Systemic Host Response Research Articles

Pathological Role and Diagnostic Value of Endogenous Host Defense Peptides in Adult and Neonatal Sepsis

Sepsis is a systemic host response to an infection leading to organ failure. This is associated with dynamic expression of endogenous host defense peptides. Dysregulation of these peptides is associated with septic morbidity and mortality. We performed a systematic search of articles indexed in PubMed, ISI Web of Knowledge, EmBase, and Scopus database from inception to October 2016. Both preclinical and clinical studies investigating the role of host defense peptides in pathogenesis and as biomarkers for sepsis were included. Of the available literature, cathelicidin, defensin, and hepcidin are among the best-characterized peptides. These regulate immune response, and crosstalk with pyroptosis and coagulation cascades. The applicability of these peptides as septic biomarkers has been investigated in vitro and in vivo studies. However, numerous studies were based on endotoxemia without an infection, jeopardizing interpretation of the outcomes. Cathelicidin and defensin were frequently reported in adult sepsis while hepcidin in neonatal sepsis. The expression level of these peptides is significantly associated with septic condition. Most of the studies employed a cross-sectional design, precluding the establishment of a temporal relationship between candidate peptide biomarkers and sepsis. Innate defense peptides have been insufficiently evaluated as either diagnostic or prognostic biomarkers. In the future, evaluation of host defense peptides as septic biomarkers may employ a longitudinal design and consider a panel of multiple peptides.

Anti-human CD14 monoclonal antibody improves survival following sepsis induced by endotoxin, but not following polymicrobial infection

Cluster of differentiation 14 (CD14), a pattern recognition receptor expressed on myeloid cells and a critical component of the innate immune system, mediates local and systemic host responses to gram-negative bacterial products, including lipopolysaccharide (LPS). Therefore, CD14 is an attractive target for development of sepsis therapies, and several monoclonal anti-CD14 antibodies have been reported. In this study, we prepared an anti-human CD14 monoclonal antibody, F1024-1-3, which suppressed LPS-induced upregulation of pro-inflammatory cytokines and an adhesion molecule in human peripheral mononuclear cells and human vascular endothelial cells. Half-maximal inhibitory concentrations in these assays ranged from 0.1 to 1μg/ml. In rabbits, intravenous administration (3mg/kg) as well as in vitro exposure of F1024-1-3 suppressed LPS-induced cytokine production in whole blood. In endotoxemia models generated by three sequential injections of LPS, intravenous administration of F1024-1-3 at 0.3–3mg/kg sharply reduced pro-inflammatory responses in a dose-dependent manner and moderately attenuated pro-coagulant responses; at 1mg/kg, the protein protected rabbits from lethality even when administered 2h after the initial LPS injection. However, F1024-1-3 (10mg/kg) given 2h post-surgery did not prevent death of rabbits in a cecal ligation and puncture model. Thus, suppression of CD14-mediated activation of leukocytes and endothelial cells alone may not be clinically efficacious for the treatment of severe sepsis and septic shock.

Criteria for Sepsis: Systemic Inflammatory Response Syndrome (SIRS) and Quick Sepsis-Related Organ Dysfunction Assessment (QSOFA)

Purpose of Review Various definitions and scoring systems for sepsis were available but none of them was perfect due to the incomplete knowledge of sepsis syndrome pathobiology. Sepsis is a collection of diseases described mainly by systemic host response to infection. An international consensus first defined sepsis in 1991 and was later updated in 2001. Definitions of sepsis, severe sepsis, and septic shock remained the same for two decades. The systemic inflammatory response syndrome (SIRS) criteria were used widely in hospitals to identify sepsis. The third international consensus definitions for sepsis and septic shock (sepsis-3) recently revisited the definition. Sepsis and septic shock definitions were revised, while severe sepsis was omitted and considered to be redundant.

The Relevance of Coding Gene Polymorphysms of Cytokines and Cellular Receptors in Sepsis.

