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Originally published online as doi:10.2353/ajpath.2008.070863 on September 11, 2008

Published online before print September 11, 2008
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(American Journal of Pathology. 2008;173:981-992.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070863

Heme Oxygenase-1 Prevents Airway Mucus Hypersecretion Induced by Cigarette Smoke in Rodents and Humans

Abdelhamid Almolki*, Armelle Guenegou*, Slawomir Golda{dagger}, Laurent Boyer*, Mourad Benallaoua{ddagger}, Nadia Amara*, Rafik Bachoual*§, Clémence Martin¶||, François Rannou{ddagger}, Sophie Lanone*, Jozef Dulak{dagger}, Pierre-Régis Burgel¶||, Jamel El-Benna**, A. Benedicte Leynaert*, Michel Aubier*{dagger}{dagger} and Jorge Boczkowski*{dagger}{dagger}

From INSERM U700,* Université Paris 7, Paris, France; INSERM U747,{ddagger} Université Paris 5, Paris, France; Faculty of Biochemistry, Biophysics, and Biotechnology,{dagger} Jagiellonian University, Krakow, Poland; Faculté des Sciences de Gabès,§ Tunisia; UPRES EA 2511, Université Paris-Descartes, Faculté de Médecine, Paris, France; Service de Pneumologie et Service de Physiologie,|| Hôpital Cochin, AP-HP, Paris, France; INSERM U773,** Centre de Recherche Bichat Beaujon CRB3; Université Paris 7, Paris, France; CIC 07,{dagger}{dagger} Assistance Publique–Hopitaux de Paris, Hôpital Bichat, Paris, France

We investigated the role of heme oxygenase-1 (HO-1), a powerful anti-inflammatory and anti-oxidant enzyme, in modulating cigarette smoke (CS)-induced mucus secretion. In both rats and mice, 5-day CS exposure increased HO-1 expression and activity, mucus secretion, MUCIN 5AC (MUC5AC) gene and protein expression, and local inflammation, along with up-regulation of dual oxidase 1 gene expression and both the activity and phosphorylation of the epidermal growth factor receptor, which is involved in MUC5AC induction. Pharmacological induction of HO-1 prevented these actions and inhibition of HO-1 expression by a specific siRNA potentiated them. In French participants to the European Community Respiratory Health Survey II (n = 210, 30 to 53 years of age, 50% males) exposed to CS, a significant increase in the percentage of participants with chronic sputum was observed in those harboring at least one allele with a long (GT)n in the HO-1 promoter gene (>33 repeats), which is associated with a low level of HO-1 protein expression, compared with those with a short number of (GT)n repeats (21.7% versus 8.6%, P = 0.047). No such results were observed in those who had never smoked (n = 297). We conclude that HO-1 has a significant protective effect against airway mucus hypersecretion in animals and humans exposed to CS.






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