Dynamic chest radiographic evaluation of the effects of tiotropium/olodaterol combination therapy in chronic obstructive pulmonary disease: the EMBODY study protocol for an open-label, prospective, single-centre, non-controlled, comparative study.

INTRODUCTION: To date, there is limited evidence on the effects of bronchodilators on respiratory dynamics in chronic obstructive pulmonary disease (COPD). Dynamic chest radiography (DCR) is a novel radiographic modality that provides real-time, objective and quantifiable kinetic data, including changes in the lung area (Rs), tracheal diameter, diaphragmatic kinetics and pulmonary ventilation during respiration, at a lower radiation dose than that used by fluoroscopic or CT imaging. However, the therapeutic effect of dual bronchodilators on respiratory kinetics, such as chest wall dynamics and respiratory muscle function, has not yet been prospectively evaluated using DCR. AIM: This study aims to evaluate the effects of bronchodilator therapy on respiratory kinetics in patients with COPD using DCR. METHODS AND ANALYSIS: This is an open-label, prospective, single-centre, non-controlled, comparative study. A total of 35 patients with COPD, aged 40-85 years, with a forced expiratory volume in the first second of 30-80%, will be enrolled. After a 2-4 weeks washout period, patients will receive tiotropium/olodaterol therapy for 6 weeks. Treatment effects will be evaluated based on DCR findings, pulmonary function test results and patient-related outcomes obtained before and after treatment. The primary endpoint is the change in Rs after therapy. The secondary endpoints include differences in other DCR parameters (diaphragmatic kinetics, tracheal diameter change and maximum pixel value change rate), pulmonary function test results and patient-related outcomes between pre-therapy and post-therapy values. All adverse events will be reported. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained from the Ethics Committee of Chiba University Hospital. The results of this trial will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCTs032210543.

Effect of Nivolumab on the Quality of Life in Recurrent/Metastatic Head and Neck Cancer.

BACKGROUND/AIM: Nivolumab is expected to further prolong survival and improve the quality of life (QOL) of patients with a poor prognosis of head and neck cancer. However, only a few studies have been conducted regarding the QOL of recurrent or metastatic head and neck cancer patients treated with nivolumab using real-world data. This study aimed to examine the effect of nivolumab on the QOL of these patients using real-world data. PATIENTS AND METHODS: This study included patients with recurrent metastatic head and neck cancer who received nivolumab at the Department of Otolaryngology and Head and Neck Surgery, Tokyo Medical University Hospital from May 1, 2017, to December 31, 2021. Among them, 50 patients who self-assessed their QOL were included in this study. The primary endpoint was the QOL evaluation score, and secondary endpoints were overall survival (OS), progression-free survival (PFS), response rate, and immune-related adverse events. OS and PFS were evaluated using the Kaplan-Meier method. RESULTS: No significant reduction in QOL was observed before or after nivolumab administration. The median OS time was 20.1 months, and 1-year OS rate was 76.4%. The median PFS time was 4.2 months, and 1-year PFS rate was 31.0%. CONCLUSION: The comparison of patient QOL before and after nivolumab use suggested that patient QOL was not compromised. The results were not inferior to those of other studies in terms of treatment efficacy and safety.

In vitro demonstration of antedrug mechanism of a pharmacokinetic booster to improve CYP3A4 substrates by CYP3A4-mediated metabolism inhibition.

We previously reported novel benzyl-ether derivatives with an imidazole ring and a hydroxyl group (A-01) or carboxyl group (B-01) and esters (2 esters of A-01, and 7 esters of B-01) as pharmacokinetics (PK) boosters. This study demonstrates how these ester compounds embody the concept of a safe pharmacokinetic booster, with potent and transient inhibition of CYP3A4-mediated drug metabolism. As a model CYP3A4 substrate and CYP3A4 enzyme, midazolam (MDZ) and rat liver microsomes were used. A-01 inhibited MDZ metabolism significantly, while B-01 induced only slight inhibition. Although rat liver microsomes hydrolyzed the ester compounds over time, several ester compounds strongly inhibited MDZ metabolism. Due to the significant activity of A-01, A-01 esters affected MDZ metabolism, irrespective of hydrolysis state. Time-dependent inhibition evaluation indicated that the B-01 ester inhibition is not mechanism-based, as hydrolysis eliminated MDZ metabolism inhibition. We report that the B-01 esters significantly inhibit CYP3A4-mediated drug metabolism, and upon hydrolysis this property is eliminated. In conclusion, B-01 ester compounds may be safe PK boosters with antedrug characteristics.

Manipulation of Macrophage Uptake by Controlling the Aspect Ratio of Graft Copolymer Micelles.

