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(Chest. 2001;120:S13-S14.)
© 2001 American College of Chest Physicians

Effect of Nitric Oxide Donors on Human Lung Fibroblast Proliferation In Vitro*

Xiangder Liu, MD; Yunkui K. Zhu, MD; Hangjun Wang, MD; Tadashi Kohyama, MD; Fuqiang Wen, MD and Stephen I. Rennard, MD, FCCP

* From the University of Nebraska Medical Center, Omaha, NE.

Correspondence to: Xiangder Liu, MD, Pulmonary and Critical Care Medicine Section, Department of Internal Medicine, University of Nebraska Medical Center, 600 South 42nd St, Omaha, NE 68198-5300

Nitric oxide (NO) is an intracellular messenger molecule involved in modulating cell proliferation and apoptosis in a variety of cells. The present study was designed to determine if NO modulated the proliferation of human lung fibroblasts. Human fetal lung fibroblasts (HFL-1) were maintained in cell culture in Dulbecco’s Modified Eagle’s Medium in the presence of 4% fetal calf serum. Cell proliferation was determined by enumerating cells with a Coulter counter. Inhibition of endogenous NO production by N-nitro-L-arginine methylester had no effect on HFL-1 cell proliferation. Three different NO-generating compounds were evaluated. Sodium nitroprusside (SNP) and diethylenetetra-amine NONOate were both found to inhibit cell proliferation in a concentration dependent manner. In contrast, 5-amino-3-3(4-morpholiny)-1,2.3-oxadiazolium chloride (SIN-1) had no effect on HFL-1 cell proliferation (Table 1) .


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  		Table 1. Cell Number 7 Days After Plating, 2 x 104 Cells per Well*

 
NO can induce signals by several mechanisms including the activation of guanylyl cyclase to produce soluble cyclic guanosine monophosphate (cGMP). In order to determine if this mechanism was responsible for the effect of SNP and NONOate, two experiments were performed. First, 1H-[1,2,4)oxadiazolo[4,3-a]quinoxalin-1 (10 µmol/L), a specific inhibitor of soluble guanylyl cyclase, was not able to alter the antiproliferative effect of SNP or NONOate. Second, 8-(4-chlorophenulthio)guanosine 3':5'-cyclic monophosphate (100 µmol/L), an analog of cGMP, did not affect HFL-1 proliferation. These data suggest that a cGMP-independent mechanism may be responsible for the growth inhibition observed. SIN-1 differs from the other NO donors in that it can generate both NO and peroxynitrite. Whether this accounts for its lack of effect on HFL-1 proliferation is unknown. This study, however, suggests that the NO donors SNP and NONOate can modulate fibroblast proliferation.

Footnotes

Abbreviations: cGMP = cyclic guanosine monophosphate; HFL-1 = human fetal lung fibroblasts; NO = nitric oxide; SIN-1 = 5-amino-3-3(4-morpholiny)-1,2.3-oxadiazolium chloride; SNP = sodium nitroprusside





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