Abstract
BackgroundIncreased expression of nitric oxide synthase (NOS) and an increase in plasma nitrite plus nitrate (NOx) have been reported in patients with pulmonary fibrosis, suggesting that nitric oxide (NO) plays an important role in its development. However, the roles of the entire NO and NOS system in the pathogenesis of pulmonary fibrosis still remain to be fully elucidated. The aim of the present study is to clarify the roles of NO and the NOS system in pulmonary fibrosis by using the mice lacking all three NOS isoforms.MethodsWild-type, single NOS knockout and triple NOS knockout (n/i/eNOS−/−) mice were administered bleomycin (BLM) intraperitoneally at a dose of 8.0 mg/kg/day for 10 consecutive days. Two weeks after the end of the procedure, the fibrotic and inflammatory changes of the lung were evaluated. In addition, we evaluated the effects of long-term treatment with isosorbide dinitrate, a NO donor, on the n/i/eNOS−/− mice with BLM-induced pulmonary fibrosis.ResultsThe histopathological findings, collagen content and the total cell number in bronchoalveolar lavage fluid were the most severe/highest in the n/i/eNOS−/− mice. Long-term treatment with the supplemental NO donor in n/i/eNOS−/− mice significantly prevented the progression of the histopathological findings and the increase of the collagen content in the lungs.ConclusionsThese results provide the first direct evidence that a lack of all three NOS isoforms led to a deterioration of pulmonary fibrosis in a BLM-treated murine model. We speculate that the entire endogenous NO and NOS system plays an important protective role in the pathogenesis of pulmonary fibrosis.
Highlights
Pulmonary fibrosis is an interstitial lung disease characterized by chronic inflammation and progressive fibrosis of the pulmonary interstitium [1]
The WT, single nitric oxide synthase (NOS)−/− mice, and n/i/endothelial NOS (eNOS)−/− mice exhibited a loss of body weight at the last administration of BLM
A quantitative image analysis indicated that a significant increase in the pathological fibrotic tissue area was seen only in the n/i/eNOS−/− mice, and no significant differences were observed among the WT and single NOS−/− mice (Figure 2C)
Summary
Pulmonary fibrosis is an interstitial lung disease characterized by chronic inflammation and progressive fibrosis of the pulmonary interstitium (alveolar walls and septa, perivascular, perilymphatic and peribronchiolar connective tissues) [1]. Free radicals, including NO, play an important role in the development of pulmonary fibrosis [6]. Increases in the expression of these NOSs in the lungs, and the plasma NOx (nitrite plus nitrate) level, a marker of NO production, have been reported in patients with pulmonary fibrosis [7,8,9]. The roles of the NOS system in the lungs have been evaluated using several types of animal models, and eNOS has been reported to exert a protective role in pulmonary fibrosis [10,11]. Increased expression of nitric oxide synthase (NOS) and an increase in plasma nitrite plus nitrate (NOx) have been reported in patients with pulmonary fibrosis, suggesting that nitric oxide (NO) plays an important role in its development. We evaluated the effects of long-term treatment with isosorbide dinitrate, a NO donor, on the n/i/eNOS−/− mice with BLM-induced pulmonary fibrosis
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