Nanostructures of drug carriers play a crucial role in nanomedicine due to their ability to influence drug delivery. There is yet no clear consensus regarding the optimal size and shape (e.g., aspect ratio) of nanoparticles for minimizing macrophage uptake, given the difficulties in controlling the shape and size of nanoparticles while maintaining identical surface properties. Here, we employed graft copolymer self-assembly to prepare polymer micelles with aspect ratios ranging from 1.0 (spherical) to 10.8 (cylindrical) and closely matched interfacial properties. Notably, our findings emphasize that cylindrical micelles with an aspect ratio of 2.4 are the least susceptible to macrophage uptake compared with both their longer counterparts and spherical micelles. This reduced uptake of the short cylindrical micelles results in a 3.3-fold increase in blood circulation time compared with their spherical counterparts. Controlling the aspect ratio of nanoparticles is crucial for improving drug delivery efficacy through better nanoparticle design.

Influence of Polymer Side Chain Size and Backbone Length on the Self-Assembly of Supramolecular Polymer Bottlebrushes.

Hydrogen bonds are a versatile tool for creating fibrous, bottlebrush-like assemblies of polymeric building blocks. However, a delicate balance of forces exists between the steric repulsion of the polymer chains and these directed supramolecular forces. In this work we have systematically investigated the influence of structural parameters of the attached polymers on the assembly behaviour of benzene trisurea (BTU) and benzene tris(phenylalanine) (BTP) conjugates in water. Polymers with increasing main chain lengths and different side chain sizes were prepared by reversible addition-fragmentation chain-transfer (RAFT) polymerization of hydroxyethyl acrylate (HEA), tri(ethylene glycol) methyl ether acrylate (TEGA) and oligo(ethylene glycol) methyl ether acrylate (OEGA). The resulting structures were analyzed using small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM). Both BTU and BTP formed fibres with PHEA attached, but a transition to spherical morphologies was observed at degrees of polymerisation (DP) of 70 and above. Overall, the main chain length appeared to be a dominating factor in inducing morphology transitions. Increasing the side chain size generally had a similar effect but mainly impeded any aggregation as is the case of POEGA. Interestingly, BTP conjugates still formed fibres, suggesting that the stronger intermolecular interactions can compensate partially for the steric repulsion.

A Case of Photoimmunotherapy for Nasopharyngeal Carcinoma Requiring Emergency Tracheostomy.

Introduction: Photoimmunotherapy (PIT) is a treatment wherein intravenous cetuximab sarotalocan sodium is administered followed by laser light irradiation. This treatment exhibits a specific antitumor effect if in tumors expressing the epidermal growth factor receptor, regardless of the carcinoma [Mitsunaga et al.: Nat Med. 2011;17(12):1685-91, Sato et al.: ACS Cent Sci. 2018;4(11):1559-69, Nakajima et al.: Cancer Sci. 2018;109(9):2889-96]. The current indications are unresectable, locally advanced, or locally recurrent head and neck cancer. If standard treatments, such as radiotherapy and chemotherapy, are available, they are given priority. However, a significant concern in PIT is the occurrence of airway emergencies related to pharyngeal edema. Prophylactic tracheostomy is often performed in cases of PIT involving the root of the tongue, hypopharynx, or larynx. Case Presentation: In this study, we administered transoral PIT to a patient diagnosed with radiation-induced nasopharyngeal carcinoma (squamous cell carcinoma (SCC) cT1N0M0 stage I). Although previous case reports and our own experiences did not report airway emergencies following PIT for nasopharyngeal carcinoma, a unique case occurred in our study [Omura et al.: Auris Nasus Larynx. 2023;50(4):641-5, Kushihashi et al.: Int J Otolaryngol Head Neck Surg. 2022;11(5, Sep):258-65]. The patient experienced poor oxygenation and a decreased level of consciousness early in the morning following the laser irradiation. Nasal endoscopy revealed airway narrowing due to upper airway edema, and intubation was challenging. Consequently, we performed emergency bedside tracheostomy and the patient's condition improved. Conclusion: Therefore, it is crucial to note that airway emergencies can be life-threatening and should be diligently monitored as a potential complication of PIT.

Expression of Preferentially Expressed Antigen in Melanoma, a Cancer/Testis Antigen, in Carcinoma In Situ of the Urinary Tract.

Carcinoma in situ (CIS) of the urinary tract comprises 1-3% of all urothelial malignancies and is often a precursor to muscle-invasive urothelial carcinoma (UC). This study aimed to examine the expression profiles of preferentially expressed antigen in melanoma (PRAME), a cancer/testis antigen, and assess its diagnostic and therapeutic applications in CIS, given that its expression in UC has been minimally studied and has not yet been analyzed in CIS. We selected consecutive patients with CIS who underwent biopsy and/or transurethral tumor resection at the Osaka Medical and Pharmaceutical University Hospital. Immunohistochemical staining for PRAME and p53 was performed. Overall, 53 patients with CIS (6 females and 47 males) were included. Notably, PRAME expression was observed in 23 of the 53 patients (43.4%), whereas it was absent in the non-neoplastic urothelial epithelium. Furthermore, no correlation was found between PRAME expression and aberrant p53 expression. Therefore, PRAME expression may serve as a useful marker for CIS of the urinary tract. Furthermore, PRAME may be a candidate for the novel therapeutic target for standard treatment-refractory CIS patients.

