ABSTRACT
Neutrophil polymorphonuclear leukocytes (neutrophils) play a critical role in host defense. A decrease in numbers of neutrophils-which may occur as a conse quence of bone marrow suppression due to haematological or lymphoproliferative malignancy and iatrogenic causes, including immunosuppressant drug therapyresults in life-threatening susceptibility to infection. Two major neutrophil micro bicidal mechanisms combat microbial infection: the generation of potent oxygenderived radicals following the triggering of a complex of membrane-associated enzymes and degradation by proteolytic and other neutrophil granule enzymes, including the potent serine protease neutrophil elastase (NE). (For reviews, see Refs. 1-3.)
These protective mechanisms may, however, be responsible for host injury; during phagocytosis, and likely during neutrophil migration through tissue, gran ule contents leak from the cell into the local milieu (3-6). In the context that 70100 billion neutrophils are released from the bone marrow each day (7) and end their lifespans within tissue, including lung (2), it is surprising that host injury does not inevitably occur continuously during neutrophil migration unless tight autocrine or paracrine controls exist. Indeed, when neutrophils are attracted into
sites of chronic inflammation, such as the lung in idiopathic pulmonary fibrosis as a result of local immune effector mechanisms, there is now clear evidence that neutrophils contribute to further host injury due to the unfettered effects of oxygen radical generation and degranulation in response to activating factors in the local milieu that overwhelm local controls (1,8-10). This chapter explores the concept that the neutrophil may minimize microenvironmental host damage to other cells and tissue matrix due to NE release during neutrophil chemotaxis by synthesizing and secreting alpha 1-antitrypsin (alAT), the natural and most potent inhibitor of NE.
