Increased alveolar concentration of nitric oxide is related to serum-induced lung fibroblast proliferation in patients with systemic sclerosis.
OBJECTIVE
Lung inflammation is present in patients with systemic sclerosis (SSc) and interstitial lung disease (ILD), but the mechanisms linking inflammatory and fibrotic processes in ILD are unknown. Our aim was to investigate whether alveolar inflammation, reflected by increased alveolar concentration of exhaled nitric oxide (C(A)NO), is related to the ability of serum from patients with SSc to induce pulmonary fibroblast proliferation (PFP) and myofibroblast conversion.


METHODS
C(A)NO was measured in all subjects (37 patients with SSc and 10 healthy controls) whose sera were used to stimulate PFP (assessed by BrdU labeling index) and myofibroblast conversion (detected by alpha-smooth muscle actin expression). The PFP index in patients with SSc was compared to control values, and between patients with SSc who had elevated (> 4.3 ppb) and normal (<or= 4.3 ppb) C(A)NO values.


RESULTS
Both C(A)NO and the PFP index were significantly greater in patients with SSc compared to controls. In patients with SSc, the PFP index was directly related to C(A)NO levels (r = 0.48; p = 0.002). The median PFP index was significantly higher in patients with SSc who had elevated C(A)NO (> 4.3 ppb; n = 25, median 1.1, range 0.98-1.23) than in patients with SSc who had normal C(A)NO (<or= 4.3 ppb; n = 12, median 0.93, range 0.82-1.08; p = 0.01). Similarly, myofibroblast conversion induced by SSc serum was significantly greater in patients with C(A)NO > 4.3 ppb than in patients whose C(A)NO was <or= 4.3 ppb (p < 0.001) and controls (p < 0.001).


CONCLUSIONS
Alveolar inflammation reflected by increased nitric oxide production was related to serum-induced PFP and myofibroblast conversion, linking the active alveolitis process to cell proliferation and lung fibrosis in patients with SSc.
Hua-Huy
Thong
T
Department of Physiology, University Paris Descartes, Cochin Hospital, APHP, Paris, France.
Tiev
Kiet Phong
KP
Chéreau
Christiane
C
Duong-Quy
Sy
S
Cabane
Jean
J
Dinh-Xuan
Anh Tuan
AT
D000199:Actins / Q000378:metabolism; D000328:Adult; D001798:Blood Proteins / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D011446:Prospective Studies; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000378:metabolism*; D044967:Serum / Q000737:chemistry / Q000378:metabolism
D000199:Actins; D001798:Blood Proteins; D009569:Nitric Oxide; D001973:Bromodeoxyuridine