Heme oxygenase modulates oxidant-signaled airway smooth muscle contractility: role of bilirubin.
Reactive oxygen species (ROS) increase the contractile response of airway smooth muscle (ASM). Heme oxygenase (HO) catabolizes heme to the powerful antioxidant bilirubin. Because HO is expressed in the airways, we investigated its effects on ASM contractility and ROS production in guinea pig trachea. HO expression was higher in the epithelium than in tracheal smooth muscle. Incubation of tracheal rings (TR) with the HO inhibitor tin protoporphyrin (SnPP IX) or the HO substrate hemin increased and decreased, respectively, ASM contractile response to carbamylcholine. The effect of hemin was reversed by SnPP and mimicked by the antioxidants superoxide dismutase (SOD) and catalase. Hemin significantly reduced the effect of carbamylcholine in rings treated with the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), compared with ODQ-treated rings without hemin incubation, suggesting that the CO-guanosine 3',5'-cyclic monophosphate pathway was not involved in the control of tracheal reactivity. SnPP and hemin increased and decreased ROS production by TR by 18 and 38%, respectively. Bilirubin (100 pM) significantly decreased TR contractility and ROS production. Hemin, bilirubin, and SOD/catalase decreased phosphorylation of the contractile protein myosin light chain, whereas SnPP significantly augmented it. These data suggest that modulation of the redox status by HO and, moreover, by bilirubin modulates ASM contractility by modulating levels of phosphorylated myosin light chain.
Samb
Abdoulaye
A
Institut National pour la Santé et la Recherche Médicale, Unité 408, Faculté de Médecine Xavier Bichat, 75018 Paris, France.
Taillé
Camille
C
Almolki
Abdelhamid
A
Mégret
Jérôme
J
Staddon
James M
JM
Aubier
Michel
M
Boczkowski
Jorge
J
D000818:Animals; D001663:Bilirubin / Q000502:physiology*; D002248:Carbon Monoxide / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D006168:Guinea Pigs; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism / Q000502:physiology*; D051547:Heme Oxygenase-1; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D018994:Myosin Light Chains / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D014132:Trachea / Q000502:physiology*
D018994:Myosin Light Chains; D016877:Oxidants; D017382:Reactive Oxygen Species; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D006152:Cyclic GMP; D001663:Bilirubin