Sepsis is an injurious systemic host response to infection, which can often lead to septic shock and death. Recently, the immune-pathogenesis and genomics of sepsis have become a research topic focusing on the establishment of diagnostic and prognostic biomarkers. As yet, none have been identified as having the necessary specificity to be used independently of other factors in this respect. However the accumulation of current evidence regarding genetic variations, especially the single nucleotide polymorphisms (SNPs) of cytokines and other innate immunity determinants, partially explains the susceptibility and individual differences of patients with regard to the evolution of sepsis. This article outlines the role of genetic variation of some serum proteins which have the potential to be used as biomarker values in evaluating sepsis susceptibility and the progression of the condition.

Plasma Monocyte Chemoattractant Protein 1 as a Predictive Marker for Sepsis Prognosis: A Prospective Cohort Study.

Sepsis is a systemic host response to infection, and patients with sepsis are frequently handled in the intensive care unit. However, mortality related to sepsis remains high throughout the world. In addition, there have been no efficient prognostic biomarkers for sepsis to be employed in clinical practice. We therefore aimed to identify prognostic biomarkers for sepsis using the chemokine/cytokine array. This study included 143 patients with sepsis, who were divided into survivor and nonsurvivor groups according to their 28-day mortality status. The cytokine array analysis was performed with plasma samples from two randomly selected patients in each sepsiofgroup. We thus identified seven cytokines with significantly and consistently different expression levels between nonsurvivors and survivors. The validity of the selected cytokines was then assessed by enzyme-linked immunosorbent assay (ELISA). We finally found monocyte chemoattractant protein 1 (MCP-1) as the most useful biomarker to distinguish the two sepsis groups; namely, non-surviving patients (n = 56) exhibited significantly higher plasma concentrations of MCP-1 compared to survivors (n = 87). MCP-1 is a CC chemokine, a potent chemoattractant that contributes to systemic inflammatory response syndrome. Areas under the receiver operating characteristic curves for prediction of 28-day mortality were 0.763 for MCP-1, 0.680 for the Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) score, 0.64 for the Sequential Organ Failure Assessment (SOFA) score, 0.621 for procalcitonin, and 0.785 for MCP-1 plus APACHE II score. In conclusion, we propose that plasma MCP-1 is a useful biomarker in predicting outcome of sepsis.

Mechanisms of Endothelial Activation in Sepsis and Cell Culture Models to Study the Heterogeneous Host Response

Sepsis is currently viewed as a fundamental disintegration of control functions from intracellular signalling to immunoregulatory and neuroendocrine mechanisms. The immediate threat in sepsis is invasive infection, and the need to activate immune defense mechanisms to clear the pathogen before irreparable damage occurs. In the process of pathogen elimination, however, the systemic host response to infection may cause collateral damage to the endothelium and may lead to the destruction of host tissues.A number of experimental models have been developed to monitor endothelial activation and to study endothelial dysfunction under septic conditions. Here, we review the application of these models to assess the highly variable host response in sepsis and to investigate the efficacy of adsorbent-based extracorporeal therapies. We also highlight the need for efficient diagnostic tools, which are indispensable to select patients who are likely to benefit from distinct adjunctive therapies.

Nonantibiotic Adjunctive Therapies for Community-Acquired Pneumonia (Corticosteroids and Beyond): Where Are We with Them?

Community-acquired pneumonia (CAP) is a leading cause of hospitalization, morbidity, and mortality. Despite advances in antibiotic treatments, mortality among patients with CAP is still high. For this reason, interest has been focused on nonantibiotic therapeutic measures directed to the host response rather than the microorganism. The development of an efficacious adjunctive treatment has important implications for reducing mortality in CAP. Some clinical studies performed in the last decade have shown a clinically beneficial effect of corticosteroids, possibly by diminishing local and systemic inflammatory host response. Recent meta-analyses showed faster resolution of symptoms, shorter time to clinically stability, reduction of mechanical ventilation needed, and reduction of mortality in the most severe population, although some methodological limitations must be taken into account. In addition, some studies using statins also suggested improved outcomes due to its anti-inflammatory effect in CAP, although this requires further research. Other adjunctive therapies such as immunoglobulins and stem cells are being explored, but are not yet in the stage of clinical trials. In summary, the use of corticosteroids and other adjuvant treatments are promising in CAP, but more studies are needed to determine their impact on mortality.

