The emphysema of α1-antitrypsin (α1AT) deficiency is conceptualized to result from insufficient α1AT allowing neutrophil elastase to destroy lung parenchyma. In addition to the deficiency of α1AT in these individuals resulting from mutations in the α1AT 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 α1AT deficiency may result, in part, from release of neutrophil chemotactic activity by alveolar macrophages as they bind uninhibited neutrophil elastase. Consistent with this hypothesis, α1AT-deficient alveolar macrophages spontaneously released nearly threefold more neutrophil chemotactic activity than normal alveolar macrophages. Analysis of α1AT-deficient macrophage supernates by reversephase HPLC, molecular sieve cbromatography, radioimmunoassay, and absorption with anti-LTB4 antibody revealed that the majority of the chemotactic activity was leukotriene B4 (LTB4), a mediator absent from normal macrophage supernates. Consistent with this hypothesis, incubation of normal macrophages with human neutrophil elastase resulted in the release of the same neutrophil chemotactic mediator. Furthermore, purified human α1AT was able to prevent the neutrophil elastase from stimulating the macrophages to release the chemotactic factor. Together, these findings suggest that the absence of a normal antineutrophil elastase screen in the lower respiratory tract permits free neutrophil elastase to bind to alveolar macrophages, resulting in the release of LTB4, a process which attracts neutrophils to the alveoli of α1AT deficient individuals, thus accelerating the lung destruction that characterizes this disorder.
|Number of pages||7|
|Journal||Journal of Clinical Investigation|
|Publication status||Published - 1 Sep 1991|
- Bronchoalveolar lavage
- Neutrophil elastase antiprotease
ASJC Scopus subject areas