Heme oxygenase inhibits human airway smooth muscle proliferation via a bilirubin-dependent modulation of ERK1/2 phosphorylation.
The aim of this study was to investigate whether the heme oxygenase (HO) pathway could modulate proliferation of airway smooth muscle (ASM) and the mechanism(s) involved in this phenomenon. In cultured human ASM cells, 10% fetal calf serum or 50 ng/ml platelet-derived growth factor AB induced cell proliferation, extracellular and intracellular reactive oxygen species (ROS) production and ERK1/2 phosphorylation. Pharmacological HO-1 induction (by 10 microm hemin or by 20 microm cobalt-protoporphyrin) and HO inhibition (by 25 microm tin-protoporphyrin or by an antisense oligonucleotide), respectively, reduced and enhanced significantly both cell proliferation and ROS production. Neither the carbon monoxide scavenger myoglobin (5-20 microm) nor the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one could reverse ASM proliferation induced by tin-protoporphyrin, making a role of the CO-cGMP pathway in HO-modulated proliferation unlikely. By contrast, bilirubin (1 microm) and the antioxidant N-acetyl-cysteine (1 mm) significantly reduced mitogen-induced cell proliferation, ROS production, and ERK1/2 phosphorylation. Furthermore, both bilirubin and N-acetyl-cysteine and the ERK1/2 inhibitor PD98059 significantly reversed the effects of HO inhibition on ASM proliferation. These results could be relevant to ASM alterations observed in asthma because activation of the HO pathway prevented the increase in bronchial smooth muscle area induced by repeated ovalbumin challenge in immunized guinea pigs, whereas inhibition of HO had the opposite effect. In conclusion, this study provides evidence for an antiproliferative effect of the HO pathway in ASM in vitro and in vivo through a bilirubin-mediated redox modulation of phosphorylation of ERK1/2.
Taillé
Camille
C
INSERM, Unité 408, Faculté de Médecine Xavier Bichat, 75018 Paris, INSERM, E9937, Université Victor Ségalen, 33076 Bordeaux 2, France.
Almolki
Abdelhamid
A
Benhamed
Moussa
M
Zedda
Christine
C
Mégret
Jérôme
J
Berger
Patrick
P
Lesèche
Guy
G
Fadel
Elie
E
Yamaguchi
Tokio
T
Marthan
Roger
R
Aubier
Michel
M
Boczkowski
Jorge
J
D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D001483:Base Sequence; D001663:Bilirubin / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006168:Guinea Pigs; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D007114:Immunization; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012132:Respiratory Muscles / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D008565:Membrane Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D017382:Reactive Oxygen Species; D010047:Ovalbumin; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D001663:Bilirubin