Main biomarkers in TBI and their properties.
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"3282",leadTitle:null,fullTitle:"Gangrene Management - New Advancements and Current Trends",title:"Gangrene Management",subtitle:"New Advancements and Current Trends",reviewType:"peer-reviewed",abstract:'Since the book "Gangrene: Current Concepts and Management Options" had been published in August 2011, certain advancements in the field have been observed and several important multicenter studies have been successfully accomplished. 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Every year, 1.1 million Americans are treated in emergency rooms for traumatic brain injury (TBI): 235,000 are hospitalized for nonfatal TBI and 50,000 died. In Finland, a prospective study found that 3.8% of the population had experienced at least one hospitalization due to traumatic brain injury before 35 years of age. Similarly, another study in New Zealand found that at 25 years of age, 31.6% of the population had experienced at least one TBI that required medical attention (hospitalization, emergency department, or doctor’s office). It is estimated that 43.3% of Americans have residual disability 1 year after the damage. The most recent estimate of the prevalence of the US civilian residents living with disability after hospitalization with TBI is 3.2 million [1].
\nTBI is assessed and classified clinically according to the Glasgow Coma Scale (GCS) [2] and by imaging: axial computed tomography (CT) and magnetic resonance imaging (MRI). However, the use of GCS as a diagnostic tool is subject to important limitations, and it is difficult to assess the eye opening in patients with serious lesions on the face; likewise, the verbal response cannot be correctly estimated in individuals who are under the influence of psychoactive drugs and/or alcohol, and in those who are intubated or sedated will have limited linguistic capacities [3]. Given that the severity of the neurological injury may be underestimated in some cases and overestimated in others, attention has been focused on early assessment strategies in patients with TBI and their inaccuracy in special and frequent circumstances [4].
\nIn view of the high rate of intubation and difficulties in the proper evaluation of the eye opening, Stocchetti et al. concluded that motor GCS score was more important than eye opening or verbal responses to predict the severity of the neurological injury. Other recent research has provided evidence that the use of sedative drugs avoids the accurate assessment of GCS during the first 24 h [5].
\nOther challenges for diagnosis are presented by the progressive nature of some brain injuries, which can lead to further neurological deterioration. In addition, neurological responses after TBI may vary over time for reasons unrelated to the injury. For example, trauma is frequently associated with alcohol and drug intoxication [6]. These factors together place the GCS in a position full of limitations that diminish its reliability as a highly sensitive test in specific and not infrequent circumstances such as those already mentioned.
\nOn the other hand, neuroimaging techniques are used to provide objective information about the injury and its location [7] and are not influenced by the aforementioned confounding factors. However, the CT scan has a low sensitivity for diffuse brain injury, when the TBI is mild [8] and the availability and usefulness of MRI in the acute stage is limited. These facts, among others, have led to the search for alternative methods to assess the damage, being of special interest, the search for biomarkers, which are more reliable indicators of neuronal injury, due to its molecular context and its early expression.
\nResearch in this field has increased exponentially in the last 20 years, with most publications on the subject in the last 10 years. Most markers are associated with cell damage. Table 1 presents a summary of the TBI biomarkers most studied to date, including information about their nature, tissue location, molecular weight, half-life, basal levels, and physiopathological significance.
\nBiomarker | \nLocation | \nMolecular mass [KDa] | \nNature | \nHalf life | \nBasal concentrations | \nSignificance | \n
---|---|---|---|---|---|---|
UCH-L1 | \nNeuronal | \n20 [41] 24 [42] | \nUbiquitination enzyme | \n20 minutes [43] | \n0.12 ng/mL [44] | \nNeuronal injury | \n
NSE | \nNeuronal | \n90 [45] 78 [46] | \nEnzyme | \n24 h [46] 48 h [41] | \n<12.5 ng/mL [47] ≤15 ng/mL [46] | \nNeuronal injury | \n
αII-espectrina | \nNeuronal | \n280 [41] | \nCytoskeleton component protein | \n2.9 h [48] | \n— | \nApoptosis | \n
SBDP | \n120 [41] | \n1.5 days [49] | \n||||
145 [41] | \n1 day [49] | \n|||||
150 [41] | \n1 day [49] | \n|||||
S-100B | \nGlial (astrocytes) | \n21 [50] | \nCalcium binding protein | \n97 minutes [47] 112 minutes [43] | \n0.328–0.01 pg/mL [11] | \nBBBD | \n
MBP | \nGlial (oligodendrocytes and Schwann cells) | \n18.5 [50] | \nMyelin sheath component protein | \n12 h [43] | \n<0.3 ng/mL [50] | \nWhite matter injury | \n
GFAP | \nGlial (astrocytes) | \n40–53 [30] | \nCytoskeleton component protein | \n— | \n<0.03 ng/mL [30] | \nBBBD and neuronal injury | \n
Main biomarkers in TBI and their properties.
The main physiopathological mechanisms reflected by the glial or neuronal biomarkers are the disruption of the blood-brain barrier (BBBD) and neuronal injury, respectively. Taking into account this basis, it would be advantageous to have a panel of complementary biomarkers that show different temporal profiles and that reflect different physiopathological conditions subsequent to TBI. In a parallel manner, Papa et al. [9] propose that an ideal biomarker should have the following characteristics:
demonstrate high sensitivity and specificity for brain injury;
stratify the patients according to the severity of the injury;
have rapid appearance in the accessible biological liquid;
provide information about injury mechanisms;
have biokinetic properties;
monitor the progress of the disease and the response to the treatment;
predict the functional result; and
easily measured by simple techniques widely available.
In this chapter, we present a compendium of the most studied biomarkers in the TBI, its possible applications, and the current techniques for its detection.
\nAs explained in previous paragraphs, there is no single biomarker that is sufficiently sensitive and specific to study the physiopathological mechanisms that derive from head trauma. Next, we will mention some of the most studied biomarkers given its rapid elevation after trauma and its relationship with the mechanism of injury. One of the most studied biomarkers is the Ca binder protein S-100β, a glial protein at the astrocyte level that is related to alterations in the blood-brain barrier [10]. Its rapid elevation and its considerable concentration release in the serum facilitate the study of the protein and its correlation with the severity of the injury. Due to the type of cells found in the central nervous system, it is necessary to study biomarkers that allow us to demonstrate not only glial injury but also neuronal. One of the most studied biomarkers in this sense is the C-terminal hydrolase of ubiquitin-L1, which is a highly specific cytoplasmic neuronal enzyme [11, 12]. Finally, we will delve into glial fibrillary acidic protein (GFAP), which is also a glial protein and is part of the cytoskeleton of astrocytes and is also related to the disruption of the blood-brain barrier [11, 13].
\nS-100 β is a central nervous system (CNS) protein found predominantly in astrocytes and is the most studied peripheral biomarker of BBBD. This calcium binding protein (CBP) S-100β increases initially after the accident and then decreases rapidly after the traumatic injuries. In cell models, their release has been demonstrated from the first 15 seconds after the trauma. In humans, the earliest that has been detected is 30 minutes posttrauma. The approximate half-life of this protein is 97 minutes [10], the peak occurs on day 0, and the concentrations decrease toward the sixth day in both CSF and serum.
