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J. Biol. Chem., Vol. 278, Issue 29, 27160-27168, July 18, 2003

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Heme Oxygenase Inhibits Human Airway Smooth Muscle Proliferation via a Bilirubin-dependent Modulation of ERK1/2 Phosphorylation^*

Camille Taillé , Abdelhamid Almolki , Moussa Benhamed , Christine Zedda , Jérôme Mégret , Patrick Berger , Guy Lesèche ¶, Elie Fadel ||, Tokio Yamaguchi **, Roger Marthan , Michel Aubier  and Jorge Boczkowski  

From the INSERM, Unité 408, Faculté de Médecine Xavier Bichat, 75018 Paris, INSERM, E9937, Université Victor Ségalen, 33076 Bordeaux 2, the ^¶Service de Chirurgie Vasculaire et Thoracique, Hôpital Beaujon, 92118 Clichy, and the ^||Service de Chirurgie Thoracique, Centre Chirurgical Marie Lannelongue, 92350 le Plessis Robinson, France, and the ^**Medical Research Institute, Tokyo Medical and Dental University, 113-8549 Tokyo, Japan

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 µM hemin or by 20 µM cobalt-protoporphyrin) and HO inhibition (by 25 µM 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 µM) 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 µM) 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.

Received for publication, January 13, 2003 , and in revised form, March 24, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: INSERM U408, Faculté deMédecine Xavier Bichat, 16 rue Henri Huchard, 75018 Paris, France. Tel.: 33-1-44-85-62-51; Fax: 33-1-42-26-33-30; E-mail: jbb2{at}bichat.inserm.fr.

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