductance regulator, CFTR; mice homozygous for the S489X mutation of the CFTR, CFTR-/- mice; normal littermates of CFTR-/- mice, CFTR+/+ mice; electrical field stimulation, EFS; inducible NOS, iNOS; NG-nitro-L-arginine methylester, L-NAME; neuronal NOS, nNOS; nitric oxide, NO; NO synthase, NOS; prostaglandin, PG; standard error of the mean, SEM; substance P, SP; percentage of maximal tracheal tension, %T max.




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