\nGoyal et al. [14] reported basal levels of S-100β in healthy CSF controls of 0.0754–0.0034 ng/mL and in serum of 0.328–0.101 pg/mL. This protein has been studied extensively in mild TBI (mTBI), so that high levels in serum are associated with an increase in the incidence of post-concussion syndrome [15] and neurological dysfunction. There are also several studies that have reported a correlation between serum levels of S-100β and the presence of pathological findings in cerebral magnetic resonance imaging (MRI), as well as abnormalities in neuropsychological exploration after mTBI [16].
\nMost studies show that the S-100β measurement can distinguish injured patients from noninjured patients with an uncertain degree of utility in predicting mortality either acutely or at several points in time (Table 2) [17, 18, 19]. In general terms, S-100β is a sensitive but not specific predictor of CT abnormalities. Using low serum cut-off values, the sensitivity oscillates between 90 and 100% with a specificity between 4 and 65%.
\nReference | \nDetection method | \nSample | \nFindings | \n
---|---|---|---|
Goyal et al. [14] | \nELISA | \nCSF and serum | \nIncrease in CSF and serum first 6 days post-trauma Correlation between serum and CSF levels decreased over time Level in CSF is a potential predictor of GOS and DRS Mean and peak are predictors of mortality in severe TBI | \n
Berger et al [51] | \nAutomated LIAISON system [AB DiaSorin, Bromma, Sweden] | \nSerum | \nSignificantly elevated in intracranial injury It cannot replace the clinical examination or the use of CT in mTBI It can serve as support for the selection of patients for TC S: 90–100%, E: 4–65% | \n
Biberthaler et al [19] | \nElecsys S100 [Roche Diagnostics, Mannheim, Germany] | \nSerum | \nIncrease was related to findings in the CT scan S: 99%, E: 30% | \n
Biberthaler et al [52] | \nLong term and Rapid test | \nSerum | \nConcentrations were significantly correlated using the two measurement techniques; cut-off value calculated: 0.18 ng/mL. S: 100%, E: 46% | \n
Bazarian, et al [21] | \nELISA | \nSerum | \nS: 80%, E: 40% | \n
Summary of the evidence reported in the literature on biomarkers in S-100B.
Müller et al. [17] reported a sensitivity of 0.95 (95% CI 0.76–1.0) for S-100β measured within the first 12 h with a specificity of 31% (95% CI 0.25–0.38) relative to abnormal findings on skull CT scan in a study of 226 adult patients admitted to the hospital with a diagnosis of mild TBI (GCS 13–15). Biberthaler et al. [19] found similar results using a cut-off level of S-100β of 0.1 ng/mL, measured within the first 3 h posttrauma in 1309 patients with mTBI and correlating them to head CT findings. The sensitivity was 99% (95% CI 0.96–1.0), and the specificity was 30% (95% CI 0.29–0.31).
\nThe usefulness of S-100β as a marker does not seem to be affected by the concomitant consumption of alcohol. Mussack et al. conducted a study in which they included patients with mild TBI with demonstrated blood alcohol levels (mean = 182 mg/dL), and found that the sensitivity of S-100β in the first 3 h posttrauma was 100% (95% CI 0.83 a 1.0) and the specificity was 50% (95% CI 0.41–0.59) [20].
\nOn the other hand, Bazarian et al. studied 96 patients with TBI, GCS 13–15 who also presented trauma of extracranial localization, and found a sensitivity of 80% (95% CI 0.36–0.96) and a specificity of 40% (95% CI 0.01–0.09) for S-100β with a cut-off value of 0.08 ng/mL [21].
\nFrom the studies described above, it can be deduced that the sensitivity increases as the time elapsed between the trauma and the sample taking (window) decreases, as well as an increase in specificity is observed when the cut-off value increases. In contrast, the limitations of the use of S-100β as a marker are due to the marked decrease in sensitivity and specificity in the context of the polytraumatized patient, since the presence of concomitant extracranial trauma also causes the release and plasma elevation of this protein. The presence of S-100β has been reported in tissues other than the nervous one, mainly in adipose tissue [22]. From this observation, a negative effect on the specificity of this marker is expected, due to the increase that would occur in the context of extracranial lesions, as occurs in the polytraumatized patient.
\nPham et al. [22] characterized the tissue specificity of S-100β and evaluated the extracranial sources of this marker and how they affect serum levels of this marker. For this purpose, they performed the extraction of proteins from nine different human tissues (liver, bladder, kidney, colon, lung, muscle, pancreas, adipose tissue, brain, tonsils, stomach, and skin) and their subsequent analysis through ELISA and Western blot in 200 subjects receiving chemotherapy for the management of CNS lymphomas. A dose of mannitol (1.4M) was administered intra-arterially in the carotid or vertebral artery, subsequently confirming the presence of BBBD by a head CT performed immediately after chemotherapy.
\nThe results presented in that study showed that extracranial sources of S-100β do not affect serum levels. Therefore, the diagnostic value and the negative predictive value of S-100β are not compromised in the context of patients with neurological diseases, but without traumatic lesions, whether cerebral or extracranial.
\nGoyal et al. [14] also evaluated S-100β as a prognostic biomarker in adult subjects with severe TBI (sTBI) by comparing the results with the S-100β temporal profiles in both CSF (n = 138 subjects) and serum (n = 80 subjects) for 6 days. The variables used to evaluate the extracerebral sources of S-100β in serum were: long bone fracture, Injury Severity Score (ISS), and isolated skull trauma. After TBI, levels of S-100β in CSF and serum were increased compared to healthy controls during the first 6 days after TBI (p ≤ 0.005 and p ≤ 0.031). Although levels in CSF and serum had a high correlation at the early post-TCE time points, this association decreased with time. The bivariate analysis showed that subjects who had temporary CSF profiles with higher concentrations of S-100B had higher acute mortality (p < 0.001) and worse Glasgow Outcome Scale (GOS; p = 0.002) and disability scores (DRS) (p = 0.039) 6 months after the injury. Temporary profiles in serum were associated with acute mortality (p = 0.015), possibly as a result of the extracerebral sources of S-100β in the serum, represented by high ISSs (p = 0.032).
\nDue to its temporal elevation profile, and the pathophysiological mechanisms that cause its release toward serum, S-100β constitutes an excellent candidate as an early biomarker of TBI, with the possible limitation in patients with concomitant trauma in other sites that leads to the serum elevation of S-100β from extracranial sources.
\nThe C-terminal hydrolase of ubiquitin-L1 (ubiquitin C-terminal hydrolase-L1, UCH-L1) is an E2 conjugation enzyme present in the cytoplasm of almost all neurons [13] and has previously been used as a neuronal histological marker due to its great abundance and specific expression in these cells [11]. Its location has also been shown in neurons of the peripheral nervous system, particularly in the neuromuscular junction [12], as well as in cells of the neuroendocrine system. In addition, the presence of UCH-L1 has been demonstrated in aortic endothelial cells and in smooth muscle and tumor cells [23]. This enzyme accomplishes the function of adding and removing ubiquitin from proteins in order to promote its degradation via the proteasome-dependent pathway [24].
\nUCH-L1 is one of the most recent biomarkers proposed for TBI, and for this reason, there are still limited data that demonstrate its usefulness (Table 3).
