The spinal cord injury-induced immune deficiency syndrome: results of the SCIentinel study.

Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84 h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of -0.43 (95% CI: -0.66; -0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [-0.27 (95% CI: -0.45; -0.10)] and immunoglobulin A [-0.25 (95% CI: -0.49; -0.01)] levels [ln (g/l × 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI.

Influence of clinical and radiological parameters on the likelihood of neurological improvement after surgery for degenerative cervical myelopathy.

OBJECTIVE: Degenerative cervical myelopathy (DCM) is routinely treated with surgical decompression, but disparate postoperative outcomes are frequently observed, ranging from complete neurological recovery to persistent decline. Although numerous clinical and radiological factors have been independently associated with failure to improve, the relative impact of these proposed risk factors remains obscure. In this study, the authors assess the combined role of clinical and radiographic parameters in contributing to failure to attain neurological improvement after surgery. METHODS: A consecutive series of patients who underwent surgery for DCM between July 2013 and August 2018 at a single institution was identified from a prospectively maintained database. Retrospective chart review was undertaken to record perioperative clinical and radiographic parameters. Failure to improve on the last follow-up evaluation after surgery, defined as a change in modified Japanese Orthopaedic Association (mJOA) score less than 2, was the primary outcome in univariate and multivariate analyses. RESULTS: The authors included 183 patients in the final cohort. In total, 109 (59.6%) patients improved (i.e., responders with ΔmJOA score ≥ 2) after surgery and 74 (40.4%) were nonresponders with ΔmJOA score < 2. Baseline demographic variables and comorbidity rates were similar, whereas baseline Nurick score was the only clinical variable that differed between responders and nonresponders (2.7 vs 3.0, p = 0.02). In contrast, several preoperative radiographic variables differed between the groups, including presence and degree of cervical kyphosis, number of levels with bidirectional cord compression, presence and number of levels with T2-weighted signal change, intramedullary lesion (IML) length, Torg ratio, and both narrowest spinal canal and cord diameter. On multivariate analysis, preoperative degree of kyphosis at C2-7 (OR 1.19, p = 0.004), number of levels with bidirectional compression (OR 1.83, p = 0.003), and IML length (OR 1.14, p < 0.001) demonstrated the highest predictive power for nonresponse (area under the receiver operating characteristic curve 0.818). A risk factor point system that predicted failure of improvement was derived by incorporating these 3 variables. CONCLUSIONS: When a large spectrum of both clinical and radiographic variables is considered, the degree of cervical kyphosis, number of levels with bidirectional compression, and IML length are the most predictive of nonresponse after surgery for DCM. Assessment of these radiographic factors can help guide surgical decision-making and more appropriately stratify patients in clinical trials.

Spinal Cord Injury Impairs Lung Immunity in Mice.

Pulmonary infection is a leading cause of morbidity and mortality after spinal cord injury (SCI). Although SCI causes atrophy and dysfunction in primary and secondary lymphoid tissues with a corresponding decrease in the number and function of circulating leukocytes, it is unknown whether this SCI-dependent systemic immune suppression also affects the unique tissue-specific antimicrobial defense mechanisms that protect the lung. In this study, we tested the hypothesis that SCI directly impairs pulmonary immunity and subsequently increases the risk for developing pneumonia. Using mouse models of severe high-level SCI, we find that recruitment of circulating leukocytes and transcriptional control of immune signaling in the lung is impaired after SCI, creating an environment that is permissive for infection. Specifically, we saw a sustained loss of pulmonary leukocytes, a loss of alveolar macrophages at chronic time points postinjury, and a decrease in immune modulatory genes, especially cytokines, needed to eliminate pulmonary infections. Importantly, this injury-dependent impairment of pulmonary antimicrobial defense is only partially overcome by boosting the recruitment of immune cells to the lung with the drug AMD3100, a Food and Drug Administration-approved drug that mobilizes leukocytes and hematopoietic stem cells from bone marrow. Collectively, these data indicate that the immune-suppressive effects of SCI extend to the lung, a unique site of mucosal immunity. Furthermore, preventing lung infection after SCI will likely require novel strategies, beyond the use of orthodox antibiotics, to reverse or block tissue-specific cellular and molecular determinants of pulmonary immune surveillance.

