IQGAP1-mediated mechanical signaling promotes the foreign body response to biomedical implants.

The aim of this study was to further elucidate the molecular mechanisms that mediate pathologic foreign body response (FBR) to biomedical implants. The longevity of biomedical implants is limited by the FBR, which leads to implant failure and patient morbidity. Since the specific molecular mechanisms underlying fibrotic responses to biomedical implants have yet to be fully described, there are currently no targeted approaches to reduce pathologic FBR. We utilized proteomics analysis of human FBR samples to identify potential molecular targets for therapeutic inhibition of FBR. We then employed a murine model of FBR to further evaluate the role of this potential target. We performed histological and immunohistochemical analysis on the murine FBR capsule tissue, as well as single-cell RNA sequencing (scRNA-seq) on cells isolated from the capsules. We identified IQ motif containing GTPase activating protein 1 (IQGAP1) as the most promising of several targets, serving as a central molecular mediator in human and murine FBR compared to control subcutaneous tissue. IQGAP1-deficient mice displayed a significantly reduced FBR compared to wild-type mice as evidenced by lower levels of collagen deposition and maturity. Our scRNA-seq analysis revealed that decreasing IQGAP1 resulted in diminished transcription of mechanotransduction, inflammation, and fibrosis-related genes, which was confirmed on the protein level with immunofluorescent staining. The deficiency of IQGAP1 significantly attenuates FBR by deactivating downstream mechanotransduction signaling, inflammation, and fibrotic pathways. IQGAP1 may be a promising target for rational therapeutic design to mitigate pathologic FBR around biomedical implants.

Do Battlefield Injury-acquired Indwelling Metal Fragments Induce Metal Immunogenicity?