\nReference | \nDetection method | \nSample | \nFindings | \n
---|---|---|---|
Papa et al. [24] | \nELISA | \nCSF | \nIncrease at 6, 12, 24, 48, 72, 96, 120, 144, and 168 h post-trauma, X = 44.2 ng/mL (±7.9), versus controls X = 2.7 ng/mL (±0.7) (p < 0.001). Also elevated when it exists: lower GCS at 24 h, post-trauma complications, deaths in the first 6 weeks, or serious sequelae at 6 months. | \n
Brophy et al. [53] | \nELISA | \nCSF and serum | \nSignificant correlation between biokinetics and means of (UCH-L1) in CSF and serum in severe TBI (rs = 0.59, p < 0.001) (AUC, rs = 0.3, p = 0.027). Increased levels <24 h posttrauma, statistically significant in Cmax (0–24 h) in CSF and serum in those who died. | \n
Mondello et al. [26] | \nSandwich ELISA | \nCSF and serum | \nIt remains elevated up to 7 days after TBI, serum AUC and statistically significant CSF at all-time points up to 24 h (p < 0.001). Levels in <12 h in GCS 3–5 > GCS 6–8 (p = 0.07 and p = 0.02, Mann-Whitney test, respectively). Significantly higher and prolonged serum and CSF levels in non-survivors. A level of >5.22 ng/mL was a predictor of mortality (OR 4.8). | \n
Papa et al. [11] | \nELISA | \nSerum | \nElevated in GCS 15 vs. controls without trauma (AUC 0.8) and controls with trauma. Higher elevation in GCS 15 plus TAC or neurosurgical intervention requirement. It provides evidence as a potential marker of mild TBI. | \n
Kou et al. [27] | \nElectrochemiluminescence immunoassay (ECL-IA) | \nSerum | \nComplements brain MRI in the detection of injury. Significantly elevated levels in patients in the acute state of mild TBI. | \n
Diaz-Arrastia et al. [28] | \nSandwich ELISA | \nSerum | \nMeasurement <24 h posttrauma distinguished presence and absence of intracranial lesions (AUC of 0.713). No correlation between levels in mild TCE and recovery at 6 months. Significant increase in levels in moderate/severe TCE compared with mild TBI. Good sensitivity to discriminate between TCE and controls (AUC 0.87). Combination with GFAP showed greater sensitivity and specificity for the diagnosis of TBI (AUC 0.94). | \n
Puvenna et al. [15] | \nELISA | \nSerum | \nThere were no significant differences between the levels of negative controls and TCE <6 h posttrauma, independent of the CT. The levels were high after each game but without correlation with the number of hits received. | \n
Summary of the evidence reported in the literature on UCH-L1.
Three isoenzymes of UCH (UCH-L1, UCH-L2, and UCH-L3) have been identified, being UCH-L1, the only one present in high concentrations in the central nervous system [24]. In a prospective case-control study with 66 patients, Papa et al. [24] obtained ventricular CSF samples for each patient after 6, 12, 24, 48, 72, 96, 120, 144, and 168 h after TBI for the UCH-L1 detection by ELISA. The severity was determined by the Glasgow Scale (GCS) and CT findings. Mortality and neurological sequelae were evaluated at 6 months. This study showed that patients with TBI had a significant elevation of CSF UCH-L1 levels at each point in time compared to controls, with total mean in TBI patients = 44.2 ng/mL (±7.9) vs. 2.7 ng/mL (±0.7) in controls (p < 0.001). Significantly elevated levels of UCH-L1 were found in patients with a lower score in the GCS at 24 h, in those who had presented post-trauma complications, in those who died within the first 6 weeks, and in those with severe sequelae at 6 months. These data suggest that this marker would be useful in determining severity in patients with TBI. Similar studies with larger samples are required to validate these findings.
\nAdditional studies have confirmed the positive correlation between the concentrations of UCH-L1 at the CSF level and serum samples [25]. Similarly, Mondello et al. [26] conducted a case-control study with 95 patients with severe TBI in order to evaluate the CSF and serum concentrations of UCH-L1 by sandwich ELISA and its association with clinical results. The temporal profile of the marker in both CSF and serum was studied during the first 7 days following the trauma and compared with controls showing significantly higher levels compared to the controls throughout the 7-day period, also confirming a high sensitivity and specificity for the diagnosis of TBI versus controls, with statistically significant serum AUC and CSF values at all-time points up to 24 h (p < 0.001).
\nThe levels of UCH-L1 in the first 12 h in both CSF and serum in patients with GCS 3–5 were also significantly higher than in those with GCS 6–8. In addition, UCH-L1 levels in CSF and serum appeared to distinguish between patients with severe TBI survivors and nonsurvivors within the study, such that those who died had significantly higher CSF and serum UCHL1 levels, as well as greater permanence of these levels over time. In this study, a serum level of UCH-L1 > 5.22 ng/mL was a predictor of mortality (OR 4.8).
\nPapa et al. [11] also analyzed UCH-L1 in serum taken in the first 4 h posttrauma in patients with mild (n = 86) and moderate (n = 10) TBI, as well as in controls with trauma and controls without trauma. For patients with a GCS of 15, serum UCH-L1 was significantly elevated compared to controls without trauma, with an AUC of 0.87, and was also compared with controls with trauma, and was even higher in those patients with GCS of 15 who also had positive findings on the CT scan or required some neurosurgical intervention, suggesting that UCH-L1 may be a potential marker of mild TBI. Additionally, 5% of patients with GCS of 15 (4/77) required neurosurgical intervention, which was higher than the 1% found in patients with GCS 14–15 reported in the study by Jagoda et al., in which the samples were taken within the first 24 h posttrauma [10].
\nIt is inferred from these data that the earlier it is detected posttrauma, the sensitivity of this marker increases. In a smaller study (n = 9), serum UCHL1 (taken <6 h posttraumatic) was found to be significantly elevated in patients with mild TBI [27].
\nIn another study focused on all levels of severity of TBI, serum UCH-1 measured before 24 h posttrauma could distinguish patients with intracranial lesions from those without intracranial lesions with an AUC = 0.713 [28]. However, there was no correlation between UCH-L1 levels in patients with mTBI and recovery at 6 months as measured by the GOSE scale. While there was a significant increase in UCH-L1 levels in patients with moderate/severe TBI compared to mild TBI, patients with mild TBI were not compared with controls.
\nIn a research carried out in a secondary school, Puvenna et al. [15] selected 15 American football players; they obtained serum samples before and after each of two different games. They did not observe significant differences between the levels of UCH-L1 between the negative controls and the positive individuals for mild TBI within the first 6 h posttrauma, regardless of whether or not positive CT findings existed. In addition to this, there was no correlation between the serum levels of UCH-L1 and the number of impacts received. The levels of UCH-L1 and S-100β, markers of neuronal injury and BBBD, respectively, were both elevated after each game. However, only S-100β, unlike UCH-L1, was correlated with the number of hits received and the UCH-L1 elevation did not correlate with the S-100β increments. The authors suggest that elevated postgame UCH-L1 levels may be due to the release of this protein from the neuromuscular junction.
\nIt can be concluded that there are very divergent data regarding the use of UCH-L1 as a serum biomarker of mild TBI. Some studies suggest that it is a promising marker, while others do not find a correlation with the lesion. Release from sources other than the central nervous system could contribute to elevated serum levels.
