Evaluation of Risk Factors for Chronic Obstructive Pulmonary Disease in the Middle-Aged and Elderly Rural Population of Northeast China Using Logistic Regression and Principal Component Analysis.

Purpose: To investigate the environmental, immune, and inflammatory factors associated with chronic obstructive pulmonary disease (COPD) in middle-aged and older Chinese individuals. Patients and Methods: A community-based case-control study was conducted among 471 patients with COPD and 485 controls. The information on COPD of the participants was collected through face-to-face interviews, and serum samples were measured at the laboratory. The main risk factors for COPD were analyzed using principal component analysis (PCA) and logistic regression. Results: Nine hundred and fifty-six respondents were included in the analysis. The results of the PCA-logistic regression analysis showed significant differences in the environmental factors, medical history, and serum C-reactive protein (CRP) levels between patients and controls. COPD was markedly more usual in those with smoking index >200 (OR, 1.42; 95% CI, 1.28-1.57); exposure to outdoor straw burning (OR, 1.64; 95% CI, 1.47-1.83); use of coal, wood, and straw indoors (OR, 2.31; 95% CI, 1.92-2.78); history of respiratory disease and coronary heart disease (OR, 3.58; 95% CI, 3.12-4.10), congestive heart failure (OR, 1.23; 95% CI, 1.09-1.38), and cerebrovascular disease (OR, 1.15; 95% CI,1.02-1.31); and higher serum level of CRP (OR, 1.20; 95% CI, 1.11-1.30). Compared to the logistic regression analysis, PCA logistic regression analysis identified more important risk factors for COPD. Conclusion: PCA-logistic regression analysis was first utilized to explore the influencing factors among rural residents in Northeast China Environmental aged 40 years and above, it was found that environmental factors, medical history, and serum CRP levels mainly affected the prevalence of COPD.

Effect of atrazine on accumulation of iron via the iron transport proteins in the midbrain of SD rats.

Atrazine (ATR), a widely used herbicide that belongs to the triazine class, has detrimental effects on several organ systems. It has also been shown that ATR exposure results in dopaminergic neurotoxicity. However, the mechanism of herbicides causing ferroptosis in neurons is less concerned. So, the present study aimed to investigate the effects of long-term oral exposure to ATR on ferroptosis in adult male rats. In this study, we show that there was a dose-dependent increase in the concentration of iron in the midbrain. Simultaneously, the expression of tyrosine hydroxylase (TH) and Synuclein (α-syn) were altered by the ATR. We carried out miRNA profiling brain tissue in order to identify factors that mediate ferroptosis. We also found that the mRNA and protein expression of the transferrin receptor (TFR), divalent metal transporter 1 (DMT1), hephaestin (HEPH), and ferroportin 1 (Fpn1) in the midbrain were affected by ATR. Based on the current results and previously published data, it is clear that exposure of adult male rats to high doses of ATR leads to iron loading in the midbrain. The long-term adverse effects of ATR on the midbrain have a special relevance after exposure.

Programmed Multidrug Delivery Based on Bio-Inspired Capsule-Integrated Nanocoatings for Infected Bone Defect Treatment.

Infection and delayed wound healing are two major serious complications related to traumatic injuries and cause a significant burden to patients and society. Most currently available drug delivery materials typically carry a single drug, lack protection from drug loading, and face challenges in on-demand and precisely controlled drug release. Here, we report a flower (Cirsium arvense)-inspired capsule-integrated multilayer nanofilm (FICIF), synthesized using a layer-by-layer self-assembly, for programmed multiple drug co-delivery for trauma (open fracture as an example) treatments. Our approach allows polypeptide multilayer nanofilms and innovative impregnated capsules to assemble hierarchical reservoirs with specific drug binding sites, shielding protection capability, and ordered packing structures. The resultant FICIF nanocarriers enable sustained and on-demand co-delivery of a unique immune-tuning cytokine (interleukin 12p70) and a growth factor (bone morphogenetic protein 2) in clinical use, resulting in extraordinary anti-infection (3 orders of magnitude improved bacterial killing) and bone regeneration (5 times enhanced bone healing) in treating infected rat femur fractures. The successful synthesis of these biomimetic high-performance delivery nanocoatings is expected to serve as a source of inspiration for the development of biomaterials for various clinical applications.

