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Effect of rising dose of Serp-1 on macrophage infiltration at 7 days post-injury. (A) Clinical scores. Clinical testing on SCI rats was performed starting at day one post-SCI and then each day for 6 days. The hind end locomotor test was performed as described in Table 2 and the hind limbs pinch withdrawal test was performed as described in Table 3. The daily scoring results in graphs indicate no beneficial effect of Serp-1 treatment. The body weights were taken before the SCI surgery then at days 3 and 7 post-SCI and are expressed as percent of the pre-SCI body weight of individual rats. (B) Histologic analysis. Histology of spinal cords 7 days post-SCI infused subdurally with saline (1-3), 8 µg Serp-1 (4-6) and 200 µg Serp-1 (7-9) reveals large areas of damage including cavities of injury (COI, *) delineated by surrounding tissue (>) and infiltrated by numerous macrophages laden with blue granules of myelin in luxol fast blue and hematoxylin and eosin (LFB + H&E stain) (middle column). Large proportion of macrophages in the COI are CD68+ (right column, brown color). While in the saline treatment macrophages in the COI are numerous (2,3), in the Serp-1 treatment at 200 µg the numbers of macrophages are lower on CD68+ labelling (9) and the amount of un-phagocytized myelin-rich necrotic debris is markedly greater (8). Luxol fast blue with hematoxylin and eosin counterstain (LFB + H&E)-two left columns. Anti-CD68 antibody stain, the right column. Size bars-

Effect of rising dose of Serp-1 on macrophage infiltration at 7 days post-injury. (A) Clinical scores. Clinical testing on SCI rats was performed starting at day one post-SCI and then each day for 6 days. The hind end locomotor test was performed as described in Table 2 and the hind limbs pinch withdrawal test was performed as described in Table 3. The daily scoring results in graphs indicate no beneficial effect of Serp-1 treatment. The body weights were taken before the SCI surgery then at days 3 and 7 post-SCI and are expressed as percent of the pre-SCI body weight of individual rats. (B) Histologic analysis. Histology of spinal cords 7 days post-SCI infused subdurally with saline (1-3), 8 µg Serp-1 (4-6) and 200 µg Serp-1 (7-9) reveals large areas of damage including cavities of injury (COI, *) delineated by surrounding tissue (>) and infiltrated by numerous macrophages laden with blue granules of myelin in luxol fast blue and hematoxylin and eosin (LFB + H&E stain) (middle column). Large proportion of macrophages in the COI are CD68+ (right column, brown color). While in the saline treatment macrophages in the COI are numerous (2,3), in the Serp-1 treatment at 200 µg the numbers of macrophages are lower on CD68+ labelling (9) and the amount of un-phagocytized myelin-rich necrotic debris is markedly greater (8). Luxol fast blue with hematoxylin and eosin counterstain (LFB + H&E)-two left columns. Anti-CD68 antibody stain, the right column. Size bars-

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Spinal cord injury (SCI) initiates a severe, destructive inflammation with pro-inflammatory, CD68+/CD163−, phagocytic macrophages infiltrating the area of necrosis and hemorrhage by day 3 and persisting for the next 16 weeks. Inhibition of macrophage infiltration of the site of necrosis that is converted into a cavity of injury (COI) during the fir...

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... results of the 7 day long dosing study are summarized in the Figure 1. counted and the average for each rat in a treatment group (Table 1) was averaged and standard deviation calculated [3,4]. ...
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... results of the 7 day long dosing study are summarized in the Figure 1. Clinical testing on SCI rats was performed starting at day one post-SCI and then each day for 6 days. ...
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... antibody stain, the right column. Size bars- Figure 1. Effect of rising dose of Serp-1 on macrophage infiltration at 7 days post-injury. ...
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... infiltration in form of the COI, (asterix in Figure 1B) and of arachnoiditis obliterated large areas of the spinal cord 7 days post-SCI. In the COI of rats infused with saline there were numerous large phagocytic cells with oval, sometimes subcleaved nucleus and abundant cytoplasm containing blue granules of myelin and/or red blood cells ( Figure 1B2). ...