\nGlial fibrillary acidic protein (GFAP) is a protein derived from glial cells, which is a part of the intermediate filament of the cytoskeleton of astrocytes, where it is the most abundant protein. It is considered a specific marker of CNS diseases, and is also related to several neuronal processes’ harmful agents that compromise the integrity of the blood-brain barrier [29], and has been shown to be a potentially useful biomarker for predicting clinical outcomes in TBI. Its normal level in serum is <0.03 ng/mL [30], so any elevation thereof will indicate BBBD (Table 4).
\nReference | \nDetection method | \nSample | \nFindings | \n
---|---|---|---|
Kou et al. [27] | \nElectrochemiluminescence immunoassay (ECL-IA) | \nSerum | \nSignificantly elevated in all cases of intracranial hemorrhage, with potential screening capacity. Small size of the sample does not allow to validate the conclusions. | \n
Mondello et al. [35] | \nSandwich ELISA | \nSerum | \nEvaluation of GNR (GFAP/UCH-L1): Median = 0.85, positive correlation with age (R = 0.45, p = 0.003). Greater in focalized lesions vs. diffuse lesion (1.77 vs. 0.48, respectively, p = 0.003). Different type of lesions (AUC = 0.72, p = 0.003). More precise early measurement (<12 h posttrauma) vs. late (AUC = 0.80, p = 0.002). Independent association with the type of injury, but not with the GCS. Independent predictor of mortality. | \n
Papa et al. [36] | \nELISA | \nSerum | \nS-100B and GFAP significantly elevated in all patients, especially in intracranial injuries. For GCS 14–15, AUC = 0.82 in identification of intracranial lesions for GFAP (0.77 for S-100B). With extracranial lesions and cut-off 0.067 ng/mL, GFAP: S = 100% and E = 55% to predict intracranial lesions. GFAP outperforms S-100B in the identification of intracranial lesions in mild and moderate TBI, even in the presence of extracranial lesions. | \n
Papa et al. [54] | \nELISA | \nSerum | \nGFAP-BDP significantly elevated in mild TCE vs. controls with or without trauma. AUC = 0.88 to identify brain injury in GCS 15. Higher levels in GCS 15 with positive CT. | \n
Okonkwo et al. [55] | \nELISA | \nSerum | \nGFAP-BDP <24 h posttrauma distinguished between mild and moderate/severe TBI (AUC of 0.87). Controls were not included, mild to moderate TCE was not compared, and most of the statistical analysis was made with all levels of severity at the time. | \n
Summary of the evidence reported in the literature on GFAP in TBI.
Due to its great immunoreactivity, GAFP has been used as an indicator of brain injury in experimental models of mTCE [31]. The first successful measurement of GFAP in human blood was made in 1999 in 12 of 25 patients with severe TBI [32]. Using a weight drop model with mice [33] to evaluate two levels of mTBI, one with hemorrhage (complicated mTBI) and another without bleeding (uncomplicated mTBI), Yang et al. [34] found that serum GFAP was significantly elevated in both injury models at 90 minutes and 6 h after injury, but had returned to normal at 24 h.
\nIn the study of Kou et al. [27], significantly elevated serum levels of GFAP in the first 24 h posttrauma in 9 mTBI patients was also reported; this elevation being even more significant in those with hemorrhagic lesions; however, the small size of the sample does not allow the conclusions to be validated.
\nIn another study, Mondello et al. [35] evaluated whether the relationship between a neuronal marker (UCH-L1) and a glial marker (GFAP) correlates with the presence of different intracranial pathologies after brain trauma. They obtained serum samples from 59 patients with sTBI on admission to the hospital and measured levels of UCH-L1 and GFAP. The glial/neuronal ratio (GNR) was measured as the quotient between the concentrations of GFAP and UCH-L1. Logistic regression analysis identified variables associated with the type of injury. The increase in GNR was associated independently with the type of injury, but not with the age, gender, GCS, or trauma mechanism. This quotient was significantly higher in the patients who died, but it was not an independent predictor of mortality. The GNR had a median of 0.85 and correlated positively with age.
\nWhen evaluating the CT scan of the skull on admission, 29 patients presented a diffuse lesion and 30 localized lesions. The GNR was significantly higher in the group with focal lesions compared to the group with diffuse lesions. The receiver operating characteristic (ROC) analysis showed that the GNR discriminated between the two types of injury. GNR was more accurate when performed early than when it was done late (Table 4).
\nThese data indicate that the GNR provides valuable information about the different types of injury, which is of great clinical utility. In addition, the GNR can help to identify the pathophysiological mechanisms subsequent to the different types of TBI. This is very useful when implementing therapeutic measures.
\nIn an investigation carried out by Papa et al. [36], the capacity of the GFAP taken <4 h posttrauma was compared to predict intracranial lesions in the CT compared to S-100β. Although patients had GCS 9–15, only 3 of 209 patients had GCS <13 and only 10% had intracranial lesions, both S-100β and GFAP were significantly elevated in all patients, and even more so in those with intracranial lesions. For those patients with GCS 14–15, the AUC for the identification of intracranial lesions was 0.82 for GFAP and 0.77 for S-100β.
\nIn the presence of extracranial lesions and using a cut-off value of 0.067 ng/mL, GFAP was 100% sensitive and 55% specific in the prediction of intracranial lesions. With a cut-off value of 0.20 ng/mL, S-100β also had 100% sensitivity but only 5% specificity. This study concludes that GFAP exceeds S-100β in the identification of intracranial lesions in mild and moderate TBI, even in the presence of extracranial lesions.
\nIn general, GFAP seems to increase in TBI and could represent a more sensitive marker than S-100β for the identification of intracranial lesions. However, for further validation, more studies are needed that focus specifically on mTBI (GCS 13–15), which include appropriate controls and adequate statistical comparisons.
\nOne of the main purposes of the search for potential biomarkers in the TBI is to predict the presence of pathological findings in head CT and brain MRI; however, the studies published in this regard are inconclusive, and the evidence favors the use of S-100β over other markers in mTBI, as a predictor of negative-CT.
\nFor example, Posti et al. [37] showed that patients with orthopedic trauma had higher levels of GFAP at admission, than those with mTBI and negative-CT (p = 0.026), and did not show that UCH-L1 levels presented significant differences in both groups, performing measurements at different time points, which suggest that these markers are not useful for distinguishing patients with negative-CT mTBI from patients with orthopedic trauma, and that high levels of UCH-L1 or GFAP can lead to a false diagnosis of mTBI in polytraumatized patients, leading to the unnecessary use of neuroimaging.
\nOn the other hand, the use of the S-100β marker has been recommended in the Scandinavian guidelines for the initial management of minimal, mild, and moderate head injuries in adults [38] as an alternative to reduce the number of CT in the subgroup of mTBI with low risk of intracranial complications or surgical interventions. More studies are needed that show the usefulness of S-100β as a predictor of neurodeterioration in moderate TBI.
\nThe use of neuroimaging is necessary to improve the accuracy of biomarkers in the diagnosis and prognosis of patients who have suffered a TBI, with CT being the first option and the one with the most studies in relation to the release and correlation of biomarkers. Some reviews report higher serum S-100β levels in more severe, focal lesions, compared to diffuse lesions using Marshall scale, and a strong correlation between S100B increasing and the severity of the CT finding when using the sum of Rotterdam CT score and Stockholm CT score [54].