Pinecone-Inspired Nanoarchitectured Smart Microcages Enable Nano/Microparticle Drug Delivery.

Drug delivery plays a vital role in medicine and health, but the on-demand delivery of large-sized drugs using stimuli-triggered carriers is extremely challenging. Most present capsules consist of polymeric dense shells with nanosized pores (<10 nm), thus typically lack permeability for nano/microparticle drugs. Here, a pinecone-inspired smart microcage with open network shells, assembled from cellulose nanofibrils (CNFs), is reported for nano/microparticle drug delivery. The approach allows the nanoarchitectured, functionalized CNFs to assemble into mechanically robust, haystack-like network shells with tunable large-through pores and polypeptide-anchored points on a large scale. Such open network shells can intelligently open/close triggered by lesion stimuli, making the therapy "always on-demand." The resulting pinecone-inspired microcages exhibit integrated properties of superior structural stability, superhydrophilicity, and pH-triggered, smart across-shell transport of emerging antimicrobial silver nanoparticles and bioactive silicate nanoplatelets (sizes of >100 nm), which enable both extraordinary anti-infection and bone regeneration. This work provides new insights into the design and development of multifunctional encapsulation and delivery carriers for medical and environmental applications.

An Injectable Conductive Three-Dimensional Elastic Network by Tangled Surgical-Suture Spring for Heart Repair.

Designing scaffolds with persistent elasticity and conductivity to mimic microenvironments becomes a feasible way to repair cardiac tissue. Injectable biomaterials for cardiac tissue engineering have demonstrated the ability to restore cardiac function by preventing ventricular dilation, enhancing angiogenesis, and improving conduction velocity. However, limitations are still among them, such as poor mechanical stability, low conductivity, and complicated procedure. Here, we developed thermal plastic poly(glycolic acid) surgical suture and mussel-inspired conductive particle's adhesion into a highly elastic, conductive spring-like coils. The polypyrrole (PPy)-coated biospring acted as an electrode and then was assembled into a solid-state supercapacitor. After being injected through a syringe needle (0.33 mm inner diameter), the tangled coils formed an elastically conductive three-dimensional (3-D) network to modulate cardiac function. We found that cardiomyocytes (CMs) grew along the spring coils' track with elongated morphologies and formed highly oriented sarcomeres. The biospring enhanced the CMs' maturation in synchronous contraction accompanied by high expressions of cardiac-specific proteins, α-actinin, and connexin 43 (cx43). After the elastic, conductive biosprings were injected into the myocardial infarction (MI) area, the left ventricular fractional shortening was improved by about 12.6% and the infarct size was decreased by about 34%. Interestingly, the spring can be utilized as a sensor to measure the CMs' contractile force, which was 1.57 × 10-3 ± 0.26 × 10-3 mN (∼4.1 × 106 cells). Accordingly, this study highlights an injectable biospring to form a tangled conductive 3-D network in vivo for MI repair.

Silver nanoparticles present high intracellular and extracellular killing against Staphylococcus aureus.

OBJECTIVES: Bone and joint infections caused by Staphylococcus aureus are becoming increasingly difficult to treat due to rising antibiotic resistance, resilient biofilms and intracellular survival of S. aureus. It has been challenging to identify and develop antimicrobial agents that can be used to kill extracellular and intracellular bacteria while having limited toxicity towards host cells. In addressing this challenge, this study investigates the antimicrobial efficacy and toxicity of silver nanoparticles (AgNPs). METHODS: Intracellular bacteria were generated using a co-culture model of human osteoblast cells and S. aureus. Extracellular and intracellular S. aureus were treated with AgNPs, antibiotics and their combinations, and numbers of colonies were quantified. Toxicity of AgNPs against human osteoblast cells was determined by quantifying the number of viable cells after treatment. RESULTS: AgNPs demonstrated excellent antimicrobial activity against extracellular S. aureus with a 100% killing efficacy at concentrations as low as 56 µM, along with a high intracellular killing efficacy of 76% at 371 µM. AgNPs were non-toxic or slightly toxic towards human osteoblasts at the concentrations studied (up to 927 µM). Moreover, smaller-sized (40 nm) AgNPs were more efficacious in killing bacteria compared with their larger-sized (100 nm) counterparts and synergistic antimicrobial effects against extracellular bacteria were observed when AgNPs were combined with gentamicin. CONCLUSIONS: AgNPs and their combination with antibiotics have demonstrated high extracellular and intracellular bacterial killing and presented unique aspects for potential clinical applications, especially for chronic and recurrent infections where intracellular bacteria may be the cause.