Polymeric core-crosslinked particles prepared via a nanoemulsion-mediated process: from particle design and structural characterization to in vivo behavior in chemotherapy.

Various polymeric nanoparticles have been used as drug carriers in drug delivery systems (DDSs). Most of them were constructed from dynamic self-assembly systems formed via hydrophobic interactions and from structures that are unstable in an in vivo environment owing to their relatively weak formation forces. As a solution to this issue, physically stabilized core-crosslinked particles (CP) with chemically crosslinked cores have received attention as alternatives to the dynamic nanoparticles. This focused review summarizes recent advances in the construction, structural characterization, and in vivo behavior of polymeric CPs. First, we introduce a nanoemulsion-mediated method to create polyethylene glycol (PEG)-bearing CPs and their structural characterization. The relationship between the PEG chain conformations in the particle shell and the in vivo fate of the CPs is also discussed. After that, the development and advantages of zwitterionic amino acid-based polymer (ZAP)-bearing CPs are presented to address the poor penetration and the internalization of PEG-based CPs into tumor tissues and cells, respectively. Finally, we conclude and discuss prospects for application of polymeric CPs in the DDS field.

Molecular Bottlebrushes for Immunostimulatory CpG ODN Delivery: Relationship among Cation Density, Complex Formation Ability, and Cytotoxicity.

Artificially designed short single-stranded DNA sequences containing unmethylated CG (CpG ODNs) are agonists for toll-like receptor 9 (TLR9); thus, they have great potential as vaccine adjuvants for cancer immunotherapy and preventing infectious diseases. To deliver effectively CpG ODNs into cells bearing TLR9, nanoparticle polyion complexes of cationic polymers that are able to ingest multiple CpG ODN molecules have been developed; however, their structures and synthesized polycations are hard to control and bioincompatible, respectively. To solve these issues, we designed cationic molecular bottlebrushes (CMBs) with branches that are made from copolymers of 2-methacryloyloxyethyl phosphorylcholine and 2-methacryloyloxyethyl trimethylammonium chloride. Several instrumental methods were carried out to determine the structure of a CMB and its complex with CpG ODNs. The complexation did not change the overall shape of the original CMB, and the bound CpG ODNs were captured by the outer layer of the CMB. The moderation of cations was important to reduce toxicity and improve secretion of inflammatory cytokines.

Protective effects of alpha-mangostin encapsulated in cyclodextrin-nanoparticle on cerebral ischemia.

The production of reactive oxygen species (ROS) during and after the onset of an ischemic stroke induces neuronal cell death and severely damages brain function. Therefore, reducing ROS by administrating antioxidant compounds is a promising approach to improving ischemic symptoms. Alpha-mangostin (α-M) is an antioxidant compound extracted from the pericarp of the mangosteen fruit. Reportedly, α-M decreases neuronal toxicity in primary rat cerebral cortical neurons. In this study, we investigated the neuroprotective activity of α-M in both in vitro and in vivo assays. Pretreatment with α-M inhibited excessive cellular ROS production after oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro using an SH-SY5Y (human neuroblastoma) cell line. In addition, α-M maintained mitochondrial membrane potential and suppressed mitochondrial-specific ROS production induced by OGD/R. Meanwhile, the low bioavailability of α-M due to its poor water solubility has been an insuperable obstruction impeding extensive investigations of the biological functions of α-M and its medical applications. To overcome this problem, we synthesized a cyclodextrin-based nanoparticle (CDNP) that is known to increase the loading efficiency and binding constant of α-M, compared with cyclodextrins themselves. This nano-formulated α-M (α-M/CDNP) was optimized for an in vivo ischemic stroke model. Our results indicated that α-M/CDNP (25 mg/kg/injection) reduced infarct volume and improved neurological behavior (p = 0.036 and p = 0.046, respectively). These in vivo results suggest that α-M appears to cross the blood-brain barrier (BBB) with the help of a nano-formulation with CDNP. Combining an in vitro BBB model and a physicochemical binding assay between α-M and albumin, it is speculated that α-M released from CDNP would interact with albumin during its prolonged circulation in the blood, and the resultant α-M/albumin complex may cross the BBB through the absorptive-mediated transcytosis pathway. These findings suggest the potential clinical application of α-M in ischemic stroke treatment.