\nOlivecrona et al. reported how S-100β and neuronal specific enolase (NSE) levels correlate with CT findings using the aforementioned scales. Specifically, S-100β levels, but not to the NSE levels, correlates with Morris-Marshall score for the classification of traumatic subarachnoid hemorrhage (tSAH). This is probably associated with the physiopathological pathways described by each of these biomarkers after a neurotrauma. Likewise, the volume of the parenchymal contusions is also associated with the S-100β levels. Furthermore, in mild TBI, initial low levels of S-100β can be used as a predictor of a stationary injury, suggesting that the CT classification does not evolve [55].
\nDiagnosis of severity and prognosis of CT findings cannot be performed by a single biomarker test. Instead, a combination of biomarkers of diverse origins and pathways displays a better performance. Thereby, the joint use of GFAP, heart fatty acid binding protein (H-FABP), S-100β, and IL-10 results in a more efficient diagnostic tool with a 46% specificity and 100% sensitivity for predicting CT injuries. This biomarker panel increases specificity by 14% compared to the best single biomarker [56].
\nThe ALERT-TBI study, developed in 22 centers in USA and Europe, validated the ability of the combination of UCH-L1 and GFAP to predict CT injuries within 12 h of mTBI, resulting in a sensitivity of 97.6%, a negative predictive value (NPV) of 99.6%, and a specificity of 36.4%. Therefore, when indicating CT only in those patients with a positive GFAP and UCH-L1 test, the CT use could be reduced by approximately one-third. The extent of these findings to patients with moderate TBI is uncertain [57].
\nThe study of the available evidence on the different serum markers in TBI presented in this chapter allows us to conclude that, currently, there is not a single biomarker capable of predicting the clinical deterioration of patients with high sensitivity and specificity. However, the pathophysiological mechanisms of TBI suggest that instead, a panel of markers that reflect different aspects of traumatic injury should be available, including BBBD and neuronal injury.
\nThe literature has shown that the joint use of S-100β and GFAP or UCH-L1 would represent a valuable early prognostic and follow-up tool in TBI in addition to the GCS and the CT, thus guiding the decisions of initial management and aggressive interventions.
\nLikewise, given that the kinetic profile of these markers is different, since it presents peaks of appearance earlier than others and different times of permanence in serum, its usefulness would also be correlated with different post-traumatic stages, so that S-100β and UCH-L1 are better early markers [24, 25], whereas GFAP is a better predictor of CT lesions and surgical interventions in the first 7 days posttrauma in mild and moderate TBI [27].
\nIn addition to the above, the literature also shows that these biomarkers are being measured with techniques that demand the use of complex equipment and procedures (such as ELISA) in which the use of labels is necessary [6, 39], displaying the need for the development of rapid and cost-effective techniques that allow the implementation of biomarkers in the clinical setting.
\nWe thank Universidad del Norte and Colciencias for the financial support of the research project in which the development of this work is framed.
\nThe authors declare no conflict of interest.
Air pollution is a worldwide concern because of the health problems associated with its uncontrolled emissions that affect all the biological systems. Within the wide range of pollutants, the suspended particles or particulate matter (PM) are of particular interest, which became more important since IARC listed them as carcinogens. The toxicity of PM is the consequence of the elements adhered to its surface [1]. An example of this are the particles generated by the combustion of fossil fuels and its derivatives, these particles usually consist of a carbon core on which complex mixtures of compounds are adhered, such as: polyaromatic hydrocarbons, toxins, sulfates, nitrates, and especially transition metals like vanadium, manganese, chromium, among others [2]. Metals are considered to play an important role in the induction of toxic effects reported in the literature [3].
Metals are the largest category of globally distributed pollutants with a tendency to accumulate in some human tissues and with a high toxic potential at relatively low concentrations. Constant exposure to certain metals has been linked to inflammation, cell damage, and cancer [4]. Each metal has its own mechanisms of action [5]. Some of them produce its adverse effects alone, while others interact with various factors resulting in greater damage in different organs and systems [4]. It is known that metals, including vanadium, have different toxic pathways, and oxidative stress is the most frequent mechanism [5].
Oxidative stress is the consequence of an imbalance between the production of free radicals and the antioxidant capacity of an organism [6]. It may result from the increase in exposure to oxidants, due to the decrease in the protection against oxidants, or because both events occur simultaneously [7].
A free radical represents any chemical species of independent existence that has one or more missing electrons spinning in its external atomic orbitals. This electrochemical configuration is unstable and gives them property of being a highly reactive and short-lived chemical species [8]. Most of the free radicals of biological interest are usually extremely reactive and have a very short life span (microsecond fractions). When a radical reacts with a non-radical compound, it results in other free radicals, thus generating chain reactions that produce biological effects [9], coupled with the fact that when they collide with a biomolecule and subtract an electron (oxidizing it), it loses its specific function in the cell [8].
Regardless of the origin, free radicals can interact with the biomolecules found in the cell such as nucleic acids [10], proteins, lipids, and carbohydrates [9], thereby causing potentially serious modifications and consequences in the cell [10].
Vanadium is an element that is find in various oxidation states and participates in reactions that lead to the production of free radicals such as superoxide, peroxovanadyl, and the highly reactive radical hydroxyl [8].
The increasing production of free radicals leads the cell to an imbalance in its redox state and thus generating oxidative stress; therefore, the cellular dysfunction will be reflected in the failure of organs and systems.
The cell is the basic functional unit of life and its dysfunction induced by oxidative stress might produce DNA damage and cell death.
The International Agency for Research on Cancer lists vanadium pentoxide (V2O5) as “a possible carcinogen for humans” in group 2B. The above was based on evidence of lung cancer generation in mice that was published by the National Toxicology Program [11]. However, evidence on the carcinogenicity of vanadium has been widely questioned by Duffus in 2007 [12] and Starr et al. [13]. Information related to the carcinogenic and genotoxic potential of vanadium pentoxide (V2O5) is limited [14]. In both animal and human models, the effects on the DNA caused by vanadium include single strand breaks, micronuclei, chromosomal aberrations (structural and numerical), and oxidation of nitrogenous bases [15, 16]. The spectrum of alterations that DNA might have as a consequence of free radicals interaction, in this case caused by vanadium, are: deoxyribose oxidation, modification of nitrogen bases, chain cross-linking, and ruptures [6]. The double or single chain breaks that are generated by the interaction of free radicals with DNA are produced by the fragmentation of the sugar-phosphate skeleton or indirectly by the cleavage of oxidized bases [17].
The above indicates that vanadium is an element with mutagenic potential, because its genotoxic, aneugenic, and clastogenic effects, although there are not strongly data supporting that vanadium is carcinogenic, this possibility should not be eliminated, because the DNA damage caused by the exposure and therefore genetic instability, processes closely related to the generation of malignancy [18].
Cell death is central to physiological homeostasis; the balance between cellular differentiation, proliferation, and death support aspects of biology, including embryogenesis, organ function, tissue remodeling, immune regulation, and carcinogenesis. Cell death was once believed to be the result of one of three different processes: apoptosis, autophagy or necrosis; however, in the last decade about 15 different types have been reported, highlighting that a cell can die via different pathways which depends on the intensity of the stimuli [19]. Reactive oxygen species (ROS) activates cell death and plays different roles in the biological systems which can be either injurious or beneficial. Generation of ROS might be caused by metals such as: arsenic, cadmium, chromium, cobalt, copper, gold, iron, nickel, rhodium titanium or vanadium [8]. Vanadium compounds can interconvert into different species (vanadyl and vanadate) event which is constantly occurring inside the cell in the presence of ROS [20].
