Articles: serine-proteinase-inhibitors-physiology.
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Efficient clearance of mucus and inhaled pathogens from the lung is dependent on an optimal airway surface liquid (ASL) volume, which is maintained by the regulated transport of sodium and chloride across the airway epithelium. Accumulating evidence suggests that impaired mucus clearance in cystic fibrosis (CF) airways is a result of ASL depletion caused by excessive Na(+) absorption through the epithelial sodium channel (ENaC). ⋯ Using primary human airway epithelial cells, we demonstrate that: (i) protease inhibitors are present in the ASL and prevent the activation of near-silent ENaC, (ii) when the ASL volume is increased, endogenous protease inhibitors become diluted, allowing for proteolytic activation of near-silent channels, and (iii) in CF, the normally present near-silent pool of ENaC is constitutively active and the alpha subunit undergoes increased proteolytic processing. These findings indicate that the ASL volume modulates the activity of ENaC by modification of the serine protease-protease inhibitor balance and that alterations in this balance contribute to excessive Na(+) absorption in cystic fibrosis.
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Anesthesia and analgesia · Dec 2004
The effect of dilution on plasma coagulation kinetics determined by thrombelastography is dependent on antithrombin activity and mode of activation.
Hemodilution-associated hypercoagulability has been the focus of several investigations because significant morbidity and mortality have been associated with perioperative thrombophilia. Because most investigations implicate imbalances in procoagulant/anticoagulant activity as the etiology of hemodilution-associated hypercoagulability, we determined the effects of dilution on coagulation kinetics and clot strength with thrombelastography (TEG(R)). Control plasma (+/-celite activation) and antithrombin (AT)-deficient (<10% activity) plasma were diluted 0%, 10%, 20%, and 30% with saline. ⋯ Celite activation eliminated dilution-associated changes in R values in control plasma but resulted in linear decreases (R(2) = 0.88-0.96, P < 0.0001) in alpha, A, and G in response to dilution. Thus, our data indirectly support the concept that decreases in AT activity cause dilution-mediated hypercoagulability in plasma. Finally, celite activation permits quantification of dilution with TEG.
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Anesthesia and analgesia · Oct 2002
Hemodilution with albumin, but not Hextend, results in hypercoagulability as assessed by Thrombelastography in rabbits: role of heparin-dependent serpins and factor VIII complex.
Isovolemic hemodilution (IVHD) has been advocated as an effective method of reducing the need for transfusion but has been associated with hypercoagulability. We tested the hypothesis that IVHD enhances hemostatic function by decreasing circulating antithrombin activity in rabbits. Furthermore, it was determined whether different replacement solutions would affect hemostasis. Sedated rabbits were randomly assigned to groups that underwent IVHD (40% blood volume removed) with 5% human albumin (n = 10) or a 6% hetastarch solution (Hextend). Antithrombin and Factor VIII complex (VIII:C) activities were determined, and thrombelastography(R) was performed with or without platelet inhibition. IVHD resulted in a significant (P < 0.05) decrease in antithrombin (32%-39%) without fluid-specific differences observed. VIII:C did not change in the albumin group, whereas the hetastarch group had a significant (P < 0.05) decrease (43%) in VIII:C that was also significantly (P < 0.05) less than the albumin group. The time to clot initiation was decreased, and the rate of clot formation increased significantly via thrombelastography(R) in albumin animals. No significant change in clot kinetics was observed in hetastarch animals. In rabbits, the primary determinant of hemostasis after IVHD was the interaction of changes in antithrombin activity and VIII:C. These data serve as a rational basis to determine whether IVHD-mediated hypercoagulability encountered clinically may be attenuated or exacerbated by the choice of colloid administered. ⋯ Isovolemic hemodilution (IVHD) is associated with hypercoagulability. Rabbits hemodiluted with albumin, but not Hextend, became hypercoagulable secondary to a loss of antithrombin activity with simultaneous maintenance of Factor VIII complex activity (VIII:C). Hextend-treated animals had proportionate decreases in both antithrombin activity and VIII:C. IVHD-mediated hypercoagulability encountered clinically may be attenuated or exacerbated by the choice of colloid administered.