Recent advances in musculoskeletal local drug delivery.

Musculoskeletal disorders are a significant burden on the global economy and public health. Advanced drug delivery plays a key role in the musculoskeletal field and holds the promise of enhancing the repair of degenerated and injured musculoskeletal tissues. Ideally, drug delivery should have the ability to directly deliver therapeutic agents to the diseased/injured sites with a desirable drug level over a period of time. Here, we present a mini-review of the current state-of-the-art research associated with local drug delivery and its use for the treatment of musculoskeletal disorders. First, an overview of drug delivery strategies, with a focus on issues related to musculoskeletal pathology, potential therapeutic strategies, conventional and non-conventional drugs, and various delivery systems, is introduced. Then, we highlight recent advances in the emerging fields of musculoskeletal local drug delivery, involving therapeutic drugs (e.g., genes, small molecule therapeutics, and stem cells), novel delivery vehicles (e.g., 3D printing and tissue engineering techniques), and innovative delivery approaches (e.g., multi-drug delivery and smart stimuli-responsive delivery). The review concludes with future perspectives and associated challenges for developing local drug delivery for musculoskeletal applications. STATEMENT OF SIGNIFICANCE: Three important aspects are highlighted in this manuscript: 1) The advanced musculoskeletal drug delivery is introduced from the aspects ranging from musculoskeletal disorders, potential therapeutic solutions, and various drug delivery systems. 2) The recent advances in the emerging fields of musculoskeletal local drug delivery, involving therapeutic drugs (e.g., genes, small molecule therapeutics, and stem cells), novel delivery vehicles (e.g., 3D printing and tissue engineering technique), and innovative delivery approaches (e.g., multi-drug delivery and smart stimuli-responsive delivery), are highlighted. 3) The challenges and perspectives of future research directions in the development of musculoskeletal local drug delivery are presented.

Capsule-Integrated Polypeptide Multilayer Films for Effective pH-Responsive Multiple Drug Co-Delivery.

Many applications using drug-carrying biomedical materials require on-demand, localized delivery of multiple therapeutic agents in precisely controlled and patient-specific time sequences, especially after assembly of the delivery vehicles; however, creating such materials has proven extremely challenging. Here, we report a novel strategy to create polypeptide multilayer films integrated with capsules as vehicles for co-delivery of multiple drugs using layer-by-layer self-assembly technology. Our approach allows the multilayered polypeptide nanofilms and preimpregnated capsules to assemble into innovative biomedical materials with high and controllable loading of multiple drugs at any time postpreparation and to achieve pH-responsive and sustained release. The resulting capsule-integrated polypeptide multilayer films effectively co-deliver various drugs with very different properties, including proteins (e.g., growth factors) and nanoparticles, achieving bovine serum albumin loading of 80 µg cm-2 and release of 2 weeks, and histone loading of 100 µg cm-2 and release of 6 weeks; which also enable Staphylococcus aureus killing efficacy of 83% while maintaining osteoblast viability of >85% with silver nanoparticle delivery; and >5-fold cell adhesion and proliferation capability with live cell percentage of >90% via human recombinant bone morphogenetic protein 2 delivery. The successful development of such fascinating materials can not only function as advanced nanocoatings to reduce two major complications of orthopedic bone injuries (i.e., infection and delayed bone regeneration) but also provide new insights into the design and development of multifunctional materials for various other biomedical applications.