Studies in vivo and in vitro showed that vanadium compounds induce cell death in leukemia [21], lung cancer [22] cervical and breast carcinoma [23], neuroblastoma [24], liver carcinoma [25], osteosarcoma [26], and pancreatic ductal adenocarcinoma [27]. In vitro studies demonstrated that the cell lines stimulated with vanadium compounds produce H2O2 and O2 and induce autophagy, necroptosis, and mitotic catastrophe [27]. Apoptosis is the main type of cell death associated with vanadium compounds, reporting the release of cytochrome c from mitochondria [21] and the disruption of the mitochondrial membrane potential [25]. This type of cell death is mediated through the activation of p53 and p21 [27], which modulate the activation or inactivation of phosphorylation of some proteins such as MEK, ERK 1/2, PI3K, p38, JNK, TNF-alpha, and NFkB [28].
The systemic vanadium effects observed in vivo and in vitro are briefly described below.
The reprotoxic effects of vanadium in male reproductive system in laboratory animals include interruption of spermatogenesis [29], morphological and biochemical changes in spermatogenic cells [30], abnormalities in the shape and movement of sperm, as well as decrease in the weight of the testis, epididymis, and prostate [31].
One of the mechanisms of vanadium toxicity includes imbalance in the cellular redox state [30]; testicular cells are highly susceptible to free radical actions because its membranes are rich in polyunsaturated fatty acids, which limits the fluidity of the membrane and alters the functioning of integral membrane proteins [32].
In rat’s testis, after given sodium metavanadate (NaVO3), an increase in malondialdehyde (MDA) was found, which is a product of lipid peroxidation, as well as a decrease in the activity of superoxide dismutase (SOD) and catalase [33]. Intraperitoneal administration of NaVO3 caused in the testis a decrease in the number of germ cells, the presence of degenerated cells, and necrosis of the seminiferous tubules, associated to the increase in testicular lipid peroxidation and inhibition of the activity of antioxidant enzymes (SOD and catalase) [34]; alteration in spermatogenesis, decrease in serum testosterone, LH and FSH levels, inhibition of steroidogenic enzyme activity, increase in testicular vanadium concentration, inhibition of antioxidant enzymes (SOD, catalase and GPx), increased levels of lipid peroxidation [29], and abnormalities in the form of sperm have also been reported [35].
During female reproductive processes, such as ovarian follicle development, ovarian steroid synthesis, ovulation, fertilization, and implantation, require certain amounts of ROS [36]; however, due to the oxidizing effects of vanadium, the delicate balance between ROS generation and the cellular antioxidant system can be altered.
In the case of the female reproductive system of rats, it has been observed that the administration of vanadium sulfate (VOSO3) causes oxidative stress and biochemical alterations in uterine cells, such as the decrease in the activity of alkaline phosphatase and adenosine triphosphatase; while in the ovary, the damage of the oocyte and ovarian follicles was observed, as well as stromal fibrosis [37]. In an inhalation model of vanadium in non-pregnant females, histological alterations were found in the ovary and uterus and lipid peroxidation, indicated by the increase in the levels of 4-hydroxynonenal (4-HNE) a marker of oxidative stress [30].
Vanadium crosses the placental barrier and exerts its toxic effects on embryos and fetuses; in rats, it has been observed that fetal weight decreases and the number of implants and fetuses, while the number of resorptions, malformations, and dead fetus increases [31]. The fetotoxic and embryotoxic effects of vanadium have also been associated with oxidative stress since both in fetuses and in mothers exposed to vanadyl sulfate (VOSO4), and lipid peroxidation was observed in the liver [37].
Kidney chronic disease (CKD) has increased worldwide. The main risk factors for the development of this disease are diabetes, metabolic syndrome, and hypertension. However, there are a segment of population that has none of these risk factors and there are other factors that are being studied as a possible cause of renal injury. One of them is the environmental pollution, particularly pollution by metals in atmosphere and water. Arsenic, cadmium, mercury, lead, and vanadium have been reported as nephrotoxic metals because of the production of ROS and the induction of oxidative stress. These metals enter the body by oral or inhaled exposure, then they are absorbed, enter into the systemic circulation, and distributed into the organs where they may accumulate. Finally, most of them are eliminated by the kidney, reason why this organ is one of the most affected structures by metals [38]. Also, there are reports that in CKD when there is a problem to eliminate pollutant metals, these can concentrate into kidney cells and the damage worsened when it occurs in humans, both in children and adults [39]. Oxidative stress and inflammation are the principal mechanisms of renal injury; in addition, arsenic, cadmium, mercury, and lead are associated to hyperglycemia that may aggravate the oxidative stress and the renal damage. Vanadium is an exception because it has a hypoglycemic effect, but this does not ameliorate its toxicity [40].
Vanadium is nephrotoxic, as it has been proved mainly in animal models, but also in humans [41]. In a report of human acute poisoning by oral ammonium metavanadate, hypoglycemia, bronchoconstriction, and acute renal insufficiency were the causes of death; in a chronic model of vanadium exposure reported glomerulonephritis, glomerular and tubular necrosis that lead to renal insufficiency and hypertension [42]. The reported findings in other study with ammonium metavanadate p.o. at doses of 30, 45, and 60 mg/kg were edema, vacuolization, and degeneration of epithelial tubular cells at 21st day of exposure [43]. Another research group, using different compounds and doses of vanadium (45 and 90 mg/kg) reported thickening of glomerular basement membrane, pyknotic nuclei, cellular vacuolization, and pyelonephritis [44]. In our group, in a subchronic model of vanadium inhalation, we found foci of inflammatory cells, vacuolation, loss of microvilli of epithelial tubular cells, and changes in urine parameters as proteinuria and hematuria associated to the increase, in a time dependent manner, of 4-hidroxynonenal (4-HNE) [45] (Figure 1A and B). Oxidative stress is also the toxic vanadium mechanism reported by other groups, for example, Marouane et al. [46] found lipid peroxidation, protein denaturation, DNA degradation, and cell membrane disintegration; in addition, Scibior et al. [47] reported elevated malonaldehyde (MDA) as a marker of oxidative stress and enhanced total antioxidant status in a rat model of 12-week oral sodium metavanadate exposure.
4-hydrxynonenal (4-HNE) in kidney and liver as a marker of oxidative stress. (A) Kidney tubules in control group with a basal 4-HNE immunoreactivity. (B) In vanadium group, 4-HNE immunoreactivity increased in microvilli of proximal tubules after 8th-week exposure. (C) Liver of control group with a basal 4-HNE immunoreactivity. (D) Liver of vanadium group after 8th-week exposure with increase in 4-HNE immunoreactivity in hepatocytes, some of them with a very intense mark.
The immune system is an interactive network of lymphoid organs, cells, humoral factors, and cytokines whose function is to distinguish between self and non-self-antigens in the host system, thus providing mechanisms against infections and tolerance to the components of the host. When an antigen attacks the host, two distinct, yet interrelated, branches of the immune system are activated, the nonspecific/innate and specific/adaptive immune response. Both of these systems have certain physiological mechanisms, which enable the host to recognize foreign materials as foreign materials and to neutralize, eliminate, or metabolize them [48]. The immune system is a target of air pollutants, such as vanadium that might impair its function and induce oxidative stress.