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... infiltration in form of the COI, (asterix in Figure 1B) and of arachnoiditis obliterated large areas of the spinal cord 7 days post-SCI. In the COI of rats infused with saline there were numerous large phagocytic cells with oval, sometimes subcleaved nucleus and abundant cytoplasm containing blue granules of myelin and/or red blood cells ( Figure 1B2). These cells were tightly packed in the periphery of COI leaving little unphagocytized myelin-rich material and scattered blood cells. ...
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... cells were tightly packed in the periphery of COI leaving little unphagocytized myelin-rich material and scattered blood cells. Large proportion of infiltrating cells were CD68+ (Figure 1B3), marker for pro-inflammatory macrophages [16,17]. The numbers of phagocytic macrophages were lower in the COI of rats infused with 8 µg of Serp-1 ( Figure 1B5,6) and markedly lower in rats infused with 200 µg of Serp-1 ( Figure 1B8,9) with large amounts of myelin-rich necrotic debris and red blood cells between scattered macrophages ( Figure 1B8) further supporting the observation of inhibition of active macrophage phagocytosis. ...
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... proportion of infiltrating cells were CD68+ (Figure 1B3), marker for pro-inflammatory macrophages [16,17]. The numbers of phagocytic macrophages were lower in the COI of rats infused with 8 µg of Serp-1 ( Figure 1B5,6) and markedly lower in rats infused with 200 µg of Serp-1 ( Figure 1B8,9) with large amounts of myelin-rich necrotic debris and red blood cells between scattered macrophages ( Figure 1B8) further supporting the observation of inhibition of active macrophage phagocytosis. ...
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... proportion of infiltrating cells were CD68+ (Figure 1B3), marker for pro-inflammatory macrophages [16,17]. The numbers of phagocytic macrophages were lower in the COI of rats infused with 8 µg of Serp-1 ( Figure 1B5,6) and markedly lower in rats infused with 200 µg of Serp-1 ( Figure 1B8,9) with large amounts of myelin-rich necrotic debris and red blood cells between scattered macrophages ( Figure 1B8) further supporting the observation of inhibition of active macrophage phagocytosis. ...
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... proportion of infiltrating cells were CD68+ (Figure 1B3), marker for pro-inflammatory macrophages [16,17]. The numbers of phagocytic macrophages were lower in the COI of rats infused with 8 µg of Serp-1 ( Figure 1B5,6) and markedly lower in rats infused with 200 µg of Serp-1 ( Figure 1B8,9) with large amounts of myelin-rich necrotic debris and red blood cells between scattered macrophages ( Figure 1B8) further supporting the observation of inhibition of active macrophage phagocytosis. ...
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... standardized macrophage counts were lower for all levels of treatment with Serp-1 ( Figure 1C) with the greatest inhibitory effect at 200 µg/week (p < 0.001) and this amount of Serp-1 was used in the next phase of the study to determine the therapeutic effect of the prolonged infusion (See Figure 2). It was shown previously that subdural infusion of 1.0 mg/week of Serp-1 did not result in greater inhibition of macrophage infiltration in the COI [3]. ...
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... 14 days post-SCI, the COIs were infiltrated with numerous phagocytic macrophages with no extracellular necrotic debris or red blood cells in saline treated rats ( Figure 2B2) but lower numbers of macrophages were scattered among necrotic debris in Serp-1 treated rats ( Figure 2B5) indicating inhibitory effect on macrophage infiltration and phagocytosis. At 28 days post-SCI, the numbers of macrophages were markedly lower in the COI in both treatment groups ( Figure 2B7,10) and extracellular debris still evident in Serp-1 treatment ( Figure 2B11). At 56 days, numbers of phagocytic macrophages were again reduced in saline treatment rats ( Figure 2B13,14) and rare in Serp-1 rats ( Figure 2B17,18). ...
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... 14 days post-SCI, the COIs were infiltrated with numerous phagocytic macrophages with no extracellular necrotic debris or red blood cells in saline treated rats ( Figure 2B2) but lower numbers of macrophages were scattered among necrotic debris in Serp-1 treated rats ( Figure 2B5) indicating inhibitory effect on macrophage infiltration and phagocytosis. At 28 days post-SCI, the numbers of macrophages were markedly lower in the COI in both treatment groups ( Figure 2B7,10) and extracellular debris still evident in Serp-1 treatment ( Figure 2B11). At 56 days, numbers of phagocytic macrophages were again reduced in saline treatment rats ( Figure 2B13,14) and rare in Serp-1 rats ( Figure 2B17,18). ...