BACKGROUND: A battlefield-related injury results in increased local and systemic innate immune inflammatory responses, resulting in wound-specific complications and an increased incidence of osteoarthritis. However, little is known about whether severe injuries affect long-term systemic homeostasis, for example, immune function. Moreover, it also remains unknown whether battlefield-acquired metal fragments retained over the long term result in residual systemic effects such as altered immune reactivity to metals. QUESTIONS/PURPOSES: Does a retained metal fragment from a battlefield injury contribute to increased (1) adaptive metal-specific immune responses, (2) systemically elevated metal ion serum levels, and (3) serum immunoglobulin levels compared with combat injuries that did not result in a retained metal fragment? METHODS: In this pilot study, we analyzed metal-immunogenicity in injured military personnel and noninjured control participants using lymphocyte transformation testing (LTT, lymphocyte proliferation responses to cobalt, chromium and nickel challenge at 0.001, 0.01 and 0.1-mM concentrations in triplicate for each participant), serum metal ion analysis (ICP-mass spectroscopy), and serum immunoglobulin analysis (IgE, IgG, IgA, and IgM ). Military personnel with a battlefield-sustained injury self-recruited without any exclusion for sex, age, degree of injury. Those with battlefield injury resulting in retained metal fragments (INJ-FRAG, n = 20 male, mean time since injury ± SD was 12 ± 10 years) were compared with those with a battlefield injury but without retained metal fragments (INJ-NO-FRAG, n = 12 male, mean time since injury ± SD was 13 ± 12 years). A control group comprised of male noninjured participants was used to compare measured immunogenicity metrics (n = 11, males were selected to match battlefield injury group demographics). RESULTS: Military participants with sustained metal fragments had increased levels of metal-induced lymphocyte responses. The lymphocyte stimulation index among military participants with metal fragments was higher than in those with nonretained metal fragments (stimulation index = 4.2 ± 6.0 versus stimulation index = 2.1 ± 1.2 (mean difference 2.1 ± 1.4 [95% confidence interval 5.1 to 0.8]; p = 0.07) and an average stimulation index = 2 ± 1 in noninjured controls. Four of 20 participants injured with retained fragments had a lymphocyte proliferation index greater than 2 to cobalt compared with 0 in the group without a retained metal fragment or 0 in the control participants. However, with the numbers available, military personnel with retained metal fragments did not have higher serum metal ion levels than military participants without retained metal fragment-related injuries or control participants. Military personnel with retained metal fragments had lower serum immunoglobulin levels (IgG, IgA, and IgM) than military personnel without retained metal fragments and noninjured controls, except for IgE. Individuals who were metal-reactive positive (that is, a stimulation index > 2) with retained metal fragments had higher median IgE serum levels than participants who metal-reactive with nonmetal injuries (1198 ± 383 IU/mL versus 171 ± 67 IU/mL, mean difference 1027 ± 477 IU/mL [95% CI 2029 to 25]; p = 0.02). CONCLUSIONS: We found that males with retained metal fragments after a battlefield-related injury had altered adaptive immune responses compared with battlefield-injured military personnel without indwelling metal fragments. Military participants with a retained metal fragment had an increased proportion of group members and increased average lymphocyte reactivity to common implant metals such as nickel and cobalt. Further studies are needed to determine a causal association between exposure to amounts of retained metal fragments, type of injury, personnel demographics and general immune function/reactivity that may affect personal health or future metal implant performance. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Azithromycin-Ciprofloxacin-Impregnated Urinary Catheters Avert Bacterial Colonization, Biofilm Formation, and Inflammation in a Murine Model of Foreign-Body-Associated Urinary Tract Infections Caused by Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a multifaceted pathogen causing a variety of biofilm-mediated infections, including catheter-associated urinary tract infections (CAUTIs). The high prevalence of CAUTIs in hospitals, their clinical manifestations, such as urethritis, cystitis, pyelonephritis, meningitis, urosepsis, and death, and the associated economic challenges underscore the need for management of these infections. Biomaterial modification of urinary catheters with two drugs seems an interesting approach to combat CAUTIs by inhibiting biofilm. Previously, we demonstrated the in vitro efficacy of urinary catheters impregnated with azithromycin (AZM) and ciprofloxacin (CIP) against P. aeruginosa Here, we report how these coated catheters impact the course of CAUTI induced by P. aeruginosa in a murine model. CAUTI was established in female LACA mice with uncoated or AZM-CIP-coated silicone implants in the bladder, followed by transurethral inoculation of 108 CFU/ml of biofilm cells of P. aeruginosa PAO1. AZM-CIP-coated implants (i) prevented biofilm formation on the implant's surface (P ≤ 0.01), (ii) restricted bacterial colonization in the bladder and kidney (P < 0.0001), (iii) averted bacteriuria (P < 0.0001), and (iv) exhibited no major histopathological changes for 28 days in comparison to uncoated implants, which showed persistent CAUTI. Antibiotic implants also overcame implant-mediated inflammation, as characterized by trivial levels of inflammatory markers such as malondialdehyde (P < 0.001), myeloperoxidase (P < 0.05), reactive oxygen species (P ≤ 0.001), and reactive nitrogen intermediates (P < 0.01) in comparison to those in uncoated implants. Further, AZM-CIP-coated implants showed immunomodulation by manipulating the release of inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-10 to the benefit of the host. Overall, the study demonstrates long-term in vivo effectiveness of AZM-CIP-impregnated catheters, which may possibly be a key to success in preventing CAUTIs.

A case series and a review of the literature on foreign modelling agent reaction: an emerging problem.

Foreign modelling agent reactions (FMAR) are the result of the injection of unapproved high-viscosity fluids with the purpose of cosmetic body modelling. Its consequences lead to ulceration, disfigurement and even death, and it has reached epidemic proportions in several regions of the world. We describe a series of patients treated for FMARs in a specialised wound care centre and a thorough review of the literature. A retrospective chart review was performed from January 1999 to September 2015 of patients who had been injected with non-medical foreign agents and who developed cutaneous ulceration needing treatment at the dermatology wound care centre. This study involved 23 patients whose ages ranged from 22 to 67 years with higher proportion of women and homosexual men. The most commonly injected sites were the buttocks (38·5%), legs (18%), thighs (15·4%) and breasts (11·8%). Mineral oil (39%) and other unknown substances (30·4%) were the most commonly injected. The latency period ranged from 1 week to 17 years. Complications included several skin changes such as sclerosis and ulceration as well as systemic complications. FMAR is a severe syndrome that may lead to deadly complications, and is still very common in Latin America.

