The Natural History of the Neutrophil Elastase and Coagulation Factor Response to E.coli in a Baboon Model of E.coli/Sepsis Suggests That Elevated Neutrophil Elastase Activity Is Sustained Regardless of Outcome in Clinical Sepsis.

Neutrophil elastase (NE) functions in the destruction of gram negative bacteria. NE consumption/inactivation of coagulation factors may contribute to the coagulopathies that accompany infections upon insuffcient regulation by its primary plasma inhibitor, alpha-1-protease inhibitor (A1PI). The temporal relationships between NE levels, A1PI activity and antigen, and the activity of Factor (F) II, V, VII, VIII, IX, X, and fibrinogen were studied in three baboons after infusion of 2.40 x 10⁶ cfu/kg (low/sublethal), 1.05 x 10⁸ cfu/kg (medium/sublethal), and 6.49 x 10⁸ cfu/kg (lethal) of E.coli. Immunoblotting for A1PI under native conditions indicated that the A1PI/NE complex levels increased by 5- to 93-fold after 24hrs and remained 3- to 580-fold above baseline at 72hrs and 53hrs following sublethal and lethal E.coli challenge, respectively. The A1PI specific activity (activity/antigen) decreased by 55% and 30% after 48–72hrs and 48–53hrs following the medium and lethal dose, respectively. Increased amounts of 2 forms of A1PI resolved by native PAGE/immunoblotting correlated with decreased inhibitor specific activity. At the lethal dose of E.coli, decreases (%) in fibrinogen (96%), FV (60%), and FVIII (60%) occurred within 2–6hrs. By 53hrs, FV and FVIII levels returned to normal and fibrinogen was twice normal. Similar changes of smaller magnitudes occurred at the lower doses of E.coli. At the lethal dose of E.coli, decreases in FII (50%), FVII (80%), FIX (80%), and FX (60%) occurred over the first 24hrs and these levels were sustained through 53hrs. Similar changes of smaller magnitudes occurred at the lower doses. In conclusion, there is a temporal association between coagulation factor consumption/inactivation, appearance of the A1PI/NE complex, and A1PI inactivation during E.coli/sepsis in baboons. The marked elevation of the A1PI/NE complex beyond 24hrs, even after sublethal challenge, indicates for the first time that increased neutrophil and NE activities persist beyond the initial inflammatory and coagulopathic stages into the subsequent cell injury and degeneration stages that terminate in either recovery or death from E.coli/sepsis.