Traumatic spinal cord injury (SCI) is a life changing neurological condition with substantial socioeconomic implications for patients and their care-givers. Recent advances in medical management of SCI has significantly improved diagnosis, stabilization, survival rate and well-being of SCI patients. However, there has been small progress on treatment options for improving the neurological outcomes of SCI patients. This incremental success mainly reflects the complexity of SCI pathophysiology and the diverse biochemical and physiological changes that occur in the injured spinal cord. Therefore, in the past few decades, considerable efforts have been made by SCI researchers to elucidate the pathophysiology of SCI and unravel the underlying cellular and molecular mechanisms of tissue degeneration and repair in the injured spinal cord. To this end, a number of preclinical animal and injury models have been developed to more closely recapitulate the primary and secondary injury processes of SCI. In this review, we will provide a comprehensive overview of the recent advances in our understanding of the pathophysiology of SCI. We will also discuss the neurological outcomes of human SCI and the available experimental model systems that have been employed to identify SCI mechanisms and develop therapeutic strategies for this condition.

/pdf/traumatic-spinal-cord-injury-an-overview-of-pathophysiology-2kheasgwgf.pdf

Traumatic Spinal Cord Injury: An Overview of Pathophysiology, Models and Acute Injury Mechanisms.

In inflammatory conditions such as RA, the neutrophil has tended to be dismissed as a short-lived, terminally differentiated, irrelevant bystander cell. However, this is clearly not the case. A better understanding of the complex heterogeneous pathways and processes that constitute RA, in parallel with a more sophisticated knowledge of neutrophil biology has identified many potential roles for these cells in the persistence of inflammation and progression of joint damage, which should not be underestimated. Not only are neutrophils found in high numbers within the rheumatoid joint, both in synovial tissue and in joint fluid, they have a huge potential to directly inflict damage to tissue, bone and cartilage via the secretion of proteases and toxic oxygen metabolites, as well as driving inflammation through antigen presentation and secretion of cytokines, chemokines, prostaglandins and leucotrienes. Drugs already used to treat RA down-regulate many neutrophil functions, including migration to the joint, degranulation and production of inflammatory mediators, and these cells should be considered as important targets for the development of new therapies in the future.

/pdf/neutrophil-function-in-inflammation-and-inflammatory-3d4j7ltn91.pdf

Neutrophil function in inflammation and inflammatory diseases

Transfusion-related acute lung injury.

After injury, muscle healing occurs through different phases, including (1) degeneration and inflammation, (2) muscle regeneration, and (3) development of fibrosis.

The severity and type of muscle injury influence the healing process.

Enhancement of muscle regeneration and prevention of muscle fibrosis can improve muscle healing.

Growth factors, including basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), and nerve growth factor (NGF), can improve muscle regeneration, but the post-injury healing process remains incomplete.

The use of anti-fibrosis agents that antagonize the effect of transforming growth factor-β1 (TGF-β1) can prevent fibrosis and improve muscle healing, resulting in nearly complete recovery.

Optimal muscle recovery may require the use of novel technologies, such as gene therapy and tissue engineering, to achieve both high levels and long-term persistence of these growth factors and cytokines within the injured muscle.

Muscle injury presents a challenging problem in traumatology, as injured muscles heal very slowly and often with incomplete functional recovery. It has been observed that injured muscles can initiate regeneration promptly, but the healing process is often inefficient and hindered by the formation of scar tissue, which may contribute to the tendency for muscle injury to recur. The enhancement of muscle regeneration and the prevention of muscle fibrosis through the use of biological approaches are being investigated in an effort to improve muscle healing after injury. In this Current Concepts Review, we will outline the structure and histological organization of skeletal muscle and describe the basic physiology of skeletal muscle contraction. We will subsequently summarize the biological and pathological processes that occur in skeletal muscle after injury (i.e., degeneration, inflammation, regeneration, and fibrosis) and present the clinical treatments currently available for injured skeletal muscle. Finally, we will discuss current trends in research, which include the improvement of regeneration and the inhibition of fibrosis in injured skeletal …

Muscle injuries and repair: current trends in research.

Neutrophils are the first to be recruited to a site of infection or a diseased site. Among various inflammatory mediators, CXC chemokines including IL-8 (CXCL8), MIP-2 (CXCL2), and KC (CXCL1) are the most critical for such recruitment. Neutrophils have been considered as effector cells that kill bacteria or destroy affected tissues mainly through the production of reactive oxygen species. Recent studies, however, revealed that neutrophils are involved in the production of chemokines in response to a variety of stimulants including LPS, TNF-alpha, and IFN-gamma, thereby contributing to immunomodulation. These functions are also regulated by selectins during infiltration into various sites. In this review, I summarize the current knowledge on this area and propose that neutrophils are a fascinating target for basic as well as clinical scientists.

The role of chemokines in neutrophil biology.