[Foreign material in the gingival tissues admixed with a clinical picture of Mucous Membrane Pemphigoid: A coincidence or inter-related conditions?].

We present a case of a 74-year old female who complained of chronic vesicular and ulcerative lesions distributed on her gingivae. The lesions did not respond to conventional periodontal treatment. The clinical appearance was consistent - with vesiculo-bullous conditions, such as Pemphigus Vulgaris and Mucous Membrane Pemphigoid. These conditions have an auto- immune etiology, whereby pathologic auto-antibodies are generated against structures that constitute the epithelial cell-cell or cell-connective tissue attachment systems. Accurate diagnosis is mandatory due to the high risk, at least in part of them, to spread to extra- oral sites, such skin, eyes and other types of mucosae and cause severe morbidity and even death. Diagnosis is based on routine biopsy aimed to identify the characteristic histomorphological features and on direct immunofluorescence that highlights the type and pattern of the deposition of the auto-antibodies with the affected tissue. The present biopsy did not show features of a vesiculo-bullous condition. However, the presence of a foreign material in the form of fine granules was highlighted by polarized microscopy. Immunofluorescence revealed a %pattern of auto-antibodies that was supportive of Mucous Membrane Pemphigoid. In lack of involvement of any other oral site, the patient has been treated with local agents, as commonly accepted. The present case emphasizes the need to consult specialists from various disciplines, especially in those cases where the clinical response to a common practice is not as expected. Furthermore, diagnosis is not always straightforward, and sometimes a pathologic condition may be the "product" of more than one single etiology.

Computational modeling of phagocyte transmigration for foreign body responses to subcutaneous biomaterial implants in mice.

BACKGROUND: Computational modeling and simulation play an important role in analyzing the behavior of complex biological systems in response to the implantation of biomedical devices. Quantitative computational modeling discloses the nature of foreign body responses. Such understanding will shed insight on the cause of foreign body responses, which will lead to improved biomaterial design and will reduce foreign body reactions. One of the major obstacles in computational modeling is to build a mathematical model that represents the biological system and to quantitatively define the model parameters. RESULTS: In this paper, we considered quantitative inter connections and logical relationships among diverse proteins and cells, which have been reported in biological experiments and literature. Based on the established biological discovery, we have built a mathematical model while unveiling the key components that contribute to biomaterial-mediated inflammatory responses. For the parameter estimation of the mathematical model, we proposed a global optimization algorithm, called Discrete Selection Levenberg-Marquardt (DSLM). This is an extension of Levenberg-Marquardt (LM) algorithm which is a gradient-based local optimization algorithm. The proposed DSLM suggests a new approach for the selection of optimal parameters in the discrete space with fast computational convergence. CONCLUSIONS: The computational modeling not only provides critical clues to recognize current knowledge of fibrosis development but also enables the prediction of yet-to-be observed biological phenomena.

In vivo expression of Streptococcus pyogenes immunogenic proteins during tibial foreign body infection.

