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EDITORIAL FOCUS
Merck Research Laboratories, West Point, Pennsylvania
THE ACTIN CYTOSKELETON PROVIDES the scaffolding that allows cells to crawl and eat. Localized dismantling of the semi-rigid interlinked actin filament network is necessary for cell motility and phagocytosis and is regulated by a variety of actin-binding proteins. Gelsolin, as its name implies, was first identified in cytoplasmic extracts as an actin-severing protein that, in the presence of ionized calcium, disassembled actin filaments, thereby increasing cytosolic fluidity. The ubiquitous presence and phylogenetic conservation of gelsolin in motile cells support its essential role as an intracellular regulatory protein. The later unanticipated discovery of substantial quantities of gelsolin in mammalian plasma was at first reflexively dismissed as an artifact of preparation. However, multiple laboratories soon confirmed that plasma indeed contained a factor that depolymerized actin, functionally mimicking intracellular gelsolin. Subsequently, it was recognized that plasma gelsolin contained an extra 23 amino acid residues at the NH2 terminus not present in the cytoplasmic isoform and was preordained to enter into the extracellular space (12, 14, 15, 35). Confident that the natural economy would not expend this effort willy-nilly, researchers embarked on an investigative tour de force to define the physiological role of plasma gelsolin. That journey remains a work in progress, but the paper by Osborn and colleagues (25; see p. 1323 of this issue) in this issue of AJP-Cell Physiology sheds some novel experimental light on a potential mechanism of action for this multifunctional protein. Their basic research may bear translational fruit as the study of plasma gelsolin moves from bench to bedside.
Circulating gelsolin levels decrease shortly after a variety of diverse insults encountered in clinical practice, such as major trauma, hematopoietic stem cell transplantation, extensive burns, prolonged hyperoxia, preterm birth, malaria, and sepsis (5, 7, 8, 13, 16, 18, 20, 30, 31). In many cases, the initial injury is followed by a second wave of complications hours to days later, resulting in respiratory distress syndrome and/or multi-organ failure (7, 16, 23, 28). These repeated observations prompted a number of relevant phenomenological questions. 1) Do declining gelsolin levels precede or follow the second wave of injury? 2) Does the nadir of the plasma gelsolin concentration provide useful prognostic information above and beyond other acute-phase reactants? 3) Is gelsolin depletion involved in the pathophysiology of late complications or simply an epiphenomenon? And, ultimately, 4) could replenishment of plasma gelsolin during a window of opportunity diminish or abort the injurious cascade?
The time course and magnitude of plasma gelsolin depletion are consistent with the hypothesis that low gelsolin levels result from the original insult and allow the development of secondary complications, the severity of which correlates with the degree of hypogelsolinemia (7, 16, 23). Thus a two-hit model has emerged: the inciting hit causes depletion of gelsolin by overwhelming the body's capacity to keep up with the demand, whereas the second hit results from loss of damage control due to exhaustion of gelsolin stores.
Why then do circulating gelsolin levels fall precipitously after such a heterogeneous spectrum of major injuries? How does plasma gelsolin protect the injured host from escalating damage? The most parsimonious explanation is that a toxic substance released by the original insult both consumes extracellular gelsolin and, subsequently, inflicts further injury. Given that gelsolin had been unfairly pigeonholed to some degree as an actin-scavenging protein, and actin is an abundant intracellular constituent that might plausibly leak from damaged cells with dire consequences, actin seemed a likely culprit for this dual role (18, 24). Actin has been demonstrated in the plasma in certain situations, and resultant gelsolin-actin complexes are rapidly cleared from the circulation (21, 26, 29). Free actin has toxic effects that can be attenuated by gelsolin or Gc-globulin (also known as vitamin D-binding protein) (9, 11). However, actin is not invariably detectable in plasma when gelsolin levels are diminished (23), perhaps because filaments get trapped in the interstitial fluid surrounding sites of cellular disruption. Gelsolin also has other extracellular ligands, most notably anionic lipids such as lysophosphatidic acid and lipopolysaccharides (2, 10). Actin likely contributes to the removal of gelsolin from the circulation primarily by luring it to the site of injury, but whether actin routinely enters the circulation in sufficient quantities to be a direct cause of remote organ damage is less clear.
An array of inflammatory mediators is produced after major injuries, prominently including platelet-activating factor (PAF) (28, 38). The exuberance of the host response can itself become detrimental in many instances (28). Targeting individual components of the proinflammatory cascade (from bacterial lipopolysaccharide through TNF-
, interleukin-1
, and PAF) in randomized, placebo-controlled clinical trials of sepsis has proven mostly disappointing (6, 28). Some of these cytokines as well as gram-negative bacterial endotoxin contain peptide or phospholipid moieties known to bind gelsolin (2, 3, 10, 25). Accordingly, a unique physiological role for plasma gelsolin could derive from its modulation of multiple nonspecific overzealous host responses to serious injury. Gelsolin may also inhibit certain actions of bacterial products when infection is the precipitant (2). The work of Osborn et al. (25) elevates these speculations to empirical observations, providing further mechanistic evidence pertinent to how gelsolin might interrupt the second wave of host-amplified injury (2, 10, 33, 36). Their paper convincingly demonstrates that gelsolin can dampen cellular responses to lysophosphatidic acid and PAF in vitro (25).
Genetically engineered animals missing both intracellular and extracellular gelsolin have been developed to investigate the role of gelsolin in organ injury (37). In experimental models of lung and liver injury, gelsolin-null mice experienced more tissue damage than their wildtype counterparts despite decreased migration of inflammatory cells to the sites of injury (1, 19, 37). Because cytoplasmic gelsolin is essential for normal chemotaxis, a chimeric animal exclusively missing plasma gelsolin would be better suited for dissection of the relative contributions of the deficiencies of each isoform to the pathophysiology. A naturally occurring plasma gelsolin defective in actin-severing activity has been described in a small number of patients diagnosed with familial Finnish-type amyloidosis, but clinical and biochemical studies of this rare entity have not yet revealed any novel clues regarding gelsolin function (22, 34).
The clinical implications of this body of research are also being pursued. Inhalational use of recombinant human gelsolin decreases the viscosity of airway secretions from patients with cystic fibrosis and asthma (3, 32) while potentiating the bactericidal activity of cationic endogenous antimicrobial peptides and exogenous antibiotics (36). Appropriately timed infusions of recombinant human gelsolin can abort evolving injury or reduce mortality rates in animal models of hyperoxia, burns, and sepsis (4, 17, 27). Depressed gelsolin concentrations appear to reliably segregate patients at particularly high risk of secondary complications after many common first hits (7, 8, 16, 18, 31). Preemptive physiological repletion of this normal plasma constituent in patients identified by marked hypogelsolinemia as being at substantial risk for delayed multi-organ dysfunction could provide an efficacious and well-tolerated therapeutic intervention.
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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