Incubation of highly purified human C1 inhibitor with equally pure human leukocyte proteinase 3, resulted in a dose- and time-dependent inactivation of C1 inhibitor hemolytic activity. Furthermore, this inactivation was accompanied by proteinase 3-dependent cleavage of the C1 inhibitor into an 83,000 molecular weight fragment. The formation of the 83,000 molecular weight fragment followed a time course which was similar to that observed for the inactivation of hemolytic activity. Within 120 minutes more than 90% of the hemolytic activity was lost. This inactivation of C1 inhibitor appeared to be selective as purified human C1q was not degraded in a similar time period. Moreover, when 100 micrograms IgG, isolated from each of 21 Wegener's granulomatosis patients with cytoplasmic anti-nuclear antibodies immunofluorescent titers to proteinase 3 greater then 1:64, was incubated with 3 milliunits of proteinase 3, little to no cleavage of C1 inhibitor was observed. In contrast, 100 micrograms of IgG isolated from 14 normal donors was ineffective in affording protection to C1 inhibitor upon incubation with proteinase 3. Our results suggest that neutrophil infiltration and activation could lead to local complement consumption at the tissue sites.

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Virus infection of alveolar macrophages (AM) both in vivo and in vitro has been associated with a decreased ability of these cells to kill bacteria, together with enhanced production of metabolites of arachidonic acid. These metabolites, especially PGE2, may be inhibitory to some phagocyte functions. Primary cultures of bovine AM obtained by bronchoalveolar lavage of normal cattle were infected in vitro with parainfluenza-3 (PI3 virus) virus. Killing of Staphylococcus epidermidis by AM was determined on days 1-4 post-infection (p.i.) PI3 virus-infected AM killed significantly fewer bacteria on day 4 p.i. compared to uninfected controls (12.1 +/- 1.3% infected vs. 52.7 +/- 7.2% controls, P less than or equal to 0.05). Bacterial killing by virus-infected AM, but not control AM, was significantly enhanced on day 4 p.i. by addition of cyclooxygenase inhibitors 1 hr prior to bactericidal assay (28.0 +/- 4.5% indomethacin, 36.0 +/- 4.1% mefenamic acid, 38.6 +/- 7.3% piroxicam, 37.0 +/- 6.4% NDGA, 44.9 +/- 7.7% ETYA, P less than or equal to 0.05). Phagocytosis of opsonized sheep erythrocytes and superoxide generation by virus-infected AM were not significantly increased by cyclooxygenase inhibition. Phagosome-lysosome fusion was severely impaired in virus-infected AM. Pretreatment of virus-infected AM with indomethacin significantly enhanced the percentage of cell expressing fusion activity. This data suggests that in vitro bactericidal dysfunction associated with virus infection of AM is partially the result of enhanced production of prostaglandins or thromboxane by AM and/or an abnormal response to normal levels of endogenously produced cyclooxygenase metabolites. The data further indicate the presence of cyclooxygenase sensitive (phagosome-lysosome fusion) and insensitive (phagocytic) components of virus-induced bactericidal dysfunction in AM.