Group A streptococcus (GAS) is an important human pathogen that causes a number of diseases with a wide range of severities. While all known strains of GAS are still sensitive to penicillin, there have been reports of antibiotic treatment failure in as many as 20% to 40% of cases. Biofilm formation has been implicated as a possible cause for these failures. A biofilm is a microbially derived, sessile community where cells grow attached to a surface or as a bacterial conglomerate and surrounded by a complex extracellular matrix. While the ability of group A streptococcus to form biofilms in the laboratory has been shown, there is a lack of understanding of the role of GAS biofilms during an infection. We hypothesized that during infections, GAS exhibits a biofilm phenotype, complete with unique protein expression. To test this hypothesis, a rabbit model of GAS osteomyelitis was developed. A rabbit was inoculated with GAS using an infected indwelling device. Following the infection, blood and tissue samples were collected. Histological samples of the infected tibia were prepared, and the formation of a biofilm in vivo was visualized using peptide nucleic acid fluorescent in situ hybridization (PNA-FISH) and confocal microscopy. In addition, Western blotting with convalescent rabbit serum detected cell wall proteins expressed in vitro under biofilm and planktonic growth conditions. Immunogenic proteins were then identified using matrix-assisted laser desorption ionization-time of flight tandem mass spectrometry (MALDI-TOF/TOF MS). These identities, along with the in vivo results, support the hypothesis that GAS forms biofilms during an infection. This unique phenotype should be taken into consideration when designing a vaccine or any other treatment for group A streptococcus infections.

Enterococcus faecalis overcomes foreign body-mediated inflammation to establish urinary tract infections.

Urinary catheterization elicits major histological and immunological changes that render the bladder susceptible to microbial invasion, colonization, and dissemination. However, it is not understood how catheters induce these changes, how these changes act to promote infection, or whether they may have any protective benefit. In the present study, we examined how catheter-associated inflammation impacts infection by Enterococcus faecalis, a leading cause of catheter-associated urinary tract infection (CAUTI), a source of significant societal and clinical challenges. Using a recently optimized murine model of foreign body-associated UTI, we found that the implanted catheter itself was the primary inducer of inflammation. In the absence of the silicone tubing implant, E. faecalis induced only minimal inflammation and was rapidly cleared from the bladder. The catheter-induced inflammation was only minimally altered by subsequent enterococcal infection and was not suppressed by inhibitors of the neurogenic pathway and only partially by dexamethasone. Despite the robust inflammatory response induced by urinary implantation, E. faecalis produced biofilm and high bladder titers in these animals. Induction of inflammation in the absence of an implanted catheter failed to promote infection, suggesting that the presence of the catheter itself is essential for E. faecalis persistence in the bladder. Immunosuppression prior to urinary catheterization enhanced E. faecalis colonization, suggesting that implant-mediated inflammation contributes to the control of enterococcal infection. Thus, this study underscores the need for novel strategies against CAUTIs that seek to reduce the deleterious effects of implant-mediated inflammation on bladder homeostasis while maintaining an active immune response that effectively limits bacterial invaders.

Blockade of cannabinoid receptors reduces inflammation, leukocyte accumulation and neovascularization in a model of sponge-induced inflammatory angiogenesis.

OBJECTIVE: Angiogenesis depends on a complex interaction between cellular networks and mediators. The endocannabinoid system and its receptors have been shown to play a role in models of inflammation. Here, we investigated whether blockade of cannabinoid receptors may interfere with inflammatory angiogenesis. MATERIALS AND METHODS: Polyester-polyurethane sponges were implanted in C57Bl/6j mice. Animals received doses (3 and 10 mg/kg/daily, s.c.) of the cannabinoid receptor antagonists SR141716A (CB1) or SR144528 (CB2). Implants were collected at days 7 and 14 for cytokines, hemoglobin, myeloperoxidase, and N-acetylglucosaminidase measurements, as indices of inflammation, angiogenesis, neutrophil and macrophage accumulation, respectively. Histological and morphometric analysis were also performed. RESULTS: Cannabinoid receptors expression in implants was detected from day 4 after implantation. Treatment with CB1 or CB2 receptor antagonists reduced cellular influx into sponges at days 7 and 14 after implantation, although CB1 receptor antagonist were more effective at blocking leukocyte accumulation. There was a reduction in TNF-α, VEGF, CXCL1/KC, CCL2/JE, and CCL3/MIP-1α levels, with increase in CCL5/RANTES. Both treatments reduced neovascularization. Dual blockade of cannabinoid receptors resulted in maximum inhibition of inflammatory angiogenesis. CONCLUSIONS: Blockade of cannabinoid receptors reduced leukocyte accumulation, inflammation and neovascularization, suggesting an important role of endocannabinoids in sponge-induced inflammatory angiogenesis both via CB1 and CB2 receptors.