In previous studies, effects from vanadium inhalation on the immune system have been demonstrated. Changes in the spleen morphology and a decrease in humoral immune responses have been reported [49], as well as a decrease in the number of thymic dendritic cells, its expression of CD11c and MHC-II biomarkers, and an increase of thymic medullar epithelial cells [50]. Oxidative stress could be an important mechanism involved in these effects and some mechanisms are described as follows:
Sodium metavanadate (NaVO3) induced oxidative stress through generation of ROS and depletion of the antioxidant defense systems. When the exposure is chronic, the oxidative stress turns out in severe damage [51].
The effect of vanadyl sulfate (VOSO4) in blood glucose and in the spleen, in streptozotocin (STZ)-induced diabetic rats was evaluated. The levels of lipid peroxidation (LPO) and glutathione (GSH) in the spleen were analyzed. After 60 days of treatment, spleen LPO significantly increased, but spleen GSH levels significantly decreased in the diabetic group. On the other hand, treatment with VOSO4 reversed these effects in STZ diabetic animals [52]. These studies show that vanadium induced oxidative stress in the spleen, which might disrupt the immune response.
The liver as the major site for metabolism, biotransformation and detoxification of drugs and foreign compounds, is constantly exposed to ROS resulting in oxidative stress and frequently, permanent and irreversible tissue damage [53]. Studies have shown that liver is one of the most important target tissues for vanadium toxicity with its capacity to form ROS by interacting with mitochondrial redox centers, mainly in mitochondrial respiratory processes I, II, and III [54]. Studies with HepG2 cell line have shown that exposure to vanadium causes damage to nuclear and mitochondrial DNA, as well as decreased cell viability [55]. In vivo studies from our group demonstrate that vanadium increases lipid peroxidation in V-exposed animals [56]. Figure 1C and D show the oxidative marker 4-HNE in liver parenchyma.
As a heavily irrigated, highly connected organ with neural, endocrine, digestive, absorptive, and immune functions, the gut can enter oxidative cycles mostly by two well-defined mechanisms:
Ambient-polluting microparticle swallowing: especially in heavily polluted areas (industrial centers, cities, mines, etc.), the air is charged with carbon PM, whose size varies between 10 and 2.5 (or even less) micrometers. Such particles are normally covered by metals (vanadium, for instance), which get trapped via natural defense mechanisms in the nasal and oral mucosa, slowly, descending into the pharynx and into the digestive tract carried on through saliva [30].
Direct toxic ingestion: recent research relates ingestion of food ingredients—especially sugar (sucrose or high fructose) present mostly in sugar-sweetened beverages (SSB)—with tissue damage. Although there is no specific data on gut tissue damage, it has been reported in other bodily systems—e.g., kidney [45]. This represents a particularly severe problem in a world where no matter the country, the SSB consumption increases steadily year after year [57].
Research on this matter has still a long path to walk. However, preliminary results from ongoing protocols at our laboratory show a significant rise in 4-HNE levels in the gut epithelium in response to air pollution and SSB consumption mice models, which indicate higher oxidative stress levels vs. control groups.
Air pollution has been associated to thrombosis and cardiovascular risk. Pollutants, including PM and metals may induce oxidative stress and inflammation predisposing to endothelial dysfunction, platelet activation, and procoagulant state [58]. There is epidemiological evidence that elevated concentrations of pollutants, e.g., vanadium, are associated to an increase in ER visits for acute cardiovascular effects or exacerbations of preexisting cardiovascular diseases [59].
Vanadium induces oxidative stress, and there is evidence of their toxic effects on endothelium, platelets, and myocardium. An in vitro study using HUVEC (human umbilical vein endothelial cells) exposed to different V2O5 concentrations reported an increase in ROS that damaged endothelial cells leading to apoptosis and diminished proliferation. This might be involved in endothelial dysfunction and increased cardiovascular risk associated to metals [60]. An in vivo vanadium inhalation mice model, from our group, reported thrombocytosis that is an increase in platelet number, but also the presence of giant platelets that are associated to increase reactivity [61]. Also, we found a megakaryocytosis with an increase in megakaryocytes size and granularity because of the activation of JAK/STAT pathway [40, 62, 63]. Platelet aggregation after subchronic vanadium inhalation diminished, but activation markers of platelets P-selectin or CD-62p were increased after the 4th week of exposure, maybe because of the slow elimination of vanadium, so it is possible that this metal has on platelet aggregation a long-term effects [64]. Another effect of vanadium on cardiovascular system is arrhythmia; in our group, we studied its effect on myocardium N-cadherin and connexin-43, important proteins in the intercalated discs. The reduction of both proteins and its effect on the electric stimuli conduction was proposed to explain the pathophysiology of the arrhythmias induced by vanadium [65]. Vanadium and other metals induce oxidative stress that may damage several cells of cardiovascular system.
The lung is one of the main targets of air pollution damage because it is the first site in contact with the pollutants suspended in the air. After reaching the alveolar epithelium, the pollutants can cross the alveoli-capillary barrier. There are various reports that demonstrate the damage caused to this organ by exposure to specific contaminants, such as vanadium that is part of the suspended particles.
In vivo, it has been reported that inhaled exposure to vanadium, mainly in the form of pentoxide induces histopathological changes in the lung, such as fibrosis [66], inflammation [30, 66, 67], hyperplasia and epithelial metaplasia [30, 67] and apoptotic cell death [68], among others.
Experimental evidence supports that exposure to V2O5 increases the production of ROS in lung cells. Wang et al. [68] reported increase in ROS production in mice bronchoalveolar lavage cells treated with a concentration of 10 μm of sodium metavanadate (NaVO3), in a time-exposure dependent manner (3, 10, 30, and 60 minutes) through a spin trapping essay.
On the other hand, other evidence shows that exposure to V modifies in the lung glutathione concentrations, both in its oxidized (GSSG) and reduced (GSH) forms. It is known that oxidative stress results in the depletion of GSH and the increase in GSS; so, the determination of their respective concentrations in blood and other tissues is considered a measure of intracellular oxidative stress [69].
Schuler et al. reported that in their inhalation model of V2O5 at exposure concentrations of 0.25, 1, and 4 mg/m3, there was an increase in the levels of oxidized glutathione (GSSG) in lung tissue, with the consequent reduction in the ratio between reduced and oxidized glutathione (GSH/GSSG) concentrations [70]. Kulkarni and colleagues reported the same finding in relation to GSH concentration in lung tissue in a model of exposure to V2O5 nanoparticles [66]. In addition to this finding in the same study, the significant increase in MDA levels in plasma was identified. The MDA is a final product of lipid peroxidation.
Another biomarker of oxidative damage that has been identified is the 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxoGuo) in the DNA. Schuler demonstrated the increase in the formation of 8-oxoGuoin at exposure concentrations of 1 and 4 mg/m3 of V2O5 in lung cells [70].