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... 28 days post-SCI, the numbers of macrophages were markedly lower in the COI in both treatment groups ( Figure 2B7,10) and extracellular debris still evident in Serp-1 treatment ( Figure 2B11). At 56 days, numbers of phagocytic macrophages were again reduced in saline treatment rats ( Figure 2B13,14) and rare in Serp-1 rats ( Figure 2B17,18). The COIs in the Serp-1 rats appeared as similar cavities in untreated rats at 16 weeks post-SCI [4], and were reminiscent of mature syrinxes. ...
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... 28 days post-SCI, the numbers of macrophages were markedly lower in the COI in both treatment groups ( Figure 2B7,10) and extracellular debris still evident in Serp-1 treatment ( Figure 2B11). At 56 days, numbers of phagocytic macrophages were again reduced in saline treatment rats ( Figure 2B13,14) and rare in Serp-1 rats ( Figure 2B17,18). The COIs in the Serp-1 rats appeared as similar cavities in untreated rats at 16 weeks post-SCI [4], and were reminiscent of mature syrinxes. ...
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... 14 days post-SCI, the COIs were infiltrated with numerous phagocytic macrophages with no extracellular necrotic debris or red blood cells in saline treated rats ( Figure 2B2) but lower numbers of macrophages were scattered among necrotic debris in Serp-1 treated rats ( Figure 2B5) indicating inhibitory effect on macrophage infiltration and phagocytosis. At 28 days post-SCI, the numbers of macrophages were markedly lower in the COI in both treatment groups ( Figure 2B7,10) and extracellular debris still evident in Serp-1 treatment ( Figure 2B11). At 56 days, numbers of phagocytic macrophages were again reduced in saline treatment rats ( Figure 2B13,14) and rare in Serp-1 rats ( Figure 2B17,18). ...
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... 14 days post-SCI, the COIs were infiltrated with numerous phagocytic macrophages with no extracellular necrotic debris or red blood cells in saline treated rats ( Figure 2B2) but lower numbers of macrophages were scattered among necrotic debris in Serp-1 treated rats ( Figure 2B5) indicating inhibitory effect on macrophage infiltration and phagocytosis. At 28 days post-SCI, the numbers of macrophages were markedly lower in the COI in both treatment groups ( Figure 2B7,10) and extracellular debris still evident in Serp-1 treatment ( Figure 2B11). At 56 days, numbers of phagocytic macrophages were again reduced in saline treatment rats ( Figure 2B13,14) and rare in Serp-1 rats ( Figure 2B17,18). ...
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... 28 days post-SCI, the numbers of macrophages were markedly lower in the COI in both treatment groups ( Figure 2B7,10) and extracellular debris still evident in Serp-1 treatment ( Figure 2B11). At 56 days, numbers of phagocytic macrophages were again reduced in saline treatment rats ( Figure 2B13,14) and rare in Serp-1 rats ( Figure 2B17,18). The COIs in the Serp-1 rats appeared as similar cavities in untreated rats at 16 weeks post-SCI [4], and were reminiscent of mature syrinxes. ...
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... 28 days post-SCI, the numbers of macrophages were markedly lower in the COI in both treatment groups ( Figure 2B7,10) and extracellular debris still evident in Serp-1 treatment ( Figure 2B11). At 56 days, numbers of phagocytic macrophages were again reduced in saline treatment rats ( Figure 2B13,14) and rare in Serp-1 rats ( Figure 2B17,18). The COIs in the Serp-1 rats appeared as similar cavities in untreated rats at 16 weeks post-SCI [4], and were reminiscent of mature syrinxes. ...
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... 14 days post-SCI, the COIs were infiltrated with numerous phagocytic macrophages with no extracellular necrotic debris or red blood cells in saline treated rats ( Figure 2B2) but lower numbers of macrophages were scattered among necrotic debris in Serp-1 treated rats ( Figure 2B5) indicating inhibitory effect on macrophage infiltration and phagocytosis. At 28 days post-SCI, the numbers of macrophages were markedly lower in the COI in both treatment groups ( Figure 2B7,10) and extracellular debris still evident in Serp-1 treatment ( Figure 2B11). At 56 days, numbers of phagocytic macrophages were again reduced in saline treatment rats ( Figure 2B13,14) and rare in Serp-1 rats ( Figure 2B17,18). ...