The role of neutrophils in the immune response has long been regarded as mainly phagocytic, but recent publications have indicated the production of several cytokines by polymorphonuclear leucocytes (PMN). The results of the individual reports, however, vary considerably. In this study, we established a cytokine profile of pure human neutrophils and demonstrated that minor contamination of peripheral blood mononuclear cells (PBMCs) in PMN preparations can lead to false-positive results. In our hands, peripheral blood PMN fail to produce the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha). Instead, they secrete large amounts of the chemokine IL-8 and the anti-inflammatory IL-1 receptor antagonist (IL-1ra). Additionally, PMN preparations of a high purity show production of the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and growth-related oncogene-alpha (GRO-alpha), as well as macrophage colony-stimulating factor (M-CSF). The neutrophil therefore represents a novelty by producing the antagonist of IL-1beta (i.e. IL-1ra) in the absence of IL-1beta itself. To support our results, we differentiated stem cells from human cord blood into PMN and monocytes, respectively. These in vitro-differentiated PMN showed the same cytokine profile as peripheral blood PMN lacking IL-1beta, while differentiated monocytes produced the expected IL-1beta in addition to IL-1ra. The clear anti-inflammatory nature of their cytokine profile enables PMN to antagonize pro-inflammatory signals in experimental conditions. It is therefore possible that PMN play a key role in immune regulation by counteracting a dysregulation of the inflammatory process. Clinical studies, in which administration of recombinant G-CSF had a favourable effect on the outcome of severe infections and even sepsis without worsening inflammation, could thus be explained by our results.

Polymorphonuclear leucocytes selectively produce anti-inflammatory interleukin-1 receptor antagonist and chemokines, but fail to produce pro-inflammatory mediators.

Neutrophils have been shown to express major histocompatibility complex class II (MHC II) after stimulation. However, reports concerning the functional effect of MCH II expression are still lacking. In our hands, granulocyte-monocyte colony-stimulating factor (GM-CSF) alone and in combination with interferon (IFN)-gamma, but not IFN-gamma or interleukin (IL)-3, induced a significant level of expression of human leukocyte antigen DR on neutrophils. The addition of staphylococcal enterotoxin E to neutrophils resulted in a significant increase in IL-8 production only after prestimulation with GM-CSF alone or in combination with IFN-gamma but had no effect on neutrophils preincubated with IFN-gamma alone or IL-3. Staphylococcal enterotoxin A, another bivalent superantigen, also stimulated production of IL-8 by preincubated polymorphonuclear neutrophils, whereas staphylococcal enterotoxin A mutants that are not able to cross-link MHC II molecules failed to induce IL-8 production. Taken together, our results clearly demonstrate that after induction of MHC II, neutrophils are able to respond to MHC II-specific stimulation. These findings support the ideas that the induced MHC II complex is completely functional and that neutrophils may be able to present antigens.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.70.1.80

Induction of interleukin-8 in human neutrophils after MHC class II cross-linking with superantigens.

Several cell types have been shown to produce type I interferons (IFN). Of human leukocytes, monocytes and especially type 2 dendritic cell precursors (pDC2) seem to be the main producers and also have a wide spectrum of cytokine production. However, neutrophils seem to have a limited capacity for cytokine production but possess efficient defense mechanisms vs. bacterial infection by phagocytosis and degranulation. To determine whether they also have antiviral functions, IFN-α and IFN-β were measured in preparations of pure neutrophils. The capacity of neutrophils to produce type I IFN is controversial. Additionally, macrophage inflammatory protein-1α (MIP-1α) and MIP-1β were measured, as they are described to have indirect or direct antiviral activity. As stimulants, active and inactivated Newcastle disease virus (NDV), Sendai virus, and granulocyte colony-stimulating factor (G-CSF) were used. Peripheral blood mononuclear cells (PBMC) from the same donors were highly reactive to viral stimulation, wherea...

Human Neutrophils Produce Macrophage Inhibitory Protein-1β but Not Type I Interferons in Response to Viral Stimulation

Since granulocytes are one of the first cell types at sites of inflammation, investigation of their capacity to produce cytokines has concentrated on interleukin-1 beta (IL-1 beta), IL-6, IL-8 and tumour necrosis factor-alpha (TNF-alpha). However, the results are subject to controversy. Incapability to produce cytokines as well as a broad panel of cytokines induced by isolation procedures are reported. The purpose of this study was to investigate the capacity of non-prestimulated neutrophils to produce the above-mentioned cytokines in response to stimulation with lipopolysaccharide or zymosan. In reverse transcription-polymerase chain reactions, we found IL-8 mRNA directly after isolation in unstimulated cells, whereas mRNA for IL-1 beta, IL-6 and TNF-alpha only appeared after stimulation. By means of flow cytometry we ruled out the possibility of prestimulation of the neutrophils during isolation, proving that IL-8 mRNA is produced constitutively by neutrophils. In enzyme-linked immunosorbent assays we found that, compared with controls, only IL-8 was released at significantly higher levels after 24 hr of stimulation, giving a further indication that neutrophils have an immunoregulatory influence driven by IL-8. We can confirm neither a constitutive nor a post-stimulatory release of IL-1 beta, IL-6, or TNF-alpha by neutrophils, as had been reported by others. These observations may be due to prestimulation, handling and culturing of the granulocytes, or to monocyte contamination. Collectively, our results show that granulocytes have a preformed capacity to produce the cytokine IL-8 and that the production of proinflammatory cytokines by neutrophils is limited to IL-8.

Cytokine production of neutrophils is limited to interleukin‐8

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Polymorphonuclear leucocytes selectively produce anti-inflammatory interleukin-1 receptor antagonist and chemokines, but fail to produce pro-inflammatory mediators.

Induction of interleukin-8 in human neutrophils after MHC class II cross-linking with superantigens.

Human Neutrophils Produce Macrophage Inhibitory Protein-1β but Not Type I Interferons in Response to Viral Stimulation

Cytokine production of neutrophils is limited to interleukin‐8