HIV infection rather than concurrent opportunistic infections drives most systemic procoagulant, vascular and damage responses - a prospective cohort study in central Africa.

HIV infection is accompanied by various systemic host responses, including activation of coagulation and the vascular endothelium. We sought to determine the impact of opportunistic coinfections in a central African setting. This prospective study included 98 HIV-infected individuals in Gabon initiating combination antiretroviral therapy (cART) and followed them up for 6 months. Patients were stratified according to the presence of active tuberculosis (TB; n=19), mucocutaneous opportunistic infection (n=9) or no opportunistic infection (n=70). HIV-uninfected subjects were included as controls (n=32). Plasma concentrations of 14 markers of coagulation, endothelial activation, extracellular matrix formation and tissue damage were measured with a multiplex assay at baseline and months 3 and 6 after cART initiation. HIV-infected patients showed elevated plasma levels of all biomarkers measured with exception of protein C, which was reduced. Concurrent TB was only associated with elevated concentrations of D-dimer, metallopeptidase inhibitor 1 and Tenascin-C. Mucocutaneous coinfection did not alter HIV-associated responses. Most markers measured declined but remained elevated despite response to cART. HIV infection is associated with systemic pro-coagulant, vascular and damage responses. In an ambulatory setting, concurrent opportunistic infections have little if any influence on these responses and normalization is incomplete after response to cART. This suggests that these responses are mainly driven by HIV-associated immune activation and less so by opportunistic infections.

Ion-Current-Based Temporal Proteomic Profiling of Influenza-A-Virus-Infected Mouse Lungs Revealed Underlying Mechanisms of Altered Integrity of the Lung Microvascular Barrier.

Investigation of influenza-A-virus (IAV)-infected lung proteomes will greatly promote our understanding on the virus-host crosstalk. Using a detergent-cocktail extraction and digestion procedure and a reproducible ion-current-based method, we performed the first comprehensive temporal analysis of mouse IAV infection. Mouse lung tissues at three time points post-inoculation were compared with controls (n = 4/group), and >1600 proteins were quantified without missing value in any animal. Significantly changed proteins were identified at 4 days (n = 144), 7 days (n = 695), and 10 days (n = 396) after infection, with low false altered protein rates (1.73-8.39%). Functional annotation revealed several key biological processes involved in the systemic host responses. Intriguingly, decreased levels of several cell junction proteins as well as increased levels of tissue metalloproteinase MMP9 were observed, reflecting the IAV-induced structural breakdown of lung epithelial barrier. Supporting evidence of MMP9 activation came from immunoassays examining the abundance and phosphorylation states of all MAPKs and several relevant molecules. Importantly, IAV-induced MMP gelatinase expression was suggested to be specific to MMP9, and p38 MAPK may contribute predominantly to MMP9 elevation. These findings help to resolve the long-lasting debate regarding the signaling pathways of IAV-induced MMP9 expression and shed light on the molecular mechanisms underlying pulmonary capillary-alveolar leak syndrome that can occur during influenza infection.

Polymorphisms of cystathionine beta-synthase gene are associated with susceptibility to sepsis.

