Recombinant alpha 1-antitrypsin Pittsburgh attenuates experimental gram-negative septicemia.
Alpha 1-antitrypsin-Pittsburgh (AT-P), a naturally occurring lethal mutation (358Met----Arg), has been genetically engineered (rAT-P). The protein has been shown to be a potent active site-directed inhibitor of thrombin and the contact enzymes Factor XIIf, Factor XIa, and kallikrein. Because activation of the contact system is known to occur in gram-negative septicemia, the authors have hypothesized that the administration of rAT-P might modulate the course of this syndrome. Yorkshire piglets anesthetized with pentobarbital and infused with viable Pseudomonas aeruginosa (2 X 10(8) CFU) were untreated (Group I) or treated with rAT-P (Group II) and studied in a 6-hour protocol. Coagulation studies revealed that rAT-P significantly inhibited the rapid decrease in the functional concentrations of Antithrombin III, Factor XI, and fibrinogen. In addition, rAT-P markedly reduced the serum levels of fibrinogen degradation products. Survival in Group II was significantly increased during 2-5 hours but not at 6 hours when the functional levels of rAT-P in plasma were the lowest. These results indicate that this recombinant inhibitor, even at low concentrations, affords protection in experimental gram-negative septicemia.
Colman
R W
RW
Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140.
Flores
D N
DN
De La Cadena
R A
RA
Scott
C F
CF
Cousens
L
L
Barr
P J
PJ
Hoffman
I B
IB
Kueppers
F
F
Fisher
D
D
Idell
S
S
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001794:Blood Pressure; D001798:Blood Proteins / Q000032:analysis; D005342:Fibrinolysis / Q000187:drug effects; D006400:Hematocrit; D006454:Hemoglobins / Q000032:analysis; D007705:Kinins / Q000097:blood; D007958:Leukocyte Count; D010976:Platelet Count; D011552:Pseudomonas Infections / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D011994:Recombinant Proteins; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D013552:Swine; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000627:therapeutic use*
D001798:Blood Proteins; D006454:Hemoglobins; D007705:Kinins; D011994:Recombinant Proteins; D000515:alpha 1-Antitrypsin; C038915:alpha 1-antitrypsin Pittsburgh