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Increased rigidity and priming of polymorphonuclear leukocytes in sepsis
E M Drost1, G Kassabian, H J Meiselman
1Departments of Medicine and of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California, USA.
Abstract:
It has been proposed that abnormal mechanical properties may contribute to capillary retention of polymorphonuclear leukocytes (PMN) in sepsis, leading to the development of organ dysfunction. The present study was designed to determine whether PMN rigidity is increased in severe sepsis, and whether changes in the rheologic behavior of PMN correlate with the clinical course in sepsis. Eighteen adults with severe sepsis were studied over a period of 14 d; 11 survived and seven died. PMN deformation behavior was investigated via micropore filtration, using the cell transit analyzer. On Day 0, PMN rigidity was 2.5-fold greater for sepsis patients than for five normal controls (p < 0.001). PMN rigidity progressively improved over the 14 d study period for patients who recovered, but not for those who died; clinical indicators correlated with PMN rigidity. Patient PMN also exhibited a 5-fold greater increase in rigidity in response to formyl-methionylleucylphenylalanine (fMLP) than did control PMN. Both the increased rigidity and enhanced response to fMLP could be simulated in vitro by incubation of normal PMN with tumor necrosis factor-alpha (TNF-alpha). We conclude that circulating PMN are more rigid in severe sepsis, and are "primed" for an augmented response to chemotactic stimuli. These findings support the hypothesis that cytokine-mediated increases of PMN rigidity may lead to sequestration of these cells in capillaries and to the consequent impairment of microvascular perfusion in sepsis.
Insights
Polymorphonuclear leukocytes (PMN) show increased rigidity in severe sepsis, potentially causing organ dysfunction. This PMN rigidity improved in survivors, correlating with clinical recovery, suggesting a link to sepsis progression.
Area of Science:
- Immunology
- Pathophysiology
- Biomedical Engineering
Background:
- Abnormal mechanical properties of polymorphonuclear leukocytes (PMN) may contribute to capillary retention in sepsis.
- This retention can lead to organ dysfunction during severe sepsis.
Purpose of the Study:
- To determine if PMN rigidity increases in severe sepsis.
- To investigate the correlation between PMN rheologic behavior and the clinical course of sepsis.
Main Methods:
- Micropore filtration using a cell transit analyzer to assess PMN deformation.
- Studied 18 adults with severe sepsis over 14 days, comparing them to 5 healthy controls.
Main Results:
- PMN rigidity was 2.5-fold greater in sepsis patients on Day 0 (p < 0.001).
- PMN rigidity improved in recovering patients but not in those who died, correlating with clinical indicators.
- Patient PMN showed a 5-fold greater rigidity increase in response to fMLP compared to controls.
Conclusions:
- Circulating PMN are more rigid and primed for augmented chemotactic response in severe sepsis.
- Cytokine-mediated increases in PMN rigidity may cause capillary sequestration and impair microvascular perfusion in sepsis.