Proteases and chemotactic factors in BAL fluid from subjects with subclinical emphysema

I t is generally accepted that proteases released from neutrophils and/or macrophages are involved in the development of emphysema associated with cigarette smoking. However, it has not been resolved which of these inflammatory cells is the main source of proteases responsible for lung destruction. To address this issue, we compared the concentrations of neutrophil elastase-a1 protease inhibitor complex (NE-a1 PI) and cathepsin L in BAL fluid between asymptomatic volunteers aged . 40 years who had emphysema detected by CT scans and those who had a similar smoking history but did not have emphysema. NE-a1 PI originates mainly from neutrophils, while cathepsin L is from macrophages. The immunologic levels of both proteases were significantly higher in the subjects with subclinical emphysema; but, when subjects aged , 60 years were chosen for comparison, there was no difference between the two groups for cathepsin L, although the difference remained for NE-a1 PI. These results suggested that neutrophils are more important than macrophages in the early development of emphysema. We then used enzyme-linked immunosorbent assays to determine the levels of chemotactic factors for neutrophils and monocytes in BAL fluid. The factors studied were interleukin (IL)-8 and leukotriene B4 as neutrophil chemoattractants, and monocyte chemotactic protein-1 and macrophage inflammatory protein-1a as monocyte chemoattractants. Only the level of IL-8 in BAL fluid among these chemotactic factors had a strong positive correlation with NE-a1 PI (r 5 0.74, p , 0.01), and was significantly elevated in the subjects with subclinical emphysema (p , 0.01). To examine the possibility that alveolar macrophages are responsible for the elevation of IL-8 in BAL fluid, we measured IL-8 in alveolar macrophage-conditioned media and alveolar macrophage IL-8 messenger RNA by competitive reverse transcriptasepolymerase chain reaction. We did not, however, find any significant differences between the two groups in these measurements. These studies indicate that neutrophils recruited and/or activated by IL-8 appear to be crucial in the pathogenesis of subclinical emphysema. The source of IL-8 remains to be determined. References