Funded by a Grant from the Alpha-1 Foundation
ABSTRACT
Disposal of apoptotic neutrophils by monocyte lineage cells is critical to the resolution of lung inflammation. One of alpha-1-antitrypsin (AAT)’s major function is to inhibit neutrophil (PMN) serine protease. Secretion of AAT by the liver is profoundly reduced in AAT deficiency leading to a leak of antiprotease protection in the lung. In the absence of sufficient lung AAT, PMNs accumulate in the lung. While protease-antiprotease imbalance is a major reason for lung inflammation and destruction, alveolar macrophages (MΦ) are also known to produce AAT in abundance. We hypothesize that intracellular AAT may play a critical role in the appropriate disposal of apoptotic PMNs and that MΦ from deficient individuals may not appropriately process apoptotic PMNs.
Method: To test this hypothesis, we used peripheral blood monocyte-derived MΦ from normal (PI*MM) and AAT-deficient (PI*ZZ) individuals. Twenty and forty minutes after being fed apoptotic PMNs, MΦ and Z MΦ were washed and the phagocytic indices were compared. Secretion of the pro-inflammatory cytokine TNF-alpha from normal and deficient MΦ were determined following incubation with apoptotic PMNs in the presence or absence of LPS.