Hydrogen bonds autonomously powered gelatin methacrylate hydrogels with super-elasticity, self-heal and underwater self-adhesion for sutureless skin and stomach surgery and E-skin.

Interface-interaction induced self-healing and self-adhesive are a gem-like attribute inspired by our Mother Nature. Biocompatible gelatin methacrylate (GelMA) hydrogels exhibit tunable mechanical properties which are favorable in biomedical applications. However, it is difficult to integrate high stiffness, super-elasticity, large deformability and self-healing property together. Here, we report a GelMA-based double-network (DN) hydrogel with above properties by utilizing tannic acid (TA) as a multi-functional H-bond provider. We first investigated the morphological and mechanical properties' changes of GelMA over different TA's concentrations and treating times. In comparison to pristine GelMA hydrogel (10% w/v), the GelMA-TA hydrogels presented significant increase in ultimate stress (4.3-fold), compressive modulus (2.5-fold), and especially in elongation (6-fold). Adhesion properties of GelMA-TA can be tuned by TA and have been proven to be water-resistant. To test gels' feasibility in vivo, we applied GelMA-TA gels to close skin wound and gastric incision without suture. The results indicated the gels had the capabilities of promoting wound healing with superior tissue restoration and minimal tissue adhesion. Furthermore, integrated with carbon nanotubes, the GelMA-TA-carbon nanotube gel was an alternative self-healing electric skin with strain-sensitive conductivity. This work demonstrated a strategy to yield mechanically strong hydrogel adhesives for innovative biomedical applications.

Bacteria antibiotic resistance: New challenges and opportunities for implant-associated orthopedic infections.

There has been a dramatic increase in the emergence of antibiotic-resistant bacterial strains, which has made antibiotic choices for infection control increasingly limited and more expensive. In the U.S. alone, antibiotic-resistant bacteria cause at least 2 million infections and 23,000 deaths a year resulting in a $55-70 billion per year economic impact. Antibiotics are critical to the success of surgical procedures including orthopedic prosthetic surgeries, and antibiotic resistance is occurring in nearly all bacteria that infect people, including the most common bacteria that cause orthopedic infections, such as Staphylococcus aureus (S. aureus). Most clinical cases of orthopedic surgeries have shown that patients infected with antibiotic-resistant bacteria, such as methicillin-resistant S. aureus (MRSA), are associated with increased morbidity and mortality. This paper reviews the severity of antibiotic resistance at the global scale, the consequences of antibiotic resistance, and the pathways bacteria used to develop antibiotic resistance. It highlights the opportunities and challenges in limiting antibiotic resistance through approaches like the development of novel, non-drug approaches to reduce bacteria functions related to orthopedic implant-associated infections. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:22-32, 2018.

Egg Albumen as a Fast and Strong Medical Adhesive Glue.

Sutures penetrate tissues to close wounds. This process leads to inflammatory responses, prolongs healing time, and increases operation complexity. It becomes even worse when sutures are applied to stress-sensitive and fragile tissues. By bonding tissues via forming covalent bonds, some medical adhesives are not convenient to be used by surgeons and have side effects to the tissues. Here egg albumen adhesive (EAA) is reported with ultrahigh adhesive strength to bond various types of materials and can be easily used without any chemical and physical modifications. Compared with several commercial medical glues, EAA exhibits stronger adhesive property on porcine skin, glass, polydimethylsiloxane. The EAA also shows exceptional underwater adhesive strength. Finally, wound closure using EAA on poly(caprolactone) nanofibrous sheet and general sutures is investigated and compared in a rat wound model. EAA also does not show strong long-term inflammatory response, suggesting that EAA has potential as a medical glue, considering its abundant source, simple fabrication process, inherent nontoxicity, and low cost.

ClC-7/Ostm1 contribute to the ability of tea polyphenols to maintain bone homeostasis in C57BL/6 mice, protecting against fluorosis.