Spinal infection with intraspinal abscess or empyema and acute myelopathy: comparative analysis of diagnostics, therapy, complications and outcome in primary care.

INTRODUCTION: This study on pyogenic spinal infections with intraspinal epidural involvement (PSI +) compared the outcome of patients with spinal cord injury (SCI) to those without (noSCI) taking diagnostic algorithm, therapy, and complications into account. METHODS: Patients were enrolled in an ambispective study (2012-2017). Diagnostic and therapeutic algorithms, complications, and neurological outcome were analyzed descriptively. Survival was analyzed applying Kaplan-Meier method and Cox regression. RESULTS: In total, 134 patients with a median (IQR) age of 72 (61-79) years were analyzed. Baseline characteristics were similar between the SCI (n = 55) and noSCI (n = 79). A higher percentage of endocarditis (9% vs. 0%; p = 0.03) was detected in the noSCI group. The majority (81%) received combinatorial therapy including spinal surgery and antibiotic treatment. The surgery complication rate was 16%. At discharge, improvement in neurologic function was present in 27% of the SCI patients. Length of stay, duration of ventilation and the burden of disease-associated complications were significantly higher in the SCI group (e.g., urinary tract infection, pressure ulcers). Lethality risk factors were age (HR 1.09, 95% CI 1.02-1.16, p = 0.014), and empyema/abscess extension (≥ 3 infected spinal segments, HR 4.72, 95% CI 1.57-14.20, p = 0.006), dominating over additional effects of Charlson comorbidity index, SCI, and type of treatment. The overall lethality rate was 11%. CONCLUSION: PSI + are associated with higher in-hospital mortality, particularly when multiple spinal segments are involved. However, survival is similar with (SCI) or without myelopathy (noSCI). If SCI develops, the rate of disease complications is higher and early specialized SCI care might be substantial to reduce complication rates.

Immune dysfunction after spinal cord injury - A review of autonomic and neuroendocrine mechanisms.

Infections impair neurological outcome and increase mortality after spinal cord injury (SCI). Emerging data show that pathogens more easily infect individuals with SCI because SCI disrupts neural and humoral control of immune cells, culminating with the development of "SCI-induced immune deficiency syndrome" (SCI-IDS). Here, we review data that implicate autonomic dysfunction and impaired neuroendocrine signaling as key determinants of SCI-IDS. Although it is widely appreciated that mature leukocyte dysfunction is a canonical feature of SCI-IDS, new data indicate that SCI impairs the development and mobilization of immune cell precursors in bone marrow. Thus, this review will also explore how the post-injury acquisition of a "bone marrow failure syndrome" may be the earliest manifestation of SCI-IDS.

Association of age with the timing of acute spine surgery-effects on neurological outcome after traumatic spinal cord injury.

PURPOSE: To investigate the association of age with delay in spine surgery and the effects on neurological outcome after traumatic spinal cord injury (SCI). METHODS: Ambispective cohort study (2011-2017) in n = 213 patients consecutively enrolled in a Level I trauma center with SCI care in a metropolitan region in Germany. Age-related differences in the injury to surgery interval and conditions associated with its delay (> 12 h after SCI) were explored using age categories or continuous variables and natural cubic splines. Effects of delayed surgery or age with outcome were analyzed using multiple logistic regression. RESULTS: The median age of the study population was 58.8 years (42.0-74.6 IQR). Older age (≥ 75y) was associated with a prolonged injury to surgery interval of 22.8 h (7.2-121.3) compared to 6.6 h (4.4-47.9) in younger patients (≤ 44y). Main reasons for delayed surgery in older individuals were secondary referrals and multimorbidity. Shorter time span to surgery (≤ 12 h) was associated with higher rates of ASIA impairment scale (AIS) conversion (OR 4.22, 95%CI 1.85-9.65), as mirrored by adjusted spline curves (< 20 h 20-25%, 20-60 h 10-20%, > 60 h < 10% probability of AIS conversion). In incomplete SCI, the probability of AIS conversion was lower in older patients [e.g., OR 0.09 (0.02-0.44) for'45-59y' vs.' ≤ 44y'], as confirmed by spline curves (< 40y 20-80%, ≥ 40y 5-20% probability). CONCLUSION: Older patient age complexifies surgical SCI care and research. Tackling secondary referral to Level I trauma centers and delayed spine surgery imposes as tangible opportunity to improve the outcome of older SCI patients.