Reaction of the rat tissues to implantation of polyhydroxyalkanoate films and ultrafine fibers.

The reaction of various tissues of rats to implantation of polyhydroxyalkanoate films and ultrafine fibers was studied by optic microscopy. Implantation of polyhydroxyalkanoate films into the abdominal cavity caused a peritoneal reaction, leading after 1 month to the formation of fibrous adhesions between polyhydroxyalkanoate and intestinal loops. Under the skin and in the muscle tissue polyhydroxyalkanoate films were encapsulated in a thick fibrous capsule. Implantation of polyhydroxyalkanoate ultrathin fibers led to formation of foreign body granulomas in all tissues with perifocal inflammation and sclerosis of the adjacent tissues. The polymer was fragmented in these granulomas and phagocytosed by macrophages with the formation of giant foreign body cells. Hence, polyhydroxyalkanoate materials implanted in vivo caused chronic granulomatous inflammatory reaction and were very slowly destroyed by macrophages.

Immunostimulation of Parasteatoda tepidariorum (Araneae: Theridiidae) in juvenile and adult stages. Immunity reactions to injury with foreign body and Bacillus subtilis infection.

To assess the immune potential of spiders, in the present study juvenile and adult females of Parasteatoda tepidariorum were exposed to Bacillus subtilis infection, injury by a nylon monofilament and a combination of both. The expression level of selected immune-related genes: defensin 1 (PtDEF1), lysozyme 1 (PtLYS1), lysozyme C (PtLYSC), lysozyme M1 (PtLYSM1), autophagy-related protein 101 (PtATG101), dynamin (PtDYN) and heat shock proteins (HSP70) (PtHSPB, PtHSPB2A, PtHSPB2B), production of lysozyme and HSP70 proteins, and hemocytes viability were measured. The obtained results indicated expression of the lysozyme, autophagy-related protein and HSP70 genes in both ontogenetic stages of P. tepidariorum. It has been also shown that the simultaneous action of mechanical and biological factors causes higher level of lysozyme and HSP70, cell apoptosis intensity and lower level of hemocytes viability than in the case of exposure to a single immunostimulant. Moreover, mature females showed stronger early immune responses compared to juveniles.

Human adjuvant disease induced by foreign substances: a new model of ASIA (Shoenfeld's syndrome).

OBJECTIVE: To investigate the clinical, laboratory and histological manifestations of patients who received illegal injections of foreign substances for cosmetic purposes. PATIENTS AND METHODS: We studied patients who met the following inclusion criteria: 1) history of application of foreign substances for cosmetic purposes, 2) clinical data of autoimmune disease or non-specific autoimmune manifestation (i.e. arthralgias, myalgia, malaise, fever, and weight loss), 3) detection of autoantibodies in patients' sera, 4) histological evidence of chronic inflammation and/or granulomatous reaction to foreign body. RESULTS: Fifty female patients aged 44.4 ± 10 years were studied. The mean time between application of foreign substances and onset of symptoms was 4.5 ± 4.3 years. Patients were followed for 12 ± 7.5 years. Forty-one patients were injected with mineral oil, nine patients received other substances: three iodine gadital, one guayacol, one guayacol plus silicone fluid, two collagen, two silicone fluid. The sites of application were: buttocks (36), legs and/or thighs (11), breasts (eight) hands and face (one), face (two) (seven patients received an injection to more than one site). Thirty patients presented with non-specific autoimmune manifestations, whereas 20 patients fulfilled the criteria for a defined autoimmune disease such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, overlap syndrome, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune hepatitis, and ulcerative colitis. CONCLUSIONS: Cases of human adjuvant disease following illegal injections of oil substances for cosmetic purposes are reported. Patients presented with defined autoimmune diseases as well as with non-specific autoimmune manifestations. Illegal injection of these substances could lead to serious local and systemic complications, even to death. These cases represent another model of Autoimmune/inflammatory Syndrome Induced by Adjuvants (ASIA). The use of these substances should be prohibited.

