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Evidence for Neutrophil Involvement in the Development of Subclinical Emphysema*

Tomoko Betsuyaku, MD; Masaharu Nishimura, MD; Kimihiro Takeyabu, MD; Mishie Tanino, MD; P. Venge, MD; S. Xu, PhD; Yoshikazu Kawakami, MD, FCCP
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*From the First Department of Medicine (Drs. Betsuyaku, Nishimuru, Takeyabu, Tanino, and Kawakami), Hokkaido University School of Medicine, Sapporo, Japan; and the Department of Clinical Chemistry (Drs. Venge and Xu), University Hospital, Uppsala, Sweden.

Correspondence to: Tomoko Betsuyaku, MD, First Department of Medicine, Hokkaido University School of Medicine, Sapporo 060, Japan



Chest. 2000;117(5_suppl_1):302S-303S. doi:10.1378/chest.117.5_suppl_1.302S
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Abbreviations: HNL = human neutrophil lipocalin; MMP = matrix metalloproteinase; NE-α1PI = neutrophil elastase-α1 proteinase inhibitor complex

Cigarette smoking is the major cause of pulmonary emphysema, yet only a small portion of smokers develops clinically apparent emphysema. Using BAL to compare asymptomatic smokers having emphysema detected by CT scans with individuals who have a similar smoking history but do not have emphysema, we have demonstrated that (1) the concentration of neutrophil elastase-α1 proteinase inhibitor complex (NE-α1PI) is significantly elevated in BAL fluid in the subjects with subclinical emphysema,1 (2) more NE-α1PI is released from cultured alveolar macrophages in the emphysematous smokers, which supports the idea more neutrophil elastase is taken up by macrophages in those subjects,2 and (3) the level of elastin-derived peptides in BAL fluid correlates with the level of NE-α1PI, and is significantly higher in current smokers than former smokers.3 These studies have implicated neutrophils in early emphysema. To further evaluate neutrophil involvement in subclinical emphysema, we measured human neutrophil lipocalin (HNL) and two matrix metalloproteinases (MMP), gelatinase B (MMP-9) and neutrophil collagenase (MMP-8) in BAL fluid from 65 community-based older volunteers. The subjects were classified according to the presence of emphysema by CT scan and current smoking status. HNL is a recently isolated 24 kDa protein secreted from secondary granules of activated neutrophils. It is not present in macrophages. Despite no difference in the number of neutrophils, the level of HNL was significantly elevated in BAL fluid from the subjects with subclinical emphysema compared to smokers without emphysema. MMP-9 and MMP-8 levels were also significantly higher in the smokers with emphysema than in smokers without emphysema. The appearance of 130 kDa gelatinolytic activity that was positive for HNL by immunoblot indicated the presence of HNL/MMP-9 complexes, and that neutrophil was a significant source of the MMP-9 in the BAL fluid. The number of alveolar macrophages in BAL fluid did not discriminate between smokers with and without emphysema. These data provide further evidence for neutrophil involvement in the early stage of development of pulmonary emphysema.

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