Sepsis is the systemic inflammatory host response to infection. Cystathionine beta-synthase (CBS)-dependent homocysteine (Hcy) pathway was demonstrated to affect disease severity and mortality in patients with severe sepsis/septic shock. Independent studies identified a single-nucleotide polymorphism (SNP, rs6586282, hg19 chr21:g.44478497C>T) in intron 14 of the CBS-coding gene (CBS) associated with Hcy plasma levels. We aimed to describe the association of this SNP and variants of a splice donor-affecting variable-number tandem repeat (VNTR, NG_008938.1:g.22763_22793[16_22]) 243 bp downstream of rs6586282 with severe human sepsis. We analyzed the VNTR structure and genotyped variants of rs6586282 and a neighboring SNP (rs34758144, hg19 chr21:g.44478582G>A) in two case-control studies including patients with severe sepsis/septic shock from Germany (n=168) and Greece (n=237). In both studies, we consistently observed an association of CBS VNTR alleles with sepsis susceptibility. Risk linearly increased with number of tandem repeats (per allele odds ratio in the adjusted analysis 1.34; 95% confidence interval (CI)=1.17-1.55; P<0.001). Association had also been shown for rs34758144 whose risk allele is in linkage disequilibrium with one long VNTR allele (19 repeat). In contrast, we observed no evidence for an effect on 28-day survival in patients with severe sepsis/septic shock (per allele hazard ratio in the adjusted analysis for VNTR 1.10; 95% CI=0.95-1.28; P=0.20). In a minigene approach, we demonstrated alternative splicing in distinct VNTR alleles, which, however, was independent of the number of tandem units. In conclusion, there is no ordinary conjunction between human CBS and severe sepsis/septic shock, but CBS genotypes are involved in disease susceptibility.

Type 1 and 3 collagen production by bone marrow mesenchymal stromal cells is suppressed in vitro after exposure to sepsis patient serum

Severe sepsis is a systemic host response to invading pathogen with activated inflammation, coagulation and tissue remodelling cascades and consequent organ dysfunction. Despite modern intensive care, mortality in severe sepsis remains high. Mesenchymal stromal cells (MSCs) are known to have many anti-inflammatory features and contribute to the healing process. Many research groups have demonstrated good results using MSCs as an adjunctive treatment of sepsis in animal studies. Recently, a research group conducted a phase I clinical trial to test safety of MSCs on ARDS patients ([1]). To date knowledge of sepsis influence on MSCs is scarce.

Distinct serum proteome profiles associated with collagen-induced arthritis and complete Freund's adjuvant-induced inflammation in CD38⁻/⁻ mice: The discriminative power of protein species or proteoforms.

Collagen-type-II-induced arthritis (CIA) is an autoimmune disease, which involves a complex host systemic response including inflammatory and autoimmune reactions. CIA is milder in CD38(-/-) than in wild-type (WT) mice. ProteoMiner-equalized serum samples were subjected to 2D-DiGE and MS-MALDI-TOF/TOF analyses to identify proteins that changed in their relative abundances in CD38(-/-) versus WT mice either with arthritis (CIA(+) ), with no arthritis (CIA(-) ), or with inflammation (complete Freund's adjuvant (CFA)-treated mice). Multivariate analyses revealed that a multiprotein signature (n = 28) was able to discriminate CIA(+) from CIA(-) mice, and WT from CD38(-/-) mice within each condition. Likewise, a distinct multiprotein signature (n = 16) was identified which differentiated CIA(+) CD38(-/-) mice from CIA(+) WT mice, and lastly, a third multiprotein signature (n = 18) indicated that CD38(-/-) and WT mice could be segregated in response to CFA treatment. Further analyses showed that the discriminative power to distinguish these groups was reached at protein species level and not at the protein level. Hence, the need to identify and quantify proteins at protein species level to better correlate proteome changes with disease processes. It is crucial for plasma proteomics at the low-abundance protein species level to apply the ProteoMiner enrichment. All MS data have been deposited in the ProteomeXchange with identifiers PXD001788, PXD001799 and PXD002071 (http://proteomecentral.proteomexchange.org/dataset/PXD001788, http://proteomecentral.proteomexchange.org/dataset/PXD001799 and http://proteomecentral.proteomexchange.org/dataset/PXD002071).

