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Gene Expression and Immunolocalization of 15-Lipoxygenase Isozymes in the Airway Mucosa of Smokers with Chronic Bronchitis

Lung Pathology, Department of Gene Therapy, Imperial College at the Royal Brompton Hospital and Department of Respiratory Medicine, London; London Chest Hospital, London, United Kingdom; Pfizer Global Research & Development, Sandwich, Kent, United Kingdom; Clinical and Biological Sciences, University of Torino, Torino, Italy; and Pathology, University Hospital, Belgium

Address correspondence to: Professor P. K. Jeffery, Lung Pathology, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail: p.jeffery{at}ic.ac.uk

15-lipoxygenase (15-LO) has been implicated in the inflammation of chronic bronchitis (CB), but it is unclear which of its isoforms, 15-LOa or 15-LOb, is primarily involved. To detect 15-LO gene (mRNA) and protein expression, we have applied in situ hybridization (ISH) and immunohistochemistry (IHC), respectively, to bronchial biopsies obtained from 7 healthy nonsmokers (HNS), 5 healthy smokers (HS), and 8 smokers with CB, and additionally include the airways of lungs resected from 11 asymptomatic smokers (AS) and 11 smokers with CB. Compared with HNS, biopsies in CB demonstrated increased numbers of 15-LOa mRNA+ cells (median: HNS = 31.3/mm² versus CB = 84.9/mm², P < 0.01) and protein+ cells (HNS = 2.9/mm² versus CB = 32.1/mm², P < 0.01). The HS group also showed a significant increase in protein+ cells (HNS = 2.9/mm² versus HS = 14/mm², P < 0.05). In the resected airways, 15-LOa protein+ cells in the submucosal glands of the CB group were more numerous than in the AS group (AS = 33/mm² versus CB = 208/mm²; P < 0.001). 15-LOa mRNA+ and protein+ cells consistently outnumbered 15-LOb by 7- and 5-fold, respectively (P < 0.01). Quantitative reverse transcriptase polymerase chain reaction of complementary biopsies confirmed the increased levels of 15-LOa in CB compared with that in either HNS or HS (P < 0.05). There was no difference between the subject groups with respect to 15-LOb expression. The numbers of cells expressing mRNA for 15-LOa in CB showed a positive association with those expressing interleukin (IL)-4 mRNA (r = 0.80; P < 0.01). We conclude that the upregulation of 15-LO activity in the airways of HS and of smokers with CB primarily involves the 15-LOa isoform: the functional consequences of its association the upregulation of IL-4 in chronic bronchitis requires further study.

Abbreviations: arachidonic acid, AA • asymptomatic smokers, AS • chronic bronchitis, CB • digoxygenin, Dig • hematoxylin and eosin, H&E • hydroxyeicosatetraenoic acid, HETE • healthy nonsmokers, HNS • healthy smokers, HS • immunohistochemistry, IHC • in situ hybridization, ISH • polymorphonuclear neutrophils, PMN • reverse transcriptase–polymerase chain reaction, RT-PCR • Tris-buffered saline, TBS

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