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Granulocyte colony-stimulating factor reverses septic shock-induced polymorphonuclear leukocyte dysfunction
1Department of Surgery, Brown University School of Medicine-Rhode Island Hospital, Providence 02903.
Background:
Polymorphonuclear leukocyte (PMN) function is dependent on normal Fcg receptor expression. Fibronectin and laminin are each capable of modulating the surface expression of CD32w (Fc gamma RII) and CD16 (Fc gamma RIII). Their ability to alter CD64 (Fc gamma RI) expression, however, was unclear; therefore the purpose of these studies was to define the role of CD64 (Fc gamma RI) in modulating PMN oxidative metabolism and degranulation for PMNs adherent to either fibronectin or laminin.
Methods:
Experiments were performed in two phases; initially, PMNs isolated from normal volunteers and adherent to buffer, fibronectin, or laminin were studied. Subsequently, two groups of patients were evaluated; group 1 (n = 8) represents control patients undergoing major intraabdominal procedures. Group 2 (n = 12) represents patients in septic shock from defined sources of intraabdominal infection. Monomeric immunoglobulin G was used as a specific ligand for CD64 followed by measurements of superoxide anion, hypochlorous acid, and N-acetyl-beta-glucosaminidase production to measure oxidative metabolism and azurophilic granule degranulation. Six cytokines were then tested to determine their ability to restore biologically active CD64 on group 2 PMNs.
Results:
Fibronectin or laminin increased CD64 on PMNs of normal volunteers and group 1 patients. CD64 signal transduction augmented superoxide anion, hypochlorous acid, and N-acetyl-beta-glucosaminidase production by PMNs of volunteers and group 1. Neither fibronectin nor laminin increased CD64 expression on group 2 PMNs. Granulocyte colony-stimulating factor restored both receptor number of CD64 and biologic activity of these receptors on the surface of group 2 PMNs in the presence of fibronectin or laminin.
Conclusions:
Septic shock depresses CD64 expression on the PMN surface. Restoration of this receptor by granulocyte colony-stimulating factor not only augments receptor number but also improves oxidative metabolism and primary granule degranulation in the presence of either fibronectin or laminin.
Insights
Septic shock significantly reduces CD64 (Fc gamma RI) expression on polymorphonuclear leukocytes (PMNs). Granulocyte colony-stimulating factor can restore CD64 function, improving PMN oxidative metabolism and degranulation in patients with septic shock.
Area of Science:
- Immunology
- Cell Biology
Background:
- Polymorphonuclear leukocyte (PMN) function relies on Fc gamma receptor expression.
- Fibronectin and laminin modulate CD32 (Fc gamma RII) and CD16 (Fc gamma RIII) but their effect on CD64 (Fc gamma RI) was unclear.
Purpose of the Study:
- To define the role of CD64 (Fc gamma RI) in modulating PMN oxidative metabolism and degranulation.
- To investigate the effects of fibronectin and laminin on CD64 expression and function in PMNs.
Main Methods:
- PMNs from healthy volunteers and patients (controls and septic shock) were analyzed.
- CD64 expression was measured after adherence to fibronectin or laminin.
- Oxidative metabolism and degranulation were assessed via superoxide anion, hypochlorous acid, and N-acetyl-beta-glucosaminidase production.
- Cytokines were tested for their ability to restore CD64 activity in septic shock patients.
Main Results:
- Fibronectin and laminin increased CD64 expression and activity in PMNs from healthy volunteers and control patients.
- Septic shock patients showed depressed CD64 expression and activity.
- Granulocyte colony-stimulating factor restored both CD64 expression and biological activity in septic shock PMNs.
Conclusions:
- Septic shock impairs CD64 expression on PMNs.
- Granulocyte colony-stimulating factor can restore CD64 number and function, enhancing PMN oxidative metabolism and degranulation in the context of fibronectin or laminin.
- This suggests a potential therapeutic target for sepsis-related immune dysfunction.
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