Lower Respiratory Tract Infection of the Ferret by 2009 H1N1 Pandemic Influenza A Virus Triggers Biphasic, Systemic, and Local Recruitment of Neutrophils.

Infection of the lower respiratory tract by influenza A viruses results in increases in inflammation and immune cell infiltration in the lung. The dynamic relationships among the lung microenvironments, the lung, and systemic host responses during infection remain poorly understood. Here we used extensive systematic histological analysis coupled with live imaging to gain access to these relationships in ferrets infected with the 2009 H1N1 pandemic influenza A virus (H1N1pdm virus). Neutrophil levels rose in the lungs of H1N1pdm virus-infected ferrets 6 h postinfection and became concentrated at areas of the H1N1pdm virus-infected bronchiolar epithelium by 1 day postinfection (dpi). In addition, neutrophil levels were increased throughout the alveolar spaces during the first 3 dpi and returned to baseline by 6 dpi. Histochemical staining revealed that neutrophil infiltration in the lungs occurred in two waves, at 1 and 3 dpi, and gene expression within microenvironments suggested two types of neutrophils. Specifically, CCL3 levels, but not CXCL8/interleukin 8 (IL-8) levels, were higher within discrete lung microenvironments and coincided with increased infiltration of neutrophils into the lung. We used live imaging of ferrets to monitor host responses within the lung over time with [(18)F]fluorodeoxyglucose (FDG). Sites in the H1N1pdm virus-infected ferret lung with high FDG uptake had high levels of proliferative epithelium. In summary, neutrophils invaded the H1N1pdm virus-infected ferret lung globally and focally at sites of infection. Increased neutrophil levels in microenvironments did not correlate with increased FDG uptake; hence, FDG uptake may reflect prior infection and inflammation of lungs that have experienced damage, as evidenced by bronchial regeneration of tissues in the lungs at sites with high FDG levels. Severe influenza disease is characterized by an acute infection of the lower airways that may progress rapidly to organ failure and death. Well-developed animal models that mimic human disease are essential to understanding the complex relationships of the microenvironment, organ, and system in controlling virus replication, inflammation, and disease progression. Employing the ferret model of H1N1pdm virus infection, we used live imaging and comprehensive histological analyses to address specific hypotheses regarding spatial and temporal relationships that occur during the progression of infection and inflammation. We show the general invasion of neutrophils at the organ level (lung) but also a distinct pattern of localized accumulation within the microenvironment at the site of infection. Moreover, we show that these responses were biphasic within the lung. Finally, live imaging revealed an early and sustained host metabolic response at sites of infection that may reflect damage and repair of tissues in the lungs.

Comparative proteomic analysis of lung tissue from guinea pigs with leptospiral pulmonary haemorrhage syndrome (LPHS) reveals a decrease in abundance of host proteins involved in cytoskeletal and cellular organization

Leptospiral pulmonary haemorrhage syndrome (LPHS) is a particularly severe form of leptospirosis. LPHS is increasingly recognized in both humans and animals and is characterized by rapidly progressive intra-alveolar haemorrhage leading to high mortality. The pathogenic mechanisms of LPHS are poorly understood which hampers the application of effective treatment regimes. In this study a 2-D guinea pig proteome lung map was created and used to investigate the pathogenic mechanisms of LPHS. Comparison of lung proteomes from infected and non-infected guinea pigs via differential in-gel electrophoresis revealed highly significant differences in abundance of proteins contained in 130 spots. Acute phase proteins were the largest functional group amongst proteins with increased abundance in LPHS lung tissue, and likely reflect a local and/or systemic host response to infection. The observed decrease in abundance of proteins involved in cytoskeletal and cellular organization in LPHS lung tissue further suggests that infection with pathogenic Leptospira induces changes in the abundance of host proteins involved in cellular architecture and adhesion contributing to the dramatically increased alveolar septal wall permeability seen in LPHS. Biological significanceThe recent completion of the complete genome sequence of the guinea pig (Cavia porcellus) provides innovative opportunities to apply proteomic technologies to an important animal model of disease. In this study, the comparative proteomic analysis of lung tissue from experimentally infected guinea pigs with leptospiral pulmonary haemorrhage syndrome (LPHS) revealed a decrease in abundance of proteins involved in cellular architecture and adhesion, suggesting that loss or down-regulation of cytoskeletal and adhesion molecules plays an important role in the pathogenesis of LPHS. A publically available guinea pig lung proteome map was constructed to facilitate future pulmonary proteomics in this species.

