Induction of Heme Oxygenase-1, Biliverdin Reductase and H-Ferritin in Lung Macrophage in Smokers with Primary Spontaneous Pneumothorax: Role of HIF-1α

• Published in: PloS one 2010-05, Vol.5 (5), p.e10886
• Main Authors: Goven, Delphine, Boutten, Anne, Leçon-Malas, Véronique, Marchal-Sommé, Joëlle, Soler, Paul, Boczkowski, Jorge, Bonay, Marcel
• Format: Article
• Language: English
• Subjects: Air exposure; Alveoli; Antioxidants; Biliverdin; Biliverdin reductase; Biopsy; Biosynthesis; Chronic obstructive pulmonary disease; Cigarette smoke; Cigarettes; Conditioned stimulus; Diderot, Denis (1713-1784); Disease; Emphysema; Ferritin; Gene expression; Growth factors; Health risks; Heme; Heme oxygenase (decyclizing); Hypoxia; Immunohistochemistry; Inflammation; Kinases; Lungs; Macrophages; Mimicry; Nuclear transport; Oxidative stress; Oxygenase; Pathology/Molecular Pathology; Pathology/Pathophysiology; Patients; Pneumothorax; Polymerase chain reaction; Proteins; Respiratory Medicine; Ribonucleic acid; Risk factors; RNA; RNA-mediated interference; Rodents; Smoke; Smoking; Surfactants; Transcription factors; Translocation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0010886

Background Few data concern the pathophysiology of primary spontaneous pneumothorax (PSP), which is associated with alveolar hypoxia/reoxygenation. This study tested the hypothesis that PSP is associated with oxidative stress in lung macrophages. We analysed expression of the oxidative stress marker 4-HNE; the antioxidant and anti-inflammatory proteins heme oxygenase-1 (HO-1), biliverdin reductase (BVR) and heavy chain of ferritin (H-ferritin); and the transcription factors controlling their expression Nrf2 and HIF-1α, in lung samples from smoker and nonsmoker patients with PSP (PSP-S and PSP-NS), cigarette smoke being a risk factor of recurrence of the disease. Methodology/Principal Findings mRNA was assessed by RT-PCR and proteins by western blot, immunohistochemistry and confocal laser analysis. 4-HNE, HO-1, BVR and H-ferritin were increased in macrophages from PSP-S as compared to PSP-NS and controls (C). HO-1 increase was associated with increased expression of HIF-1α mRNA and protein in alveolar macrophages in PSP-S patients, whereas Nrf2 was not modified. To understand the regulation of HO-1, BVR and H-ferritin, THP-1 macrophages were exposed to conditions mimicking conditions in C, PSP-S and PSP-NS patients: cigarette smoke condensate (CS) or air exposure followed or not by hypoxia/reoxygenation. Silencing RNA experiments confirmed that HIF-1α nuclear translocation was responsible for HO-1, BVR and H-ferritin induction mediated by CS and hypoxia/reoxygenation. Conclusions/Significance PSP in smokers is associated with lung macrophage oxidative stress. The response to this condition involves HIF-1α-mediated induction of HO-1, BVR and H-ferritin.