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... 14 days post-SCI, the COIs were infiltrated with numerous phagocytic macrophages with no extracellular necrotic debris or red blood cells in saline treated rats ( Figure 2B2) but lower numbers of macrophages were scattered among necrotic debris in Serp-1 treated rats ( Figure 2B5) indicating inhibitory effect on macrophage infiltration and phagocytosis. At 28 days post-SCI, the numbers of macrophages were markedly lower in the COI in both treatment groups ( Figure 2B7,10) and extracellular debris still evident in Serp-1 treatment ( Figure 2B11). At 56 days, numbers of phagocytic macrophages were again reduced in saline treatment rats ( Figure 2B13,14) and rare in Serp-1 rats ( Figure 2B17,18). ...
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... 28 days post-SCI, the numbers of macrophages were markedly lower in the COI in both treatment groups ( Figure 2B7,10) and extracellular debris still evident in Serp-1 treatment ( Figure 2B11). At 56 days, numbers of phagocytic macrophages were again reduced in saline treatment rats ( Figure 2B13,14) and rare in Serp-1 rats ( Figure 2B17,18). The COIs in the Serp-1 rats appeared as similar cavities in untreated rats at 16 weeks post-SCI [4], and were reminiscent of mature syrinxes. ...
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... 28 days post-SCI, the numbers of macrophages were markedly lower in the COI in both treatment groups ( Figure 2B7,10) and extracellular debris still evident in Serp-1 treatment ( Figure 2B11). At 56 days, numbers of phagocytic macrophages were again reduced in saline treatment rats ( Figure 2B13,14) and rare in Serp-1 rats ( Figure 2B17,18). The COIs in the Serp-1 rats appeared as similar cavities in untreated rats at 16 weeks post-SCI [4], and were reminiscent of mature syrinxes. ...
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... both studies, a beneficial effect of Serp-1 administration was observed and supported by lower counts of macrophages in the COI infused with Serp-1 [3] and reduced size of the crush injury with Serp-1 hydrogel [9]. In the present study however, both tests revealed no higher scores for Serp-1 treatments for 7 days ( Figure 1A) and for 56 days (Figure 2A) despite the macrophage counts and histologic analysis consistently indicating anti-inflammatory effect of Serp-1 infusion. It needs to be highlighted that for both Serp-1 and saline treatments, the scores in both neurological tests used in this study stabilized during the week 4 of the treatment and did not change during the remaining 4 weeks (Figure 2A) despite the histologic evidence of active inflammatory disease. ...

Citations

... The Myxoma virus-derived serpin, Serp-1, binds and inhibits uPA/uPAR in activated macrophages, and has some shared protease targets with PAI-1 [39]. Treatment with purified native Serp-1 has demonstrated both acute and long-term efficacy in modulating inflammation in a wide range of inflammatory disorders and injuries, including atherosclerosis, transplant, wound healing, and spinal cord injury [39][40][41][42]. More recently, a modified Serp-1 protein, PEGSerp-1, with a longer halflife (~8 h), was shown to reduce inflammation and fibrosis in healing corneal wounds, and reduced macrophage invasion of alveoli in a mouse model of diffuse alveolar hemorrhage [43][44][45]. ...
... We examined whether a pegylated version of the Myxoma virus serpin, Serp-1, would ameliorate the chronic inflammatory environment in DMD mdx /Utrn −/− mice. This protein has been shown to induce an anti-inflammatory response in wound healing, transplants, and other acute injuries without any demonstrated increase in adverse effects in multiple animal models and in one Phase IIa clinical trial [39][40][41][42][43][44][45]52,53]. Systemic PEGSerp-1 treatment of DKO mice significantly decreased muscle fibrosis and the number of infiltrating M1 pro-inflammatory macrophages. ...