In vivo studies in C4-deficient guinea pigs.

Guinea pigs with a genetically determined total deficiency of the fourth component of complement have been studied for various in vivo immunological functions. Passive cutaneous anaphylaxsis, contact and delayed hypersensitivity, and the cellular exudative response to a foreign body were normal. These animals also have normal direct and reverse passive Arthus reactions which suggest that they possess a mechanism to bypass C4 and directly activate late-acting complement components. This would appear to be an unequivocal demonstration of an alternate pathway in the complement sequence. Immune clearance of guinea pig erythrocytes sensitized with rabbit antibody was impaired in the deficient animals. Antibody production in C4-deficient animals was impaired for two of the three antigens studied.

The role of chemical mediators in the inflammatory response induced by foreign bodies: comparison with the schistosome egg granuloma.

Both divinyl benzene copolymer (plastic) beads and schistosome eggs produce inflammatory reactions after intravenous deposition into the lung of a mouse. As reported previously, the schistosome egg granuloma is an immunologic reaction of the delayed hypersensitivity type; this inflammatory process is prevented by immunosuppressive measures, and characteristically demonstrates an anamnestic response. In contradistinction, the plastic bead granuloma appears to be characteristic of a foreign body reaction; it is unaffected by immunosuppressive measures and does not demonstrate an anamnestic response with repeated exposure. The data in this report suggest that the granuloma formation around plastic beads is a nonimmunologic reaction induced by chemical mediators of inflammation. This proposal is supported by the following findings: the plastic beads activate Hageman factor in normal human and mouse plasma; the plastic beads induce vascular permeability-enhancing activity as measured in guinea pig skin and kinin-like activity in normal human and mouse plasma that is dependent on Hageman factor; ellagic acid, an agent that activates Hageman factor in vivo and is reported to diminish kininogen by consumptive depletion, markedly depresses the plastic bead granuloma. These data are consistent with the idea that the plastic bead granuloma and perhaps other foreign body inflammatory reactions are in major part dependent on kinin formation. Ellagic acid also suppressed the schistosome egg granuloma, but not to the same degree as the plastic bead granuloma. The implications of this observation are discussed in the text. Silicosis and "blue velvet disease", pathologic processes associated with the deposition of silica and magnesium trisilicate, respectively, in the lung, and the induction of a foreign body reaction may also be dependent on the activation of chemical mediators of inflammation by the silica and magnesium trisilicate particles with immunologic mechanisms participating in only a minor way, if at all. The marked suppression of experimental silicosis and blue velvet disease in mice by ellagic acid supports this idea.

Interleukin 17 and senescent cells regulate the foreign body response to synthetic material implants in mice and humans.

Medical devices and implants made of synthetic materials can induce an immune-mediated process when implanted in the body called the foreign body response, which results in formation of a fibrous capsule around the implant. To explore the immune and stromal connections underpinning the foreign body response, we analyzed fibrotic capsules surrounding surgically excised human breast implants from 12 individuals. We found increased numbers of interleukin 17 (IL17)-producing γδ+ T cells and CD4+ T helper 17 (TH17) cells as well as senescent stromal cells in the fibrotic capsules. Further analysis in a murine model demonstrated an early innate IL17 response to implanted synthetic material (polycaprolactone) particles that was mediated by innate lymphoid cells and γδ+ T cells. This was followed by a chronic adaptive CD4+ TH17 cell response that was antigen dependent. Synthetic materials with varying chemical and physical properties implanted either in injured muscle or subcutaneously induced similar IL17 responses in mice. Mice deficient in IL17 signaling established that IL17 was required for the fibrotic response to implanted synthetic materials and the development of p16INK4a senescent cells. IL6 produced by senescent cells was sufficient for the induction of IL17 expression in T cells. Treatment with a senolytic agent (navitoclax) that killed senescent cells reduced IL17 expression and fibrosis in the mouse implant model. Discovery of a feed-forward loop between the TH17 immune response and the senescence response to implanted synthetic materials introduces new targets for therapeutic intervention in the foreign body response.