Acute and non-resolving inflammation associate with oxidative injury after human spinal cord injury.

Traumatic spinal cord injury is a devastating insult followed by progressive cord atrophy and neurodegeneration. Dysregulated or non-resolving inflammatory processes can disturb neuronal homeostasis and drive neurodegeneration. Here, we provide an in-depth characterization of innate and adaptive inflammatory responses as well as oxidative tissue injury in human traumatic spinal cord injury lesions compared to non-traumatic control cords. In the lesion core, microglia were rapidly lost while intermediate (co-expressing pro- as well as anti-inflammatory molecules) blood-borne macrophages dominated. In contrast, in the surrounding rim, TMEM119+ microglia numbers were maintained through local proliferation and demonstrated a predominantly pro-inflammatory phenotype. Lymphocyte numbers were low and mainly consisted of CD8+ T cells. Only in a subpopulation of patients, CD138+/IgG+ plasma cells were detected, which could serve as candidate cellular sources for a developing humoral immunity. Oxidative neuronal cell body and axonal injury was visualized by intracellular accumulation of amyloid precursor protein (APP) and oxidized phospholipids (e06) and occurred early within the lesion core and declined over time. In contrast, within the surrounding rim, pronounced APP+/e06+ axon-dendritic injury of neurons was detected, which remained significantly elevated up to months/years, thus providing mechanistic evidence for ongoing neuronal damage long after initial trauma. Dynamic and sustained neurotoxicity after human spinal cord injury might be a substantial contributor to (i) an impaired response to rehabilitation; (ii) overall failure of recovery; or (iii) late loss of recovered function (neuro-worsening/degeneration).

Maresin 1 Promotes Inflammatory Resolution, Neuroprotection, and Functional Neurological Recovery After Spinal Cord Injury.

Resolution of inflammation is defective after spinal cord injury (SCI), which impairs tissue integrity and remodeling and leads to functional deficits. Effective pharmacological treatments for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized proresolving mediator (SPM) hosting potent anti-inflammatory and proresolving properties with potent tissue regenerative actions. Here, we provide evidence that the inappropriate biosynthesis of SPM in the lesioned spinal cord hampers the resolution of inflammation and leads to deleterious consequences on neurological outcome in adult female mice. We report that, after spinal cord contusion injury in adult female mice, the biosynthesis of SPM is not induced in the lesion site up to 2 weeks after injury. Exogenous administration of MaR1, a highly conserved SPM, propagated inflammatory resolution after SCI, as revealed by accelerated clearance of neutrophils and a reduction in macrophage accumulation at the lesion site. In the search of mechanisms underlying the proresolving actions of MaR1 in SCI, we found that this SPM facilitated several hallmarks of resolution of inflammation, including reduction of proinflammatory cytokines (CXCL1, CXCL2, CCL3, CCL4, IL6, and CSF3), silencing of major inflammatory intracellular signaling cascades (STAT1, STAT3, STAT5, p38, and ERK1/2), redirection of macrophage activation toward a prorepair phenotype, and increase of the phagocytic engulfment of neutrophils by macrophages. Interestingly, MaR1 administration improved locomotor recovery significantly and mitigated secondary injury progression in a clinical relevant model of SCI. These findings suggest that proresolution, immunoresolvent therapies constitute a novel approach to improving neurological recovery after acute SCI.SIGNIFICANCE STATEMENT Inflammation is a protective response to injury or infection. To result in tissue homeostasis, inflammation has to resolve over time. Incomplete or delayed resolution leads to detrimental effects, including propagated tissue damage and impaired wound healing, as occurs after spinal cord injury (SCI). We report that inflammation after SCI is dysregulated in part due to inappropriate synthesis of proresolving lipid mediators. We demonstrate that the administration of the resolution agonist referred to as maresin 1 (MaR1) after SCI actively propagates resolution processes at the lesion site and improves neurological outcome. MaR1 is identified as an interventional candidate to attenuate dysregulated lesional inflammation and to restore functional recovery after SCI.

