Plasma gelsolin (pGSN)
Quick links:
-> Proposed Mechanism of Action
-> General Gelsolin Information
-> Gelsolin Binding
-> pGSN Levels in Disease
-> Tissue Effects of pGSN Repletion
-> Survival Effects of pGSN Repletion
pGSN in Disease
Soon after the identification of plasma gelsolin (pGSN), it was found that the pGSN levels fall in both patients and animals subjected to a wide variety of acute insults. Dramatic reductions in plasma gelsolin levels of 50-95% were reported in multiple animal models of serious acute injury including hyperoxia in mice (Christofidou-Solomidou et al. 2002; Lung 180: 91-104), lipopolysaccharide (LPS, endotoxin) challenge (Watt et al. 1989; Circ Shock 28: 279-291, Lee et al. 2007; Crit Care Med 35: 849-855), oleic acid-induced acute lung injury (Smith et al. 1998; Am J Pathol 130: 261-267), cecal ligation/puncture model of sepsis (Lee et al. 2007; Crit Care Med 35: 849-855), major burn (Rothenbach et al. 2004; J Appl Physiol 96: 25-31) and blast injury (Chavko et al. 2006; J Trauma 61: 933-942).
In parallel, depleted pGSN levels were reported in patients with a variety of significant acute insults including major trauma (Dahl et al. 1999; Shock 12: 10-14, Mounzer et al. 1999; Am J Respir Crit Care Med 160: 1673-1681), malarial infection (Smith et al. 1988; Blood 72: 214-218), acute lung injury (Lind et al. 1988; Am Rev Resp Dis 138: 429-434), surgery (Lee et al. 2006; Ann Surg 243: 399–403), allogeneic stem cell transplantation (DiNubile et al. 2002; Blood 100: 4367-4371), specific organ dysfunction including myocardial infarction, acute liver failure, myonecrosis (Suhler et al. 1997; Crit Care Med 25: 594-598) or septic shock (Wang et al: 2008; Crit Care Med 12: R106, Lee et al. 2008; PLoS ONE 3(11): e3712). In studies that obtained serial blood samples, the fall in pGSN levels occurred rapidly after the initial insult and prior to the development of subsequent complications such as the development of sepsis syndrome, and remained depressed for days to weeks, usually until the patient began recovering. Furthermore, the degree of pGSN depletion is inversely associated with the severity of disease (Lee et al. 2006; Ann Surg 243: 399–403, Wang et al. 2008; Crit Care Med 12: R106).
Gelsolin levels were measured in patients with acute liver failure (n = 18), chronic hepatitis (n = 17), cirrhosis (n = 17), pancreatitis (n = 10), acute myocardial infarction (n = 10), myonecrosis (n = 12) and septic shock and compared to 25 healthy volunteers (Suhler et al: 1997; Crit Care Med 25: 594-598). Significant reductions in gelsolin compared to normal controls were seen in patients with acute liver failure, myocardial infarction, sepsis and myonecrosis. Additionally, there was an inverse correlation between the gelsolin concentration and the severity of illness measured by the magnitude of disease specific serum enzymes.
The degree of pGSN depletion also identifies those patients with serious, acute disease at highest risk for poor outcomes including death.
Concentrations of were assessed serially in 31 patients admitted to the Surgical ICU (Lee et al: 2006; Ann Surg 243: 399–403). Baseline pGSN (prior to the development of complications in most patients) were low in all patients but statistically lower in the group that subsequently died when compared to those who survived.
Low baseline pGSN levels (defined as less than 61 mg/L) in patients predicted longer ICU stay (measured as days alive out of the ICU to avoid confusion between early discharge for death and for recovery) and prolonged ventilator dependence (measured as hours alive off mechanical ventilation to avoid confusion between early discharge for death and for recovery).
The pGSN levels were rapidly depressed and remained low through the 5 days of follow-up in sharp contrast to the cytokine fluctuations that are seen in patients with sepsis syndrome.
This finding was confirmed in a 91 patient study of patients admitted with severe sepsis (Wang et al: 2008; Crit Care Med 12: R106) in which pGSN were low at admission to the ICU and remained low until recovery or death.
Again in this study, there was a progressive decrease in baseline pGSN between controls, critical illness without sepsis and severe sepsis syndrome.
In 65 patients with severe trauma, the admission gelsolin levels were depressed and the gelsolin level was inversely correlated with the duration of mechanical ventilation the duration of ICU stay and the total hospital stay (Mounzer et al: 1999; Am J Respir Crit Care Med 160: 1673-1681). Patients developing acute respiratory distress syndrome (ARDS) and dying had statistically significant lower admission pGSN levels than those without these complications.
In this study, low pGSN levels were defined as levels less than 2 standard deviations below the mean of the control group (low gelsolin levels).
Ten of the 13 patients (77%) with low baseline pGSN levels had “bad outcomes,” defined as mechanical ventilation for >13 days in the Trauma Intensive Unit, the development of ARDS, and/or death.
Recently (Lee et al. 2008; PLoS ONE 3: e3712), the baseline pGSN at the time of admission to the ICU in patients with sepsis was statistically lower in the patients who ultimately die compared to those who lived.
The level of pGSN predicts outcomes in patients with subacute illness as well as acute conditions. In 24 patients undergoing allogeneic hematopoietic stem cell transplantation the mean pGSN levels fell immediately after surgery. By 3 weeks, the pGSN levels remained low in the 9 patients dying of idiopathic pneumonia syndrome (IPS) within 3 months of transplantation while they rose to near-normal levels in the patients who did not develop IPS (DiNubile et al: 2002; Blood 100: 4367-4371).
The local depletion of pGSN at the site of inflammation is predicted by the current hypothesized mechanism of action for pGSN (see "Proposed Mechanism of Action") and the role of pGSN in chronic inflammatory disease was recently demonstrated in rheumatoid arthritis (RA; Osborn et al. 2008; Arthritis Res Ther 10: R117). These researchers demonstrated that the pGSN levels in synovial fluid (SF) of RA joints were markedly depressed while the serum levels were depressed compared to normal controls but less so that the joints.
Finally, CBC is particularly excited with the results of a recent case-control study in patients starting hemodialysis for end stage renal disease. In this study, a pGSN level drawn within 2 weeks of the initiation of hemodialysis proved to be an extremely powerful predictor of death over the next 12 months even after adjusting for all routine prognostic factors (Lee et al; 2009; J Am Soc Nephrology, in press). This correlation was even more extreme in the subset of patients starting hemodialysis with vascular access obtained by means of a catheter rather than an A-V shunt or fistula.
