Microvesicular Caspase-1 Mediates Lymphocyte Apoptosis in SepsisReport as inadecuate




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Objective

Immune dysregulation during sepsis is poorly understood, however, lymphocyte apoptosis has been shown to correlate with poor outcomes in septic patients. The inflammasome, a molecular complex which includes caspase-1, is essential to the innate immune response to infection and also important in sepsis induced apoptosis. Our group has recently demonstrated that endotoxin-stimulated monocytes release microvesicles MVs containing caspase-1 that are capable of inducing apoptosis. We sought to determine if MVs containing caspase-1 are being released into the blood during human sepsis and induce apoptosis



Design

Single-center cohort study

Measurements

50 critically ill patients were screened within 24 hours of admission to the intensive care unit and classified as either a septic or a critically ill control. Circulatory MVs were isolated and analyzed for the presence of caspase-1 and the ability to induce lymphocyte apoptosis. Patients remaining in the ICU for 48 hours had repeated measurement of caspase-1 activity on ICU day 3.

Main Results

Septic patients had higher microvesicular caspase-1 activity 0.05 0.04, 0.07 AFU versus 0.0 AFU 0, 0.02 p<0.001 on day 1 and this persisted on day 3, 0.12 0.1, 0.2 versus 0.02 0, 0.1 p<0.001. MVs isolated from septic patients on day 1 were able to induce apoptosis in healthy donor lymphocytes compared with critically ill control patients 17.8±9.2% versus 4.3±2.6% apoptotic cells, p<0.001 and depletion of MVs greatly diminished this apoptotic signal. Inhibition of caspase-1 or the disruption of MV integrity abolished the ability to induce apoptosis.

Conclusion

These findings suggest that microvesicular caspase-1 is important in the host response to sepsis, at least in part, via its ability to induce lymphocyte apoptosis. The ability of microvesicles to induce apoptosis requires active caspase-1 and intact microvesicles.



Author: Matthew C. Exline, Steven Justiniano, Jennifer L. Hollyfield, Freweine Berhe, Beth Y. Besecker, Srabani Das, Mark D. Wewers, Anas

Source: http://plos.srce.hr/



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