Natural Killer (NK) Cell Functionality after human Spinal Cord Injury (SCI): protocol of a prospective, longitudinal study.

BACKGROUND: Natural killer (NK) cells comprise the main components of lymphocyte-mediated nonspecific immunity. Through their effector function they play a crucial role combating bacterial and viral challenges. They are also thought to be key contributors to the systemic spinal cord injury-induced immune-deficiency syndrome (SCI-IDS). SCI-IDS increases susceptibility to infection and extends to the post-acute and chronic phases after SCI. METHODS AND DESIGN: The prospective study of NK cell function after traumatic SCI was carried out in two centers in Berlin, Germany. SCI patients and control patients with neurologically silent vertebral fracture also undergoing surgical stabilization were enrolled. Furthermore healthy controls were included to provide reference data. The NK cell function was assessed at 7 (5-9) days, 14 days (11-28) days, and 10 (8-12) weeks post-trauma. Clinical documentation included the American Spinal Injury Association (ASIA) impairment scale (AIS), neurological level of injury, infection status, concomitant injury, and medications. The primary endpoint of the study is CD107a expression by NK cells (cytotoxicity marker) 8-12 weeks following SCI. Secondary endpoints are the NK cell's TNF-α and IFN-γ production by the NK cells 8-12 weeks following SCI. DISCUSSION: The protocol of this study was developed to investigate the hypotheses whether i) SCI impairs NK cell function throughout the post-acute and sub-acute phases after SCI and ii) the degree of impairment relates to lesion height and severity. A deeper understanding of the SCI-IDS is crucial to enable strategies for prevention of infections, which are associated with poor neurological outcome and elevated mortality. TRIAL REGISTRATION: DRKS00009855 .

Anti-Inflammatory Effects of IL-27 in Zymosan-Induced Peritonitis: Inhibition of Neutrophil Recruitment Partially Explained by Impaired Mobilization from Bone Marrow and Reduced Chemokine Levels.

Rapid activation of the innate immune system is critical for an efficient host response to invading pathogens. However, the inflammatory reaction has to be strictly controlled to minimize harmful immunopathology. A number of mediators including the cytokine interleukin-27 (IL-27) appear to be responsible for limitation and resolution of inflammation. Despite increasing knowledge of its suppressive effects on T cells, the influence on neutrophils and macrophages is poorly understood. To determine the role of IL-27 in innate immune responses we analysed the effect of IL-27 in a T cell independent model of zymosan-induced peritonitis. Early administration of recombinant IL-27 strongly reduced the number of neutrophils recruited to the peritoneal cavity after zymosan application as well as the neutrophil frequency in the blood. Simultaneously, IL-27 reduced the release of neutrophils from the bone marrow upon inflammation. Although cytokine levels were not affected by IL-27 treatment, the levels of the chemokines KC, MCP-1 and MIP-1α in the peritoneal fluid were strongly decreased. These findings demonstrate that IL-27 is able to control mobilisation and recruitment of neutrophils into the peritoneal cavity and identify a novel mechanism to limit inflammation caused by innate immune cells.

The SCIentinel study--prospective multicenter study to define the spinal cord injury-induced immune depression syndrome (SCI-IDS)--study protocol and interim feasibility data.