Epidemiological investigations indicate that certain ingredients in tea bricks can antagonize the adverse effects of fluoride. Tea polyphenols (TPs), the most bioactive ingredient in tea bricks, have been demonstrated to be potent bone-supporting agents. ClC­7 is known to be crucial for osteoclast (OC) bone resorption. Thus, in this study, we investigated the potential protective effects of TPs against fluorosis using a mouse model and explored the underlying mechanisms with particular focus on ClC­7. A total of 40, healthy, 3­week­old male C57BL/6 mice were randomly divided into 4 groups (n=10/group) by weight as follows: distilled water (control group), 100 mg/l fluoridated water (F group), water containing 10 g/l TPs (TP group) and water containing 100 mg/l fluoride and 10 g/l TPs (F + TP group). After 15 weeks, and after the mice were sacrificed, the long bones were removed and bone marrow-derived macrophages were cultured ex vivo in order to perform several experiments. OCs were identified and counted by tartrate­resistant acid phosphatase (TRAP) staining. The consumption of fluoride resulted in severe fluorosis and in an impaired OC function [impaired bone resorption, and a low mRNA expression of nuclear factor of activated T-cells 1 (NFATc1), ATPase H+ transporting V0 subunit D2 (ATP6v0d2) and osteopetrosis­associated transmembrane protein 1 (Ostm1)]. In the F + TP group, fluorosis was attenuated and OC function was restored, but not the high bone fluoride content. Compared with the F group, mature OCs in the F + TP group expressed higher mRNA levels of ClC­7 and Ostm1; the transportation and retaining of Cl­ was improved, as shown by the fluorescence intensity experiment. On the whole, our findings indicate that TPs mitigate fluorosis in C57BL/6 mice by regulating OC bone resorption. Fluoride inhibits OC resorption by inhibiting ClC­7 and Ostm1, whereas TPs attenuate this inhibitory effect of fluoride.

Mussel-Inspired Multifunctional Hydrogel Coating for Prevention of Infections and Enhanced Osteogenesis.

Prevention of postsurgery infection and promotion of biointegration are the key factors to achieve long-term success in orthopedic implants. Localized delivery of antibiotics and bioactive molecules by the implant surface serves as a promising approach toward these goals. However, previously reported methods for surface functionalization of the titanium alloy implants to load bioactive ingredients suffer from time-consuming complex processes and lack of long-term stability. Here, we present the design and characterization of an adhesive, osteoconductive, and antimicrobial hydrogel coating for Ti implants. To form this multifunctional hydrogel, a photo-cross-linkable gelatin-based hydrogel was modified with catechol motifs to enhance adhesion to Ti surfaces and thus promote coating stability. To induce antimicrobial and osteoconductive properties, a short cationic antimicrobial peptide (AMP) and synthetic silicate nanoparticles (SNs) were introduced into the hydrogel formulation. The controlled release of AMP loaded in the hydrogel demonstrated excellent antimicrobial activity to prevent biofilm formation. Moreover, the addition of SNs to the hydrogel formulation enhanced osteogenesis when cultured with human mesenchymal stem cells, suggesting the potential to promote new bone formation in the surrounding tissues. Considering the unique features of our implant hydrogel coating, including high adhesion, antimicrobial capability, and the ability to induce osteogenesis, it is believed that our design provides a useful alternative method for bone implant surface modification and functionalization.

Nanotoxicity: emerging concerns regarding nanomaterial safety and occupational hard metal (WC-Co) nanoparticle exposure.

As the number of commercial and consumer products containing engineered nanomaterials (ENMs) continually rises, the increased use and production of these ENMs presents an important toxicological concern. Although ENMs offer a number of advantages over traditional materials, their extremely small size and associated characteristics may also greatly enhance their toxic potentials. ENM exposure can occur in various consumer and industrial settings through inhalation, ingestion, or dermal routes. Although the importance of accurate ENM characterization, effective dosage metrics, and selection of appropriate cell or animal-based models are universally agreed upon as important factors in ENM research, at present, there is no "standardized" approach used to assess ENM toxicity in the research community. Of particular interest is occupational exposure to tungsten carbide cobalt (WC-Co) "dusts," composed of nano- and micro-sized particles, in hard metal manufacturing facilities and mining and drilling industries. Inhalation of WC-Co dust is known to cause "hard metal lung disease" and an increased risk of lung cancer; however, the mechanisms underlying WC-Co toxicity, the inflammatory disease state and progression to cancer are poorly understood. Herein, a discussion of ENM toxicity is followed by a review of the known literature regarding the effects of WC-Co particle exposure. The risk of WC-Co exposure in occupational settings and the updates of in vitro and in vivo studies of both micro- and nano-WC-Co particles are discussed.