... Thus, targeting the uPA/uPAR complex with Serp-1, and investigating all associated interacting component receptors in the inflammatory response, has excellent potential for developing new therapeutics. The native Serp-1 protein has been tested and found safe and effective in animal models of inflammatory vascular disorders, transplants, wound healing, and after spinal cord crush injury [39][40][41][42]. In humans, Serp-1 treatment following coronary artery stent implant in a Phase 2a clinical trial demonstrated reduced markers of heart damage, no side effects (MACE = 0), and no neutralizing antibodies at µg/kg doses in patients. ...
Article
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Duchenne muscular dystrophy is an X-linked disease afflicting 1 in 3500 males that is characterized by muscle weakness and wasting during early childhood, and loss of ambulation and death by early adulthood. Chronic inflammation due to myofiber instability leads to fibrosis, which is a primary cause of loss of ambulation and cardiorespiratory insufficiency. Current standard of care focuses on reducing inflammation with corticosteroids, which have serious adverse effects. It is imperative to identify alternate immunosuppressants as treatments to reduce fibrosis and mortality. Serp-1, a Myxoma virus-derived 55 kDa secreted glycoprotein, has proven efficacy in a range of animal models of acute inflammation, and its safety and efficacy has been shown in a clinical trial. In this initial study, we examined whether pegylated Serp-1 (PEGSerp-1) treatment would ameliorate chronic inflammation in a mouse model for Duchenne muscular dystrophy. Our data revealed a significant reduction in diaphragm fibrosis and increased myofiber diameter, and significantly decreased pro-inflammatory M1 macrophage infiltration. The M2a macrophage and overall T cell populations showed no change. These data demonstrate that treatment with this new class of poxvirus-derived immune-modulating serpin has potential as a therapeutic approach designed to ameliorate DMD pathology and facilitate muscle regeneration.
... Since infusion of dexamethasone resulted in severe toxicity (Kwiecien et al., , 2019, this powerful synthetic glucocorticoid is not suitable for long term sustained administration. An 8 week long subdural infusion of Serp-1 lowered the numbers of macrophages throughout the administration and essentially eliminated them from the COI thus reducing the duration of inflammation by half considered a neuroprotective effect (Kwiecien et al., 2020b). This is the first preclinical study indicating the required duration of sustained administration of an anti-inflammatory agent, 8 weeks, to eliminate inflammation from the COI. ...
... Several studies focus on methods to intensify the protective effects of inflammation. Recent publications show positive effects of several drugs such as minocycline, melatonin, statins, subdural infusion of serpine-1, mesenchymal stem cells therapy [124][125][126][127][128][129]. All of these therapies can modulate a neuroinflammatory response, which may affect NLR. ...
Article
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Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide. The consequences of a TBI generate the activation and accumulation of inflammatory cells. The peak number of neutrophils entering into an injured brain is observed after 24 h; however, cells infiltrate within 5 min of closed brain injury. Neutrophils release toxic molecules including free radicals, proinflammatory cytokines, and proteases that advance secondary damage. Regulatory T cells impair T cell infiltration into the central nervous system and elevate reactive astrogliosis and interferon-γ gene expression, probably inducing the process of healing. Therefore, the neutrophil-to-lymphocyte ratio (NLR) may be a low-cost, objective, and available predictor of inflammation as well as a marker of secondary injury associated with neutrophil activation. Recent studies have documented that an NLR value on admission might be effective for predicting outcome and mortality in severe brain injury patients.
... There are numerous potential pharmacological neuroprotective agents that are being investigated in animal and clinical trials, which include estrogen, riluzole, glibenclamide, cetherin, fumaric acid esters, endaravone, N-Palmythiolethalomine-oxazoline, and mytramycine A. These candidate treatments so far have been used only in the short term, and their efficacy with respect to long-term inflammatory changes is yet to be seen. Recently, Serp-1 and M-T7 (myxoma virus-derived immunomodulatory proteins) have been studied in rat model SCI, including longer-term intradural infusion, with improvement in inflammatory changes pathologically [7,12]. ...
... Since anti-inflammatory agents can inhibit [9][10][11] and, after 8 weeks of administration, eliminate [12] severe inflammation in the spinal cord in a rat model, neuroimaging used in a systematic fashion can monitor the neuroprotective effect of candidate anti-inflammatory agents in clinical trials, involving SCI and TBI patients. In addition, magnetic resonance imaging (MRI) may prove very useful for monitoring edema around the areas of inflammation that apparently persist as long as inflammatory macrophages persist, which is greater than 16 weeks in the rat [8], indicating inflammatory vascular damage and vasogenic edema [13]. ...