BACKGROUND: Infections are the leading cause of death in the acute phase following spinal cord injury and qualify as independent risk factor for poor neurological outcome ("disease modifying factor"). The enhanced susceptibility for infections is not stringently explained by the increased risk of aspiration in tetraplegic patients, neurogenic bladder dysfunction, or by high-dose methylprednisolone treatment. Experimental and clinical pilot data suggest that spinal cord injury disrupts the balanced interplay between the central nervous system and the immune system. The primary hypothesis is that the Spinal Cord Injury-induced Immune Depression Syndrome (SCI-IDS) is 'neurogenic' including deactivation of adaptive and innate immunity with decreased HLA-DR expression on monocytes as a key surrogate parameter. Secondary hypotheses are that the Immune Depression Syndrome is i) injury level- and ii) severity-dependent, iii) triggers transient lymphopenia, and iv) causes qualitative functional leukocyte deficits, which may endure the post-acute phase after spinal cord injury. METHODS/DESIGN: SCIentinel is a prospective, international, multicenter study aiming to recruit about 118 patients with acute spinal cord injury or control patients with acute vertebral fracture without neurological deficits scheduled for spinal surgery. The assessment points are: i) <31 hours, ii) 31-55 hours, iii) 7 days, iv) 14 days, and v) 10 weeks post-trauma. Assessment includes infections, concomitant injury, medication and neurological classification using American Spinal Injury Association impairment scale (AIS) and neurological level. Laboratory analyses comprise haematological profiling, immunophenotyping, including HLA-DR expression on monocytes, cytokines and gene expression of immune modulators. We provide an administrative interim analysis of the recruitment schedule of the trial. DISCUSSION: The objectives are to characterize the dysfunction of the innate and adaptive immune system after spinal cord injury and to explore its proposed 'neurogenic' origin by analyzing its correlation with lesion height and severity. The trial protocol considers difficulties of enrolment in an acute setting, and loss to follow up. The administrative interim analysis confirmed the feasibility of the protocol. Better understanding of the SCI-IDS is crucial to reduce co-morbidities and thereby to attenuate the impact of disease modifying factors to protect neurological "outcome at risk". This putatively results in improved spinal cord injury medical care. TRIAL REGISTRATION DRKS-ID: DRKS00000122 (German Clinical Trials Registry).

Non-resolving aspects of acute inflammation after spinal cord injury (SCI): indices and resolution plateau.

Inflammatory resolution is an active, highly regulated process already encoded at the onset of inflammation and required to prevent the transition into chronic inflammation associated with spreading of tissue injury and exacerbated scarring. We introduce objective, quantitative measurements [resolution indices (R(i) ) and resolution plateau (R(P) )] to characterize inflammatory resolution and to determine the persistence ("dwell time") of differential leukocyte subpopulations at the lesion site after acute experimental spinal cord injury (SCI). The cell type-specific resolution interval R(i) (time between maximum cell numbers and the point when they are reduced to 50%) ranges from 1.2 days for neutrophils, 1.5 days for T lymphocytes, to 55 days for microglia/macrophages. As the resolution interval neglects exiting cell trafficking in the later period of resolution (49%-0% of lesional cells), we introduced the R(P) , a marker for the persisting, chronified leukocyte subsets, which are likely to participate in late degeneration and non-resolving inflammation. Here, we identify the acute inflammatory response in central nervous system (CNS) lesions as partly non self-limiting. Both extended resolution intervals (reduced leukocyte clearance) and elevated plateaus (permanent lesional cell numbers) provide quantitative measures to characterize residual, sustained inflammation and define cognate timeframes of impaired resolution after acute SCI.

Lumbar spinal stenosis: syndrome, diagnostics and treatment.

Lumbar spinal stenosis (LSS) comprises narrowing of the spinal canal with subsequent neural compression, and is frequently associated with symptoms of neurogenic claudication. To establish a diagnosis of LSS, clinical history, physical examination results and radiological changes all need to be considered. Patients who exhibit mild to moderate symptoms of LSS should undergo multimodal conservative treatment, such as patient education, pain medication, delordosing physiotherapy and epidural injections. In patients with severe symptoms, surgery is indicated if conservative treatment proves ineffective after 3-6 months. Clinically relevant motor deficits or symptoms of cauda equina syndrome remain absolute indications for surgery. The first randomized, prospective studies have provided class I-II evidence that supports a more rapid and profound decline of LSS symptoms after decompressive surgery than with conservative therapy. In the absence of a valid paraclinical diagnostic marker, however, more evidence-based data are needed to identify those patients for whom the benefit of surgery would outweigh the risk of developing complications. In this Review, we briefly survey the underlying pathophysiology and clinical appearance of LSS, and explore the available diagnostic and therapeutic options, with particular emphasis on neuroradiological findings and outcome predictors.

Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia.

The neuronal guidance molecule netrin-1 is linked to the coordination of inflammatory responses. Given that mucosal surfaces are particularly prone to hypoxia-elicited inflammation, we sought to determine the function of netrin-1 in hypoxia-induced inflammation. We detected hypoxia-inducible factor 1alpha (HIF-1alpha)-dependent induction of expression of the gene encoding netrin-1 (Ntn1) in hypoxic epithelia. Neutrophil transepithelial migration studies showed that by engaging A2B adenosine receptor (A2BAR) on neutrophils, netrin-1 attenuated neutrophil transmigration. Exogenous netrin-1 suppressed hypoxia-elicited inflammation in wild-type but not in A2BAR-deficient mice, and inflammatory hypoxia was enhanced in Ntn1(+/-) mice relative to that in Ntn1(+/+) mice. Our studies demonstrate that HIF-1alpha-dependent induction of netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.

Anesthetics impact the resolution of inflammation.

BACKGROUND: Local and volatile anesthetics are widely used for surgery. It is not known whether anesthetics impinge on the orchestrated events in spontaneous resolution of acute inflammation. Here we investigated whether a commonly used local anesthetic (lidocaine) and a widely used inhaled anesthetic (isoflurane) impact the active process of resolution of inflammation. METHODS AND FINDINGS: Using murine peritonitis induced by zymosan and a systems approach, we report that lidocaine delayed and blocked key events in resolution of inflammation. Lidocaine inhibited both PMN apoptosis and macrophage uptake of apoptotic PMN, events that contributed to impaired PMN removal from exudates and thereby delayed the onset of resolution of acute inflammation and return to homeostasis. Lidocaine did not alter the levels of specific lipid mediators, including pro-inflammatory leukotriene B(4), prostaglandin E(2) and anti-inflammatory lipoxin A(4), in the cell-free peritoneal lavages. Addition of a lipoxin A(4) stable analog, partially rescued lidocaine-delayed resolution of inflammation. To identify protein components underlying lidocaine's actions in resolution, systematic proteomics was carried out using nanospray-liquid chromatography-tandem mass spectrometry. Lidocaine selectively up-regulated pro-inflammatory proteins including S100A8/9 and CRAMP/LL-37, and down-regulated anti-inflammatory and some pro-resolution peptides and proteins including IL-4, IL-13, TGF-â and Galectin-1. In contrast, the volatile anesthetic isoflurane promoted resolution in this system, diminishing the amplitude of PMN infiltration and shortening the resolution interval (Ri) approximately 50%. In addition, isoflurane down-regulated a panel of pro-inflammatory chemokines and cytokines, as well as proteins known to be active in cell migration and chemotaxis (i.e., CRAMP and cofilin-1). The distinct impact of lidocaine and isoflurane on selective molecules may underlie their opposite actions in resolution of inflammation, namely lidocaine delayed the onset of resolution (T(max)), while isoflurane shortened resolution interval (Ri). CONCLUSIONS: Taken together, both local and volatile anesthetics impact endogenous resolution program(s), altering specific resolution indices and selective cellular/molecular components in inflammation-resolution. Isoflurane enhances whereas lidocaine impairs timely resolution of acute inflammation.

Spinal cord injury-induced expression of the antiangiogenic endostatin/collagen XVIII in areas of vascular remodelling.