Effects of miR-26a/miR-146a/miR-31 on airway inflammation of asthma mice and asthma children.

OBJECTIVE: This study detected the expressions of microRNA-26a (miR-26a), miR-146a and miR-31 in lung tissues and BALF (bronchoalveolar lavage fluid) of asthma mice and children. Besides, cytokine levels of interleukin-5 (IL-5), IL-8, IL-12 and tumor necrosis factor-α (TNF-α) were detected as well. We aim to provide an experimental basis for clinical treatment of asthma. PATIENTS AND METHODS: Forty female BALB/c mice were randomly assigned into control group and asthma group, respectively. Mice in asthma group (n=20) were immunized by intraperitoneal injection of OVA (ovalbumin) and provoked by atomization inhalation of OVA from the 15th day for 10 days. Mice in control group (n=20) were immunized and provoked with isodose saline during the same period. At the 26th day, mice were sacrificed for collecting lung tissues and BALF. Besides, we enrolled 17 cases of asthma children and 13 cases of children with airway foreign body as controls. BALF of each subject was collected. Total cellular score and differential counting in BALF were recorded. Expression levels of miR-26a, miR-146a, and miR-31 were detected by reverse transcription-polymerase chain reaction (RT-PCR). Levels of IL-5, IL-8, IL-12, and TNF-α were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The total cellular score in BALF of asthma mice and asthma children was higher than that of controls (p<0.05). Percentages of eosinophils, neutrophils, and lymphocytes in BALF of asthma mice and asthma children were higher than those of controls, whereas the percentage of macrophages was lower (p<0.05). Levels of IL-5, IL-8, IL-12, and TNF-α in lung tissues of asthma mice were markedly elevated compared with those of controls (p<0.05). Similarly, levels of IL-5, IL-8, IL-12, and TNF-α were higher in BALF of asthma children than controls (p<0.05). RT-PCR data showed higher mRNA levels of miR-26a, miR-146a, and miR-31 in lung tissues of asthma mice than controls (p<0.05). The mRNA levels of miR-26a, miR-146a, and miR-31 in BALF of asthma children were highly expressed compared with those of controls as well (p<0.05). CONCLUSIONS: MiR-26a, miR-146a, and miR-31 are involved in asthma progression mainly through regulating inflammatory factors and cells.

Understanding the Role of Innate Immunity in the Response to Intracortical Microelectrodes.

Intracortical microelectrodes exhibit enormous potential for researching the nervous system, steering assistive devices and functional electrode stimulation systems for severely paralyzed individuals, and augmenting the brain with computing power. Unfortunately, intracortical microelectrodes often fail to consistently record signals over clinically useful periods. Biological mechanisms, such as the foreign body response to intracortical microelectrodes and self-perpetuating neuroinflammatory cascades, contribute to the inconsistencies and decline in recording performance. Unfortunately, few studies have directly correlated microelectrode performance with the neuroinflammatory response to the implanted devices. However, of those select studies that have, the role of the innate immune system remains among the most likely links capable of corroborating the results of different studies, across laboratories. Therefore, the overall goal of this review is to highlight the role of innate immunity signaling in the foreign body response to intracortical microelectrodes and hypothesize as to appropriate strategies that may become the most relevant in enabling brain-dwelling electrodes of any geometry, or location, for a range of clinical applications.

Regulation of immune response by bioactive ions released from silicate bioceramics for bone regeneration.