... These putative mechanisms need to be considered in the imaging of chronic neurotrauma patients for proper diagnostic interpretation. Recent progress with anti-inflammatory treatment of SCI [11,12] and its potentially beneficial effect in inhibiting vasogenic edema [13] may prove to enhance the importance of MRI in clinical trials involving SCI and TBI patients. Kwiecien et al. described differentiating COI and fibrous scarring of arachnoiditis in rats, and it may be possible to identify in vivo in humans on T2-weighted imaging as the fluid-filled COI should have greater T2 hyperintensity than adjacent scarring [8]. ...
Article
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Traumatic injuries of the brain and spinal cord are a significant source of mortality and long-term disability. A recent systematic study in a rat model of spinal cord injury (SCI) indicates severe, destructive, and very protracted inflammation as the key mechanism initiated by the massive injury involving the white matter. Although the severe inflammation is localized and counteracted by astrogliosis, it has a damaging effect on the blood vessels in the surrounding spinal cord, leading to persistent vasogenic edema. To evaluate these injuries, imaging of the brain and spinal cord plays a crucial role in the acute trauma work-up, allowing clinicians to quickly identify abnormalities that require immediate medical or surgical intervention or to exclude them from the work-up. Recently, anti-inflammatory agents have been shown to inhibit and accelerate the elimination of post-SCI inflammation in preclinical studies, and an exciting potential has arisen for the use of anti-inflammatory drugs in clinical studies to achieve neuroprotection (i.e., inhibition of destruction caused by inflammation) and to inhibit vasogenic edema in SCI, traumatic brain injury, and stroke. In both subacute and chronic settings, imaging can be a guide to therapy and provide important prognostic information. In this review, we discuss the imaging work-up and evolving imaging findings of neurotrauma in the acute and chronic setting, including conventional and advanced imaging techniques. As neuroimaging is the primary mode of diagnostic analysis in neurotrauma, it is a critical component in future clinical trials evaluating neuroprotective therapies.
... We have been developing these naturally evolved viral immune-modulating proteins as a new class of therapeutics. Two of the most effective pathways around which virus-derived immune modulators have been developed are the serpins [160][161][162][163][164][165][166][167][168][169][170][171][172][173][174] and the chemokine modulators [175][176][177][178][179][180][181]. ...
... Several genes identified in Myxomavirus enhance virus pathogenicity and have proven highly effective in targeting key immune response pathways. The immune response pathways targeted by viruses are often central regulatory pathways, allowing the virus to effectively escape the host immune response [63,[160][161][162][163][164][165][166][167][168][169][170][171][172][173][174]. ...
... Serpins expressed by poxviruses target thrombotic and thrombolytic proteases as noted above, as well as apoptotic pathways, often displaying marked efficacy and potency. Myxoma virus encodes two such serpins, Serp-1 and Serp-2 that have been studied in animal models of inflammatory disease [160][161][162][163][164][165][166][167][168][169][170][171][172][173][174]. Serp-1 is a 55 kDa glycosylated secreted serpin that binds tPA, uPA, plasmin, factor X, and thrombin inhibiting immune responses driven by both clots forming and clot-dissolving cascades (Fig. 4). ...
Article
Full-text available
Progressive neurological damage after brain or spinal cord trauma causes loss of motor function and treatment is very limited. Clotting and hemorrhage occur early after spinal cord (SCI) and traumatic brain injury (TBI), inducing aggressive immune cell activation and progressive neuronal damage. Thrombotic and thrombolytic proteases have direct effects on neurons and glia, both healing and also damaging bidirectional immune cell interactions. Serine proteases in the thrombolytic cascade, tissue- and urokinase-type plasminogen activators (tPA and uPA), as well as the clotting factor thrombin, have varied effects, increasing neuron and glial cell growth and migration (tPA), or conversely causing apoptosis (thrombin) and activating inflammatory cell responses. tPA and uPA activate plasmin and matrix metalloproteinases (MMPs) that break down connective tissue allowing immune cell invasion, promoting neurite outgrowth. Serine proteases also activate chemokines. Chemokines are small proteins that direct immune cell invasion but also mediate neuron and glial cell communication. We are investigating a new class of therapeutics, virus-derived immune modulators; One that targets coagulation pathway serine proteases and a second that inhibits chemokines. We have demonstrated that local infusion of these biologics after SCI reduces inflammation providing early improved motor function. Serp-1 is a Myxomavirus-derived serine protease inhibitor, a serpin, that inhibits both thrombotic and thrombolytic proteases. M-T7 is a virus-derived chemokine modulator. Here we review the roles of thrombotic and thrombolytic serine proteases and chemoattractant proteins, chemokines, as potential therapeutic targets for SCI. We discuss virus-derived immune modulators as treatments to reduce progressive inflammation and ongoing nerve damage after SCI.