In vitro inflammatory effects of hard metal (WC-Co) nanoparticle exposure.

Identifying the toxicity of nanoparticles (NPs) is an important area of research as the number of nanomaterial-based consumer and industrial products continually rises. In addition, the potential inflammatory effects resulting from pulmonary NP exposure are emerging as an important aspect of nanotoxicity. In this study, the toxicity and inflammatory state resulting from tungsten carbide-cobalt (WC-Co) NP exposure in macrophages and a coculture (CC) of lung epithelial cells (BEAS-2B) and macrophages (THP-1) at a 3:1 ratio were examined. It was found that the toxicity of nano-WC-Co was cell dependent; significantly less toxicity was observed in THP-1 cells compared to BEAS-2B cells. It was demonstrated that nano-WC-Co caused reduced toxicity in the CC model compared to lung epithelial cell monoculture, which suggested that macrophages may play a protective role against nano-WC-Co-mediated toxicity in CCs. Nano-WC-Co exposure in macrophages resulted in increased levels of interleukin (IL)-1ß and IL-12 secretion and decreased levels of tumor necrosis factor alpha (TNFα). In addition, the polarizing effects of nano-WC-Co exposure toward the M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophage phenotypes were investigated. The results of this study indicated that nano-WC-Co exposure stimulated the M1 phenotype, marked by high expression of CD40 M1 macrophage surface markers.

Myricetin inhibits proliferation of cisplatin-resistant cancer cells through a p53-dependent apoptotic pathway.

Cisplatin is a commonly used drug for cancer treatment by crosslinking DNA, leading to apoptosis of cancer cells, resistance to cisplatin treatment often occurs, leading to relapse. Therefore, there is a need for the development of more effective treatment strategies that can overcome chemoresistance. Myricetin is a flavonoid from fruits and vegetables, showing anticancer activity in various cancer cells. In this study, we found myricetin exhibited greater cytotoxicity than cisplatin in two cisplatin-resistant ovarian cancer cell lines, OVCAR-3 and A2780/CP70, and it was less cytotoxic to the normal ovarian cell line IOSE-364. Myricetin selectively induced apoptosis in both cisplatin-resistant cancer cell lines, but did not induce apoptosis in the normal ovarian cell line. It induced both Bcl-2 family-dependent intrinsic and DR5 dependent extrinsic apoptosis in OVCAR-3 cells. P53, a multifunctional tumor suppressor, regulated apoptosis in OVCAR-3 cells through a Bcl-2 family protein-dependent pathway. Myricetin did not induce cell cycle arrest in either ovarian cancer cell line. Because of its potency and selectivity against cisplatin-resistant cancer cells, myricetin could potentially be used to overcome cancer chemoresistance against platinum-based therapy.

Tungsten Carbide-Cobalt Nanoparticles Induce Reactive Oxygen Species, AKT, ERK, AP-1, NF-κB, VEGF, and Angiogenesis.

Powder mixtures of tungsten carbide and metallic cobalt (WC-Co) are widely used in various products. Nanoparticles are engineered structures with at least one dimension of 100 nm or smaller. WC-Co is known to be associated with lung injury and diseases. Angiogenesis is a key process during vasculature, carcinogenesis, recovery of injury, and inflammatory diseases. However, the cellular effects of WC-Co nanoparticles on angiogenesis remain to be elucidated. In this study, we investigated angiogenic response and relative mechanisms after exposure to WC-Co nanoparticles. Our results showed that WC-Co nanoparticles at 5 µg/cm(2) induced ROS production which activated AKT and ERK1/2 signaling pathways in lung epithelial cells by reactive oxygen species (ROS) staining and immunoblotting; WC-Co treatment also increased transcriptional activation of AP-1, NF-κB, and VEGF by reporter assay. Further studies demonstrated that ROS are upstream molecules of AKT and ERK signaling pathways; the activation of AP-1, NF-κB, and VEGF was through ROS generation, AKT and ERK1/2 activation. In addition, WC-Co nanoparticles affected the cells to induce angiogenesis by chicken chorioallantoic membrane (CAM) assay. These results illustrate that exposure to WC-Co nanoparticles induces angiogenic response by activating ROS, AKT, and ERK1/2 signaling pathways and the downstream molecules and elucidate the potential molecular mechanisms during this process. This information may be useful for preventing potential damage from nanoparticle exposure in the future.