Neurotoxic metals as vanadium can induce oxidative damage in the brain and develop blood brain barrier disruption, neuropathology, and neuronal damage that can trigger central nervous system alterations as depression, increase in anger, fatigue, and tremors between other clinical features [71]. Also, a decrease in tyrosine hydroxylase and dopamine levels has been reported after vanadium exposure [72]. Chronical exposure to NaVO3 can cause, in mice, metal accumulation in the olfactory bulb, brain stem, and cerebellum, as well as histopathological alterations like nuclear shrinkage in the prefrontal cortex and cell death of the hippocampal pyramidal cells and cerebellum Purkinje cells [71]. The accumulation of vanadium in the brain depends more on the exposure time than on the concentration of the metal. In fact, it is reported that disruption of ependymal cells is observed after long periods of vanadium inhalation [73].
Recently, behavioral alterations due to vanadium occupational exposure have been reported. Vanadium exposed workers exhibited poor performance in the simple reaction time, digit span memory, and Benton visual retention tests [74]. Memory loss in mice exposed to vanadium for 3 months was observed; nevertheless, in these animals, memory was recovered 9 months after vanadium was removal [75]. Increased incidence of Parkinson’s disease is related to environmental metal exposure. It has been reported that vanadium pentoxide (V2O5) is neurotoxic to dopaminergic neurons via caspase-3-dependent PKCδ cleavage, so maybe vanadium can promote nigral dopaminergic degeneration [76].
The cells exposed continuously to oxidative stress are not defenseless against free radicals. All aerobic organisms count with a series of mechanisms protecting them against oxidative damage; among them are antioxidant molecules which represent a first line of defense. If the antioxidant mechanisms fail, the cell uses others such as: transient cell arrest, biomolecular repair systems or apoptosis death processes [7].
An antioxidant is any substance that when is present in low concentrations, compared to the oxidizable substrate, decreases or prevents the substrate oxidation. Oxidizable substrates comprise everything that is found in living tissues including proteins, lipids, carbohydrates, and nucleic acids [77].
Cells use a series of antioxidant compounds that react directly with oxidizing agents, functioning as “sweepers” or chemical shields [7]; these molecules have enzymatic or non-enzymatic actions. Non-enzymatic antioxidants carry out the reduction of free radicals through electron donation, thus avoiding oxidative reactions. Glutathione (GSH), alpha-tocopherol (vitamin E), ascorbic acid (vitamin C), carnosine, bilirubin, and uric acid are the main molecules performing this function.
Ascorbate is an important water-soluble antioxidant in biological fluids, because it eliminates reactive oxygen species and radicals such as: alkoxy, hydroxyl, peroxyl, and hydroperoxyl radicals, singlet oxygen, superoxide anion, and ozone. It also eliminates reactive species and radicals derived from nitrogen and chlorine and even radicals that come from other antioxidants [78].
In general, a large number of studies have been carried out to show the beneficial effects of ascorbate. Evidence indicates that supplementation with this compound protects against lipid oxidation in vivo, particularly in individuals exposed to exacerbated conditions of oxidative stress, such as smokers [79].
Epidemiological studies of treatment with this antioxidant have shown consistently favorable effects in patients with cardiovascular disease or coronary risk. In addition, it has been suggested that the increase in ascorbate consumption significantly decreases the incidence and mortality from cardiovascular diseases. Even in pathologies related to free radicals and the inability of the organism defenses against them, as is the case of cancer, epidemiological studies show that increased consumption of ascorbate decreases the incidence and mortality from cancer [79].
Experimental evidence indicates that ascorbic acid works as an antidote against acute vanadium poisoning. In mice, Jones and Basinger [80] examined several compounds and concluded that ascorbate was the most promising for human use.
Domingo et al. [81] administered NaVO3 to mice intraperitoneally and observed, as did Jones and Basinger, that ascorbate proved to be the most effective antidote against vanadium poisoning. In another study, Domingo et al. [82] showed that ascorbate stimulates urinary excretion of vanadium when mice are injected intramuscularly with VOSO4.
Another water-soluble antioxidant is carnosine which is a dipeptide composed of β-alanine and L-histidine; it is found naturally in many mammalian species, mainly in the skeletal muscle. It is estimated that 99% of the carnosine in the organism is found in muscular tissue [83].
It has been reported that carnosine may form complexes with transition metals and has antioxidant activity, which implies mechanisms such as chelation of metals, scavenging of ROS, and peroxyl radicals [83].
The antioxidant efficiency of carnosine in the nervous system, when mice are exposed to vanadium inhalation was successfully tested by our group. It was observed that in those groups with carnosine treatment, a larger size granulose cells with a greater number of dendritic spines, and in general less adverse ultrastructural morphological changes, as well as less lipid peroxidation were observed [84].
Air pollution has been continuously mentioned as one of the problems that decrease the quality and life expectancy of all living organisms, included humankind. It is true that not all the sources of pollution are from anthropological origin; however, a great deal of it are generated by humans and can be prevented or controlled by those who generate it.
The use of fossil fuels as the quasi unique source of energy and limited use of other sources of energy will maintain the air pollutant levels high enough to keep its deleterious health effects.
As it is revised in this chapter, metals are one of the air pollutants that enter through the respiratory tract, reaching by the systemic circulation every cell in living organisms. Vanadium is one of the elements adhered to PM which results from the incomplete combustion of fossil fuels. PM generates ROS, mainly those that contains transition metals (e.g., Fe, V, and Mn).
Reported previously in this chapter, one of the main toxic mechanisms of metals is oxidative stress which affects all biomolecules. DNA oxidative damage may conduct the cell to genotoxic and mutagenic changes and further to cell death or cancer.
When proteins are oxidized: cell structure, cell signaling modification, and/or disruption of cellular enzymatic processes could be noticed. The reactive molecules which results from these interactions with proteins and ROS may interplay with specific peptide residues such as: lysines, arginines, histidines, and cysteines. The result of these actions causes the formation of reactive carbonyls and protein carbonylation, and its accumulations have been related with chronic diseases and aging.
If lipids are in contact with ROS, peroxidation occurs producing MDA, a biomarker of oxidative stress that could interact with proteins forming protein adducts and inactivating the protein. Another lipid peroxidation product is 4-HNE with cytotoxic effects and the induction of pro-inflammatory cytokines, which could result in cellular dysfunction and death [85].
If the sources of V or other pollutants are not reduced and the oxidative insults prevail, we can supplement our system with antioxidants such as vitamin C. This water-soluble molecule is not synthesized by humans, and its supplementation is obtained by different dietary sources such as fruits and vegetables or by vitamin C supplements. One of the benefits of vitamin C is its antioxidant action, scavenging ROS and NOS species. In addition, it helps to regenerate alpha-tocopherol and coenzyme Q; also, vitamin C inhibits NAD(P)H oxidase decreasing ROS formation [86]. Another less known endogenous and exogenous antioxidant is carnosine that in our laboratory showed promising antioxidant effects in the nervous system [84].
The systems and organs affected by the oxidative potential of vanadium and the protective effect of antioxidants are summarized in Figure 2.
Oxidative stress by vanadium and antioxidants protective effects (this figure was created by Biorender software in www.biorender.com).
While humankind decide to work together in order to find a common solution for controlling air pollution, scientist should be working in finding more and better antioxidants to prevent and ameliorate the effects that metals, such as V adhered to PM, have on living organisms, that meanwhile might reduce oxidative stress, its injurious effects and improves the quality of life on the planet.
This work was partially supported by project PAPIIT-DGAPA UNAM IN200418.
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