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
Tissue Effects of pGSN Repletion
Plasma gelsolin (pGSN) levels fall in a wide variety of animal models of serious injury by 50-95%. This level of depletion is comparable to that reported in patients (see “pGSN Levels in Disease”). The measured mean pGSN level in healthy and injured animals is shown below for animals undergoing fatal lipopolysaccharide (LPS, endotoxin) challenge, fatal cecal ligation and puncture (CLP, a polymicrobial peritonitis), hyperoxia for 72 hours causing severe lung injury and a 40% body surface burn models. The tissue effects of replenishment of the critically depleted levels for the LPS, hyperoxia and burn models are shown below while the impact on survival in the two fatal models (LPS and CLP) is shown on the “Survival Effects of pGSN Repletion” page.
These findings demonstrate an association between depleted pGSN levels and poor outcomes making low pGSN levels a potentially useful biomarker. This association, however, cannot establish a causative link between the two. To establish such a link in animal studies, it is necessary to show that replenishment of the depressed levels of pGSN ameliorates the physiologic derangements and the outcomes of the major insults in these experimental models. CBC's human recombinant form of pGSN, rhu-pGSN also known as Solinex™, has been made available for animal studies for this purpose.
LPS:
In the lipopolysaccharide (LPS, endotoxin) challenge study, subcutaneous administration of rhu-pGSN to the mice at baseline and 24 hours increased the circulating pGSN levels to near-normal levels (Lee et al. 2007; Crit Care Med 35: 849-55).
The effect of rhu-pGSN replenishment of the natural pGSN levels dramatically decreased the mortality from 100% to 88% (see “Survival Effects of pGSN Repletion
”). Associated with this improvement in outcome, pGSN repletion suppressed the pro-inflammatory cytokine, IL-1β, indicating a reduction in the systemic inflammatory stimulation.
Hyperoxia:
Mice exposed to 95% oxygen for 72 hours develop severe lung injury associated with pulmonary edema, congestion, hemorrhage and neutrophil accumulation (Christofidou-Solomidou et al. 2002; J Investig Med 50: 54-60). Mice were exposed to hyperoxia and at 24 and 48 hours were given an IV administration of either rhu-pGSN or a bovine serum albumin control. Histologically, rhu-pGSN dramatically ameliorates the pulmonary edema, pulmonary congestion and hemorrhage (histology sections seen on panels a-c), and a marked diminution of the neutrophil accumulation in the bronco-alveolar lavage samples (spun BAL sample under magnification in panels e-f).
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These improvements are confirmed using object scoring of the degree of histological abnormality and scoring of the gross pathology was measured with an acute lung injury (ALI) score.
Burns:
Rats were randomized to undergo a 40% body surface area thermal injury, the burn group, or manipulation without burn, the sham group (Rothenbach et al. 2002; J Appl Physiol 96: 25-31) Animals were randomized to receive either rhu-pGSN (0.078, 0.78, or 7.8 mg) or albumin (7.8 mg) before and 8 hours after their burn or sham manipulation. Twenty-four hours later, pulmonary microvascular permeability was assessed by measuring the capillary filtration by use of an isolated, perfused lung model.
As seen, treatment of burned animals with intravenous infusions of rhu-pGSN prevented, in a dose-dependent fashion, the increase in pulmonary microvascular permeability that accompanies this injury. These findings are consistent with the hypothesis that pGSN depletion contributes to the pathophysiology of pulmonary microvascular dysfunction during inflammation and repletion can ameliorate the degree of inflammatory damage suffered after a major burn.
CBC has sponsored an ongoing phase 2a pharmacokinetic study of rhu-pGSN in critical ill patients admitted to the ICU without signs of sepsis syndrome but who are at high risk of complications based on a documented pGSN level <3,000 mU/ml as measured by the research SolinDx™ ELISA assay (approximately equal to <100 mg/L in the functional assay). The first cohort of 10 patients receiving 3 mg/kg of rhu-pGSN and 3 placebo patients has been completed and the preliminary results are available. The purpose of the trial was to assess the pharmacokinetics of rhu-pGSN in patients with acute depletion of their natural reserve of pGSN. It was not powered to examine biochemical or clinical outcomes. Nonetheless, a panel of cytokines was drawn as part of the protocol. Although none of the differences between the two treatment groups are statistically significant, the mean pro-inflammatory cytokine levels appear to increase over the first 24 hours in the placebo group but decrease in the rhu-pGSN group. This is directionally exactly as expected if pGSN is acting as a general inflammatory modulator. It is important to realize, however, that the small sample size precludes any definitive conclusions from being made at this time.