Biomarker-based classification of bacterial and fungal whole-blood infections in a genome-wide expression study.

Sepsis is a clinical syndrome that can be caused by bacteria or fungi. Early knowledge on the nature of the causative agent is a prerequisite for targeted anti-microbial therapy. Besides currently used detection methods like blood culture and PCR-based assays, the analysis of the transcriptional response of the host to infecting organisms holds great promise. In this study, we aim to examine the transcriptional footprint of infections caused by the bacterial pathogens Staphylococcus aureus and Escherichia coli and the fungal pathogens Candida albicans and Aspergillus fumigatus in a human whole-blood model. Moreover, we use the expression information to build a random forest classifier to classify if a sample contains a bacterial, fungal, or mock-infection. After normalizing the transcription intensities using stably expressed reference genes, we filtered the gene set for biomarkers of bacterial or fungal blood infections. This selection is based on differential expression and an additional gene relevance measure. In this way, we identified 38 biomarker genes, including IL6, SOCS3, and IRG1 which were already associated to sepsis by other studies. Using these genes, we trained the classifier and assessed its performance. It yielded a 96% accuracy (sensitivities >93%, specificities >97%) for a 10-fold stratified cross-validation and a 92% accuracy (sensitivities and specificities >83%) for an additional test dataset comprising Cryptococcus neoformans infections. Furthermore, the classifier is robust to Gaussian noise, indicating correct class predictions on datasets of new species. In conclusion, this genome-wide approach demonstrates an effective feature selection process in combination with the construction of a well-performing classification model. Further analyses of genes with pathogen-dependent expression patterns can provide insights into the systemic host responses, which may lead to new anti-microbial therapeutic advances.

Systemic host responses to oral challenges

Systemic host responses to oral challenges

Burn injury induces skeletal muscle degeneration, inflammatory host response, and oxidative stress in wistar rats.

Burn injuries (BIs) result in both local and systemic responses distant from the site of thermal injury, such as skeletal muscle. The purpose of this study was to investigate the expression of cyclooxygenase-2 (COX-2) and hydroxy-2'-deoxyguanosine (8-OHdG) as a result of inflammation and reactive oxygen species production, respectively. A total of 16 male rats were distributed into two groups: control (C) and submitted to BI. The medial part of gastrocnemius muscle formed the specimens, which were stained with hematoxylin and eosin and were evaluated. COX-2 and 8-OHdG expressions were assessed by immunohistochemistry, and cell profile area and density of muscle fibers (number of fibers per square millimeter) were evaluated by morphometric methods. The results revealed inflammatory infiltrate associated with COX-2 immunoexpression in BI-gastrocnemius muscle. Furthermore, a substantial decrease in the muscle cell profile area of BI group was noticed when compared with the control group, whereas the density of muscle fibers was higher in the BI group. 8-OHdG expression in numerous skeletal muscle nuclei was detected in the BI group. In conclusion, the BI group is able to induce skeletal muscle degeneration as a result of systemic host response closely related to reactive oxygen species production and inflammatory process.

Temporal study following burn injury in young rats is associated with skeletal muscle atrophy, inflammation and altered myogenic regulatory factors.