Acute inflammatory responses of nanoparticles in an intra-tracheal instillation rat model.

Exposure to hard metal tungsten carbide cobalt (WC-Co) "dusts" in enclosed industrial environments is known to contribute to the development of hard metal lung disease and an increased risk for lung cancer. Currently, the influence of local and systemic inflammation on disease progression following WC-Co exposure remains unclear. To better understand the relationship between WC-Co nanoparticle (NP) exposure and its resultant effects, the acute local pulmonary and systemic inflammatory responses caused by WC-Co NPs were explored using an intra-tracheal instillation (IT) model and compared to those of CeO2 (another occupational hazard) NP exposure. Sprague-Dawley rats were given an IT dose (0-500 µg per rat) of WC-Co or CeO2 NPs. Following 24-hr exposure, broncho-alveolar lavage fluid and whole blood were collected and analyzed. A consistent lack of acute local pulmonary inflammation was observed in terms of the broncho-alveolar lavage fluid parameters examined (i.e. LDH, albumin, and macrophage activation) in animals exposed to WC-Co NP; however, significant acute pulmonary inflammation was observed in the CeO2 NP group. The lack of acute inflammation following WC-Co NP exposure contrasts with earlier in vivo reports regarding WC-Co toxicity in rats, illuminating the critical role of NP dose and exposure time and bringing into question the potential role of impurities in particle samples. Further, we demonstrated that WC-Co NP exposure does not induce acute systemic effects since no significant increase in circulating inflammatory cytokines were observed. Taken together, the results of this in vivo study illustrate the distinct differences in acute local pulmonary and systemic inflammatory responses to NPs composed of WC-Co and CeO2; therefore, it is important that the outcomes of pulmonary exposure to one type of NPs may not be implicitly extrapolated to other types of NPs.

Differential responses of osteoblasts and macrophages upon Staphylococcus aureus infection.

BACKGROUND: Staphylococcus aureus (S. aureus) is one of the primary causes of bone infections which are often chronic and difficult to eradicate. Bacteria like S. aureus may survive upon internalization in cells and may be responsible for chronic and recurrent infections. In this study, we compared the responses of a phagocytic cell (i.e. macrophage) to a non-phagocytic cell (i.e. osteoblast) upon S. aureus internalization. RESULTS: We found that upon internalization, S. aureus could survive for up to 5 and 7 days within macrophages and osteoblasts, respectively. Significantly more S. aureus was internalized in macrophages compared to osteoblasts and a significantly higher (100 fold) level of live intracellular S. aureus was detected in macrophages compared to osteoblasts. However, the percentage of S. aureus survival after infection was significantly lower in macrophages compared to osteoblasts at post-infection days 1-6. Interestingly, macrophages had relatively lower viability in shorter infection time periods (i.e. 0.5-4 h; significant at 2 h) but higher viability in longer infection time periods (i.e. 6-8 h; significant at 8 h) compared to osteoblasts. In addition, S. aureus infection led to significant changes in reactive oxygen species production in both macrophages and osteoblasts. Moreover, infected osteoblasts had significantly lower alkaline phosphatase activity at post-infection day 7 and infected macrophages had higher phagocytosis activity compared to non-infected cells. CONCLUSIONS: S. aureus was found to internalize and survive within osteoblasts and macrophages and led to differential responses between osteoblasts and macrophages. These findings may assist in evaluation of the pathogenesis of chronic and recurrent infections which may be related to the intracellular persistence of bacteria within host cells.