... Destructive inflammation involves infiltration of the area of injury by numerous macrophages actively phagocytizing myelin-rich debris and red blood cells that are completely removed by the week 2 post-SCI in the rat model [1]. Administration of antiinflammatory treatments such as dexamethasone, MT-7, or Serp-1, both immunomodulatory proteins derived from Myxomavirus [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], lowers the numbers of infiltrating macrophages and slows down the removal of necrotic debris [20][21][22][23] beyond 2 weeks post-SCI. This observation indicates that for an anti-inflammatory treatment to be an effective neuroprotectant, it needs to be administered for a period of time considerably exceeding 2 weeks post-trauma to allow for slower removal of immunogenic myelin-rich debris by lowered numbers of phagocytic macrophages. ...
... Rather, the inhibition and elimination of the most severe and destructive inflammation in the body may be caused by a CNS tissue reaction, specifically astrogliosis [1,28]. In a recently completed study, subdural infusion of 0.2 mg of Serp-1 per week, sustained for 8 weeks, elimination of CD68+ phagocytic macrophages was accelerated with few macrophages remaining in the COI similar in numbers to those in the COI of untreated rats at 16 weeks post-SCI [1,23]. Importantly, un-phagocytized myelin-rich necrotic debris persisted in the COI at 4 weeks in Serp-1 in-fused rats, indicating a delay of its removal by lowered numbers of macrophages. ...
... Importantly, un-phagocytized myelin-rich necrotic debris persisted in the COI at 4 weeks in Serp-1 in-fused rats, indicating a delay of its removal by lowered numbers of macrophages. The observations made in this study testing Serp-1 anti-inflammatory agent of (1) lowered numbers of macrophages, (2) their accelerated removal from the COI, and (3) extended persistence of myelin-rich necrotic debris, indicating that this treatment was neuroprotective [23]. It needs to be also pointed out that the duration of this treatment needs to be at least 8 weeks to eliminate inflammation and accelerate the formation of the syrinx [23]. ...
Article
The spinal cord injury (SCI) initiates an extraordinarily protracted disease with 3 phases; acute, inflammatory and resolution that are restricted to the cavity of injury (COI) or arachnoiditis by a unique CNS reaction against the severity of destructive inflammation. While the severity of inflammation involving the white matter is fueled by a potently immunogenic activity of damaged myelin, its sequestration in the COI and its continuity with the cerebrospinal fluid of the subdural space allows for anti-inflammatory therapeutics infused subdurally to inhibit phagocytic macrophage infiltration and thus provide neuroprotection. The role of astrogliosis in containing and ultimately in eliminating severe destructive inflammation post-trauma appears obvious but is not yet sufficiently understood to use in therapeutic neuroprotective and neuroregenerative strategies. An apparent anti-inflammatory activity of reactive astrocytes is paralleled by their active role in removing excess edema fluid in blood brain barrier damaged by inflammation. Recently elucidated pathogenesis of neurotrauma including SCI, traumatic brain injury (TBI) and of stroke, calls for the following principal therapeutic steps in its treatment leading to recovery of neurologic function: (1) inhibition and elimination of destructive inflammation from the COI with accompanying reduction of vasogenic edema, (2) insertion into the COI of a functional bridge supporting the crossing of regenerating axons, (3) enabling regeneration of axons to their original synaptic targets by a temporary safe removal of myelin in targeted areas of white matter, (4) in vivo, systematic monitoring of the consecutive therapeutic steps. The focus of this paper is on the therapeutic step 1.
