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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 ineither 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.