OBJECT: Spinal cord injury (SCI) induces the disruption of neural and vascular structures. In contrast to the emerging knowledge of mechanisms regulating the onset of the postinjury angiogenic response, little is known about counterregulatory signals. METHODS: Using immunohistochemical methods, the authors investigated the expression of the endogenous angiogenic inhibitor endostatin/collagen XVIII during the tissue remodeling response to SCI. RESULTS: After SCI, endostatin/collagen XVIII+ cells accumulated at the lesion site, in pannecrotic regions (especially in areas of cavity formation), at the lesion margin/areas of ongoing secondary damage, and in perivascular Virchow-Robin spaces. In remote areas (> 0.75 cm from the epicenter) a more modest accumulation of endostatin/collagen XVIII+ cells was observed, especially in areas of pronounced Wallerian degeneration. The numbers of endostatin/collagen XVIII+ cells reached their maximum on Day 7 after SCI. The cell numbers remained elevated in both, the lesion and remote regions, compared with control spinal cords for 4 weeks afterwards. In addition to being predominantly confined to ED1+-activated microglia/macrophages within the pannecrotic lesion core, endostatin/collagen XVIII expression was frequently detected by the endothelium/vessel walls. Numbers of lesional endostatin/collagen XVIII+ endothelium/vessel walls were found to increase early by Day 1 postinjury, reaching their maximum on Day 3 and declining subsequently to enhanced (above control) levels 30 days after SCI. CONCLUSIONS: The authors detected that in comparison to the early expression of neoangiogenic factors, there was a postponed lesional expression of the antiangiogenic endostatin/collagen XVIII. Furthermore, the expression of endostatin/collagen XVIII was localized to areas of neovascular pruning and retraction (cavity formation). The expression of endostatin/collagen XVIII by macrophages in a "late" activated phagocytic mode suggests that this factor plays a role in counteracting the preceding "early" neoangiogenic response after SCI.

Resolvin E1 and protectin D1 activate inflammation-resolution programmes.

Resolution of acute inflammation is an active process essential for appropriate host responses, tissue protection and the return to homeostasis. During resolution, specific omega-3 polyunsaturated fatty-acid-derived mediators are generated within resolving exudates, including resolvin E1 (RvE1) and protectin D1 (PD1). It is thus important to pinpoint specific actions of RvE1 and PD1 in regulating tissue resolution. Here we report that RvE1 and PD1 in nanogram quantities promote phagocyte removal during acute inflammation by regulating leukocyte infiltration, increasing macrophage ingestion of apoptotic polymorphonuclear neutrophils in vivo and in vitro, and enhancing the appearance of phagocytes carrying engulfed zymosan in lymph nodes and spleen. In this tissue terrain, inhibition of either cyclooxygenase or lipoxygenases--pivotal enzymes in the temporal generation of both pro-inflammatory and pro-resolving mediators--caused a 'resolution deficit' that was rescued by RvE1, PD1 or aspirin-triggered lipoxin A4 analogue. Also, new resolution routes were identified that involve phagocytes traversing perinodal adipose tissues and non-apoptotic polymorphonuclear neutrophils carrying engulfed zymosan to lymph nodes. Together, these results identify new active components for postexudate resolution traffic, and demonstrate that RvE1 and PD1 are potent agonists for resolution of inflamed tissues.

Spinal cord injury-induced immune depression syndrome (SCI-IDS).

Infections are among the leading causes of death in spinal cord-injured patients, and are associated with hampered wound healing, prolonged hospitalization and impaired neurological recovery. We have analysed fluctuations of immune cell populations in an experimental rat model of spinal cord injury (SCI) by FACS analysis compared with sham-operated controls to detect the responses specifically induced by SCI. Further, to illustrate the impact of SCI only animals did not receive methylprednisolone in order to exclude confounding iatrogenic factors. Experimental SCI of rats induced a depletion of ED9(+) monocytes (< 45%, P < 0.01), CD3(+) T-lymphocytes (< 35%, P < 0.01), CD45 RA(+) B-lymphocytes (< 25%, P < 0.01), MHC class II(+) (< 40%, P < 0.01) and OX-62(+) dendritic cells (< 50%, P = 0.032) within the first week after SCI. HIS 48(+) granulocytes remained on levels similar to sham-operated controls. Our data suggest that experimental SCI induces early onset of an immune suppression that we refer to as SCI-immune depression syndrome. Iatrogenic application of methylprednisolone in patients suffering may worsen the immune suppression. A deeper understanding of the underlying mechanisms of this novel syndrome might be essential to decrease mortality, costs (time of hospitalization) and to protect the intrinsic neurological recovery potential following SCI.