Heme oxygenase modulates oxidant-signaled airway smooth muscle contractility: role of bilirubin

Abstract

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.

Induction of Heme Oxygenase-1 Inhibits NAD(P)H Oxidase Activity by Down-regulating Cytochrome b558 Expression via the Reduction of Heme Availability

“…We have previously demonstrated in airway smooth muscle that HO-1-released or exogenously added bilirubin could decrease superoxide anion production (12,16). This effect could be related to the oxidant-scavenging properties of bilirubin (14) or to the inhibition of NAD(P)H oxidase activation by this molecule (35).…”

“…Until now, this anti-oxidant effect has been mainly attributed to production of bilirubin (10 -12), one of the end products of heme catabolism with reactive oxygen species scavenging properties (13,14), or to ferritin induction after release of the central iron from heme (15). Recently, we have shown that HO-1 overexpression decreases superoxide production in airway smooth muscle (12,16), which is known to express the heme-containing gp91 phox (4), suggesting that HO-1 could affect NAD(P)H oxidase activity. This could be related to the heme content regulatory properties of HO-1.…”

Renal Hemodynamic, Inflammatory, and Apoptotic Responses to Lipopolysaccharide in HO-1−/− Mice

“…Phosphorylation of IB enables nuclear translocation of NF-B, and the attendant NF-B-dependent transcription of proinflammatory genes. Bilirubin, a product of HO, can inhibit phosphorylation 46,47 ; bile pigments may also reduce the inflammatory effects of LPS. 48 It is thus possible that bile pigments, metabolites with recognized anti-inflammatory effects, may contribute to the suppressive effects of HO-1 on activation of NF-B and NF-B-dependent inflammatory processes.…”

Hyperosmolar Solution Effects in Guinea Pig Airways. III. Studies on the Identity of Epithelium-Derived Relaxing Factor in Isolated Perfused Trachea Using Pharmacological Agents

“…HO is expressed in the epithelium and nerves of human and guinea pig large airways (Undem et al, 1996;Donnelly and Barnes, 2001) and may modulate reactivity of airway smooth muscle to agonists, such as carbachol (Samb et al, 2002). In addition, HO is thought to be involved in protection of liver and kidney cells from hyperosmolar stress (Lordnejad et al, 2001;Tian et al, 2001).…”