Carbon monoxide suppresses bleomycin-induced lung fibrosis.
Idiopathic pulmonary fibrosis is an incurable fibrosing disorder that progresses relentlessly to respiratory failure. We hypothesized that a product of heme oxygenase activity, carbon monoxide (CO), may have anti-fibrotic effects. To test this hypothesis, mice treated with intratracheal bleomycin were exposed to low-concentration inhaled CO or ambient air. Lungs of mice treated with CO had significantly lower hydroxyproline accumulation than controls. Fibroblast proliferation, thought to play a central role in the progression of fibrosis, was suppressed by in vitro exposure to CO. CO caused increased cellular levels of p21(Cip1) and decreased levels of cyclins A and D. This effect was independent of the observed suppression of MAPK's phosphorylation by CO but was dependent on increased cGMP levels. Further, CO-exposed cells elaborated significantly less fibronectin and collagen-1 than control cells. This same effect was seen in vivo. Suppression of collagen-1 production did not depend on MAPK or guanylate cyclase signaling pathways but did depend on the transcriptional regulator Id1. Taken together, these data suggest that CO exerts an anti-fibrotic effect in the lung, and this effect may be due to suppression of fibroblast proliferation and/or suppression of matrix deposition by fibroblasts.
Zhou
Zhihong
Z
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, NW 628 UPMC Montefiore, 3459 Fifth Ave., Pittsburgh, PA 15213, USA.
Song
Ruiping
R
Fattman
Cheryl L
CL
Greenhill
Sara
S
Alber
Sean
S
Oury
Tim D
TD
Choi
Augustine M K
AM
Morse
Danielle
D
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D002248:Carbon Monoxide / Q000627:therapeutic use*; D002453:Cell Cycle; D002455:Cell Division; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*
D001761:Bleomycin; D002248:Carbon Monoxide; D000242:Cyclic AMP; D006152:Cyclic GMP; D006909:Hydroxyproline