Burn injury (BI) greater than 40% has been associated with protein catabolism and it is characterized by a hypermetabolic response followed for muscle loss. The purpose of this study was to investigate the temporal effects of extensive experimental BI in the skeletal muscle distant from lesion, through morphological analysis, expression of genes related to muscle atrophy, inflammation and the myogenic regulatory factors. A total of 60 young male wistar rats were distributed into two groups, control (C) and subjected to scald burn injury (SBI). The animals were euthanized 1, 4 and 14 days post-sham or 45% of the total body surface BI. The medial head of gastrocnemii muscles were submitted to histopathological, morphometric (muscle fibers area and density), MyoD and myogenin immunoexpression, and gene expression for TNF-α, iNOS and E3 ubiquitin ligases (MuRF1 and MAFbx). Histopathological findings were consistent with increased amount of connective tissue and inflammatory process. Muscle fiber area of SBI groups was smaller than C and no differences were found in fiber muscle density. TNF-α was higher in SBI groups, one and 14 days post-injury; iNOS expression was higher on the first and fourth day post-injury. MuRF-1 was higher on the day four and MAFbx on the day 14. In conclusion, BI causes inflammation, atrophy and myogenesis stimulation in muscle as a result of systemic host response.

Recombinant HDL (Milano) protects endotoxin-challenged rats from multiple organ injury and dysfunction.

Endotoxemia, the systemic inflammatory host response to infection, leads to severe septic shock and multiple organ injury and dysfunction syndrome (MOPS), which cause mortality. Apolipoprotein A-IMilano (apoAIM), a naturally occurring cysteine mutant of apoAI with dimers as its effective form, showed an enhanced cardiovascular protective activity compared with wild-type apoAI (apoAIwt). To investigate the role of recombinant high-density lipoprotein (rHDL) reconstituted with apoAIM (rHDLM) on endotoxemia and MOPS, we examined the anti-inflammatory, anti-oxidant, and protective effects of this cysteine mutant against organ injury in endotoxin-challenged rat models compared with rHDLwt. In the present study, we demonstrated for the first time that pretreatment with rHDLM significantly attenuated liver and renal dysfunction and histopathological features of lung injury in endotoxin-challenged endotoxemia rats. Administration of rHDLM to endotoxemia rats dramatically suppressed proinflammatory cytokines and adhesion molecule increase in tumor necrosis factor α, interleukin 1β, interleukin 6, and intercellular adhesion molecule 1. In addition, rHDLM pretreatment inhibited lipid peroxidation and enhanced total antioxidant capacity in vivo. In comparison with rHDLwt, rHDLM showed enhanced capacity on anti-inflammatory and anti-oxidant functions. In summary, administration of rHDLM protected endotoxin-challenged endotoxemia and MOPS through enhanced anti-inflammatory and anti-oxidant properties.

Biomaterial-mesenchymal stem cell constructs for immunomodulation in composite tissue engineering.

Cell-based treatments are being developed as a novel approach for the treatment of many diseases in an effort to repair injured tissues and regenerate lost tissues. Interest in the potential use of multipotent progenitor or stem cells has grown significantly in recent years, specifically the use of mesenchymal stem cells (MSCs), for tissue engineering in combination with extracellular matrix-based scaffolds. An area that warrants further attention is the local or systemic host responses toward the implanted cell-biomaterial constructs. Such immunological responses could play a major role in determining the clinical efficacy of the therapeutic device or biomaterials used. MSCs, due to their unique immunomodulatory properties, hold great promise in tissue engineering as they not only directly participate in tissue repair and regeneration but also modulate the host foreign body response toward the engineered constructs. The purpose of this review was to summarize the current state of knowledge and applications of MSC-biomaterial constructs as a potential immunoregulatory tool in tissue engineering. Better understanding of the interactions between biomaterials and cells could translate to the development of clinically relevant and novel cell-based therapeutics for tissue reconstruction and regenerative medicine.