Nitric oxide and protein nitration in the cystic fibrosis airway

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Abstract

Cystic fibrosis (CF), characterized by chronic airway infection and inflammation, ultimately leads to respiratory failure. Exhaled nitric oxide (NO), elevated in most inflammatory airway diseases, is decreased in CF, suggesting either decreased production or accelerated metabolism of NO. The present studies performed on two groups of CF patients provide further support for a disordered NO airway metabolism in CF respiratory tract disease. Despite confirmation of subnormal NOS2 in the CF airway epithelium, alternative isoforms NOS1 and NOS3 were present, and inflammatory cells in the CF airway expressed abundant NOS2. Increased immunohistochemical staining for nitrotyrosine was demonstrated in lung tissues from patients with CF as compared to control. To our knowledge, this is the first report localizing nitrotyrosine in diseased CF lung tissue. While the relative NOS2 deficiency in CF respiratory tract epithelium may contribute to the lower expired NO levels, these results suggest that increased metabolism of NO is also present in advanced CF lung disease. The significance of altered NO metabolism and protein nitration in CF remains to be fully elucidated.

Section snippets

Subjects and specimens

For serum and exhaled NO measurements, subjects were recruited from a University-based outpatient adult CF center and from normal volunteers. The 18 CF patients carried various CFTR genotypes with delta-F508 and G551D predominant, in general reflecting the most common CFTR genotypes in the US CF population. All were self-described as having their baseline pulmonary symptoms and none were on systemic steroids. They were maintained on their standard regimens including standard CF nutritional

Results and discussion

The objective of this study was to develop a better understanding of the abnormalities of NO metabolism in the respiratory tract of patients with CF. As have most other investigators [15], [29] but not all [30], [31], we report a decreased exhaled NO in the CF patients studied (Table 1). The CF patients had normal serum levels of the NOS substrate l-arginine, increased serum NO2/NO3 levels, subnormal levels of NOS2 protein in airway epithelial cells but abundant NOS2 protein in airway

Acknowledgements

We thank Ms. Julie Harral for technical assistance in performance of immunohistochemical studies, Ms. Cheryl Oliver-Pickett for assistance in the serum NOx measurements, and Drs. A. van der Vliet, C.E. Cross, and J.P. Eiserich for helpful suggestions and manuscript review.

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  • Cited by (0)

    These studies were supported by a Clinical Fellowship Award from the Cystic Fibrosis Foundation (B.M.M.) and NIH HL48038 (D.M.R.).

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