... Based on limited data, there is weak evidence to suggest that hypertonic saline is no better than mannitol in efficacy and safety in the longterm management of acute traumatic brain injury [253]. Since vasogenic edema sustained by inflammation may prove to be refractory to hyperosmolar therapy, and the principle of only 11% of edema fluid shunted into the blood vessels [33,66] has to be taken under consideration, therapeutic inhibition of inflammation [254][255][256][257] and thus of vasogenic edema offers promising perspectives when antiinflammatory agents are available for clinical studies. ...
Article
Traumatic brain injury (TBI) can initiate a very complex disease of the central nervous system (CNS) starting with the primary pathology of the inciting trauma and subsequent inflammatory and CNS tissue response. Delirium has long been regarded as an almost inevitable consequence of moderate to severe TBI, but more recently has been recognized as an organ dysfunction syndrome with potentially mitigating interventions. The diagnosis of delirium is independently associated with prolonged hospitalization, increased mortality and worse cognitive outcome across critically ill populations. Investigation of the unique problems and management challenges of TBI patients is needed to reduce the burden of delirium in this population. In this narrative review, possible etiologic mechanisms behind post-traumatic delirium are discussed, including primary injury to structures mediating arousal and attention and secondary injury due to progressive inflammatory destruction ofthe brain parenchyma. Other potential etiologic contributors include dysregulation of neurotransmission due to intravenous sedatives, seizures, organ failure, sleep cycle disruption or other delirium risk factors. Delirium screening canbe accomplished in TBI patients and presence of delirium portends worse outcomes. There is evidence that multicomponent care bundles including an analgesia-prioritized sedation algorithm, regular spontaneous awakening and breathing trials, protocolized delirium assessment, early mobility and family engagement can reduce the burden of ICU delirium. The aim of this review is to summarize the approach to delirium in TBI patients with an emphasis on pathogenesis and management. Emerging CNS-active drug therapies that show promise in preclinicalstudies are highlighted.
... The biomarkers profile, observed in the CSF, collected within 24 h from the injury, also reflects inflammation as the prevalent pathogenic mechanism at this stage of this progressive pathology, that will chronically evolve in neurodegeneration and demyelination. Inflammation is a major player in the so-called "secondary degeneration", that expands the initial damage, sustaining the chronic evolution of the lesion [35], and a recognized, effective target for early pharmacological intervention [36,37]. However, being the traumatic lesion itself, such as the tissue and systemic reaction, a highly personalized process, appropriate biomarker discovery strategy should be based on serial sampling of biological fluids, from injury to stabilization. ...
Article
Full-text available
Although, biomarkers are regarded as an important tool for monitoring injury severity and treatment efficacy, and for predicting clinical evolution in many neurological diseases and disorders including spinal cord injury, there is still a lack of reliable biomarkers for the assessment of clinical course and patient outcome. In this study, a biological dataset of 60 cytokines/chemokines, growth factorsm and intracellular and extracellular matrix proteins, analyzed in CSF within 24 h of injury, was used for correlation analysis with the clinical dataset of the same patients. A heat map was generated of positive and negative correlations between biomarkers and clinical rating scale scores at discharge, and between biomarkers and changes in clinical scores during the observation period. Using very stringent statistical criteria, we found 10 molecules which correlated with clinical scores at discharge, and five molecules, which correlated with changes in clinical scores. The proposed methodology may be useful for generating hypotheses regarding “predictive” and “treatment effectiveness” biomarkers, thereby suggesting potential candidates for disease-modifying therapies using a “bed-to-bench” approach.
... Recent systematic study on the progression of inflammation initiated by the SCI indicates that the CNS response, specifically astrogliosis plays an important role in the inhibition and elimination of infiltrating macrophages, thus eliminating the inflammation [2]. With this in mind, effective anti-inflammatory therapies should result in inhibiting destructive inflammation leading to its accelerated elimination and neuroprotection also reducing edema, neurodegeneration, cognitive deficits and improving overall neurological recovery [22]. It needs to be emphasized that TBI is a pro-inflammatory condition that affects not only the brain, but also impairs functions of other organs including eyes, lung, intestines, myocardium, and vascular circulation with long lasting effects and complications which need to be considered in medical practice [23]. ...
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