Neutrophil Accumulation in the Lung in al-Antitrypsin, Deficiency Spontaneous Release of Leukotriene B4 by Alveolar Macrophages

The emphysema of al-antitrypsin (alAT) deficiency is concep-tualized to result from insufficient alAT allowing neutrophil elastase to destroy lung parenchyma. In addition to the defi-ciency ofalAT in these individuals resulting from mutations in the alAT gene, it is recognized that, for unknown reasons, there are also increased numbers of neutrophils in their lungs compared with normal individuals. With the knowledge that alveolar macrophages have surface receptors for neutrophil elastase, we hypothesized that the neutrophil accumulation in the lower respiratory tract in alAT deficiency may result, in part, from release ofneutrophil chemotactic activity by alveolar macrophages as they bind uninhibited neutrophil elastase. Consistent with this hypothesis, alAT-deficient alveolar mac-rophages spontaneously released nearly threefold more neutro-phil chemotactic activity than normal alveolar macrophages. Analysis ofalAT-deficient macrophage supernates by reverse-phase HPLC, molecular sieve chromatography, radioimmuno-assay, and absorption with anti-LTB4 antibody revealed that the majority of the chemotactic activity was leukotriene B4 (LTB4), a mediator absent from normal macrophage super-nates. Consistent with this hypothesis, incubation of normal macrophages with human neutrophil elastase resulted in the release of the same neutrophil chemotactic mediator. Further-more, purified human alAT was able to prevent the neutrophil elastase from stimulating the macrophages to release the che-motactic factor. Together, these findings suggest that the ab-sence of a normal antineutrophil elastase screen in the lower respiratory tract permits free neutrophil elastase to bind to al-veolar macrophages, resulting in the release ofLTB4, a process which attracts neutrophils to the alveoli ofalAT deficient indi-viduals, thus accelerating the lung destruction that character