Silicate bioceramics have been considered to possess a wide prospect of clinical application for orthopedic tissue regeneration due to their excellent osteogenesis and angiogenesis. However, the mechanism for silicate bioceramics stimulating bone formation is not fully understood. The host immune defense to implants is proved to greatly influence the osteogenesis and new bone formation, but up to now, few studies are focused on the silicate bioceramics modulated host immune responses. In our present study, two representative silicate bioceramics, akermanite (AKT) and nagelschmidtite (NAGEL) were used as model materials to investigate the inflammation responses in vitro and in vivo, and ß-tricalcium phosphate (ß-TCP) bioceramics were used as a control. It was found that the mouse macrophage cell RAW264.7 that cultured on AKT and NAGEL bioceramics displayed not only less viability and proliferation, but also a significant less inflammatory cytokine secretion than those on ß-TCP in vitro. The formation of foreign body giant cells and fibrous capsules, the invasion of macrophages, as well as the detected inflammatory cytokines around the implanted materials were much lower in both AKT and NAGEL bioceramic groups as compared with those in the ß-TCP controls in vivo. Furthermore, it was found that not just the certain concentration of extracellular Si-containing ionic products released from the silicate bioceramics, but also the separate Si, Mg and Ca ions revealed the activity to inhibit the macrophage inflammatory responses by the way of suppressing the activated inflammatory MAPK and NF-κB signaling pathway and promoting the caspase-dependent apoptosis of macrophages. In general, our study suggests that the silicate bioceramics could regulate immune responses by altering the ionic microenvironment between the implants and hosts, which may offer new insight about the mechanism of the bioactivity of silicate bioceramics in bone regeneration and provide profitable guidance for designing new biomaterials for bone tissue engineering. STATEMENT OF SIGNIFICANCE: Silicate bioceramics have been widely used for orthopedic tissue regeneration because of their excellent characteristics in bone formation. However, there are few studies concerning their interrelationships with the host immune defense that has been proved to greatly influence osteogenesis. In our present study, the akermanite and nagelschmidtite were used as two representative silicate bioceramics to investigate the inflammation responses in vitro and in vivo; and for the first time, the bioactive ions released from the silicate bioceramics were discovered to regulate the macrophage immune responses through both inhibiting the inflammatory signaling and activating apoptosis of macrophages. Our findings in this study may not only increase the understanding in osteogenic activity of silicate bioceramics, but also provide profitable guidance for designing and manufacturing new biomaterials for bone tissue engineering.

Biofilms in ear, nose, and throat infections: how important are they?

BACKGROUND: Biofilms present a new challenging concept in sustaining chronic, common antibiotic-resistant ear, nose, and throat (ENT) infections. They are communities of sessile bacteria embedded in a matrix of extracellular polymeric substances of their own synthesis that adhere to a foreign body or a mucosal surface with impaired host defense. The aim of this paper is to review the literature on ENT diseases that can be attributed to biofilm formation and to discuss options for future treatment. MATERIALS AND METHODS: Literature review from Medline and database sources. Electronic links and related books were also included. STUDY SELECTION: Controlled clinical trials, animal models, ex vivo models, laboratory studies, retrospective studies, and systematic reviews. DATA SYNTHESIS: Biofilm formation is a dynamic five-step process guided by interbacterial communicating systems. Bacteria in biofilms express different genes and have markedly different phenotypes from their planktonic counterparts. Detachment of cells, production of endotoxin, increased resistance to the host immune system, and provision of a niche for the generation of resistant organisms are biofilm processes that could initiate the infection process. Effective prevention and management strategies include interruption of quorum sensing, inhibition of related genes, disruption of the protective extrapolymer matrix, macrolides (clarithromycin and erythromycin), and mechanical debridement of the biofilm-bearing tissues. With regard to medical indwelling devices, surface treatment of fluoroplastic grommets and redesign of cochlear implants could minimize initial microbial colonization. CONCLUSION: As the role of biofilms in human infection becomes better defined, ENT surgeons should be prepared to deal with their unique and tenacious nature.