Gelsolin is a six-domain (G1-G6) multifunctional actin assembly regulator protein. It exists as three isoforms in humans which include two cytoplasmic and one extracellular isoform secreted into plasma. All these isoforms are encoded by a single gene located on chromosome 9 in humans. The major functions of cytoplasmic gelsolin involve actin depolymerization as well as nucleation primarily regulated by calcium, pH and phosphoinositides (Ashish et al, 2007; Garg et al, 2011; Peddada et al, 2013). To initiate polymerization, it binds to two globular actin monomers (G-actin) and to affect actin depolymerization function, it binds to filamentous actin (F-actin), severs the filament by weakening non-covalent bonds between the actin monomers and remains attached to the barbed end of filament as a cap to prevent subsequent elongation (Yin & Stull, 1999).
In plasma, gelsolin is primarily involved in the rapid severing and removal of actin filaments released from dead cells into the blood stream. Plasma gelsolin [pGSN] thus serves a protective role by clearing toxic circulating filamentous-actin released in blood due to cell necrosis (Lee & Galbraith, 1992). In addition, plasma gelsolin also has the ability to bind to a variety of proinflammatory and bioactive molecules including lyso-phosphatidic acid, sphingosine 1-phosphate, fibronectin and platelet activating factor in the body which act as mediators of many physiological functions including wound healing, neurologic development, cancer progression and angiogenesis (Bucki et al, 2010; Lind & Janmey, 1984; Lind et al, 1988; Osborn et al, 2007). pGSN has been suggested to thus sequester these bioactive mediators of inflammation and localize inflammatory and immune reactions to the sites of injury. Apart from these bioactive molecules, pGSN has the ability to bind to the bacterial surface lipids, lipoteichoic acid (LTA) and lipopolysaccharide, (LPS) which belong to Gram-positive and Gram-negative bacteria, respectively (Bucki et al, 2008; Bucki et al, 2005). This interaction compromises the ability of LTA and LPS to mediate innate immune responses in the host (Bucki et al, 2008).
Human plasma gelsolin circulates in blood at a concentration of ˜200 μg/ml (Osborn et al, 2008). Clinical significance and the therapeutic importance of this protein have been well illustrated in animal models as well as in patients with various diseases. A significant decrement (20-50%) in plasma gelsolin levels has been documented in a variety of illnesses or health complications which include major to minor trauma, burn, acute respiratory distress syndrome (ARDS), acute lung injury, acute liver injury, surgery, sepsis, hepatitis, malaria, MODS (including myocardial infarction, septic shock and myonecrosis), allogenic stem cell transplantation, and multiple sclerosis (Peddada et al, 2012). Moreover, the plasma gelsolin levels have been found to be increasing in patients recovering from the diseases. Furthermore, it has been confirmed that repletion with exogenous recombinant gelsolin significantly increases the survival rate in animal models of different acute insults (Lee et al, 2007).
On the whole, all these studies aimed at investigating the correlation of pGSN level with the severity of health problem as well as clinical outcomes suggest that: 1) pGSN level declines after a cellular injury either due to surgery, inflammation or infection and this decline correlates very well with the extent of cellular injury, 2) pGSN levels declining below a critical level greatly enhance the risk of mortality, thus based upon the admission pGSN levels, exogenous gelsolin could be administered in the patients, having critically low pGSN levels, to improve their chances of survival. Thus, pGSN holds an immense potential as an excellent prognostic biomarker for multiple health conditions as well as a therapeutically relevant protein to improve the patient's health status.
However, without knowing the exact plasma gelsolin levels of healthy individuals as well as the patient, gelsolin replacement therapy can not be a reality. Existing commercial kits for the estimation of gelsolin levels in a given sample use the method of sandwich ELISA [enzyme linked immunosorbent assay]. Briefly, gelsolin specific antibodies are coated onto the ELISA plates, these are then used for the binding of gelsolin present in standards and test samples. The bound gelsolin is then detected by using a biotin labeled anti-gelsolin antibody and streptavidin-horse radish peroxidase conjugate. Nevertheless, all these kits are intended for research use only and not for diagnostic purposes.
In short, it may be summarized that till now, no affordable, accurate and accelerated diagnostic method exists in the literature, which can be reliably used for the determination of plasma gelsolin levels of humans and other animals. Considering the emerging need to measure plasma gelsolin levels in different disease or stress conditions and therapeutic potential of injecting exogenous gelsolin and/or its forms to improve patient condition, the role of aptamers in quantifying and purifying gelsolin and its variants holds great translation potential and has not been reported till date.