Crosslinked Structure of Polyacrylic Acid Affects Pulmonary Fibrogenicity in Rats.

We conducted intratracheal instillations of polyacrylic acid (PAA) with crosslinking and non-crosslinking into rats in order to examine what kinds of physicochemical characteristics of acrylic-acid-based polymers affect responses in the lung. F344 rats were intratracheally exposed to similar molecular weights of crosslinked PAA (CL-PAA) (degree of crosslinking: ~0.1%) and non-crosslinked PAA (Non-CL-PAA) at low and high doses. Rats were sacrificed at 3 days, 1 week, 1 month, 3 months, and 6 months post-exposure. Both PAAs caused increases in neutrophil influx, cytokine-induced neutrophil chemoattractants (CINC) in the bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in the lung tissue from 3 days to 6 months following instillation. The release of lactate dehydrogenase (LDH) activity in the BALF was higher in the CL-PAA-exposed groups. Histopathological findings of the lungs demonstrated that the extensive fibrotic changes caused by CL-PAA were also greater than those in exposure to the Non-CL- PAA during the observation period. CL-PAA has more fibrogenicity of the lung, suggesting that crosslinking may be one of the physicochemical characteristic factors of PAA-induced lung disorder.

Effect of Different Molecular Weights of Polyacrylic Acid on Rat Lung Following Intratracheal Instillation.

BACKGROUND: We conducted intratracheal instillations of different molecular weights of polyacrylic acid (PAA) into rats in order to examine what kinds of physicochemical characteristics of acrylic acid-based polymer affect responses in the lung. METHODS: F344 rats were intratracheally exposed to a high molecular weight (HMW) of 598 thousand g/mol or a low molecular weight (LMW) of 30.9 thousand g/mol PAA at low and high doses. Rats were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months post exposure. RESULTS: HMW PAA caused persistent increases in neutrophil influx, cytokine-induced neutrophil chemoattractants (CINC) in the bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in the lung tissue from 3 days to 3 months and 6 months following instillation. On the other hand, LMW PAA caused only transient increases in neutrophil influx, CINC in BALF, and HO-1 in the lung tissue from 3 days to up to 1 week or 1 month following instillation. Histopathological findings of the lungs demonstrated that the extensive inflammation and fibrotic changes caused by the HMW PAA was greater than that in exposure to the LMW PAA during the observation period. CONCLUSION: HMW PAA induced persistence of lung disorder, suggesting that molecular weight is a physicochemical characteristic of PAA-induced lung disorder.

Impact of Polyethylene Glycol (PEG) Conformations on the In Vivo Fate and Drug Release Behavior of PEGylated Core-Cross-Linked Polymeric Nanoparticles.

In cancer chemotherapy, core-cross-linked particles (CCPs) are a promising drug carrier due to their high structural stability in an in vivo environment, resulting in improved tumor delivery. A biocompatible polymer of polyethylene glycol (PEG) is often utilized to coat the surface of CCPs to avoid nonspecific adsorption of proteins in vivo. The PEG density and conformation on the particle surface are important structural factors that determine the in vivo fate of such PEGylated nanoparticles, including their pharmacokinetics and pharmacodynamics. However, contrary to expectations, we found no significant differences in the in vivo pharmacokinetics and pharmacodynamics of the PEGylated CCPs with the different PEG densities including mushroom, brush, and dense brush conformations. On the contrary, the in vivo release kinetics of hydrophilic and hydrophobic model drugs from the PEGylated CCPs was strongly dependent on the PEG conformation and the drug polarity. This may be related to the water-swelling degree in the particle PEG layer, which promotes and inhibits the diffusion of hydrophilic and hydrophobic drugs, respectively, from the particle core to the water phase. Our results provide guidelines for the design of cancer-targeting nanomedicine based on PEGylated CCPs.

Zwitterionic Amino Acid Polymer-Grafted Core-Crosslinked Particle toward Tumor Delivery.

Zwitterionic amino acid polymers (ZAPs) exhibit biocompatibility and recognition capability for amino acid transporters (AATs) overexpressed on cancer cells. They are potential cancer-targeting ligands in nanoparticle-based nanomedicines utilized in cancer chemotherapy. Here, a poly(glutamine methacrylate) (pGlnMA)-grafted core-crosslinked particle (pGlnMA-CCP) is prepared through the formation of nanoemulsions stabilized using amphiphilic block copolymers comprising pGlnMA as the hydrophilic block. The chain conformation of the grafted polymer and the particle structure of pGlnMA-CCP are precisely elucidated by dynamic light scattering, X-ray scattering, and transmission electron microscopy. pGlnMA-CCP demonstrates active cellular uptake and deep penetration behaviors for cancer cells and spheroids, respectively, via an AAT-mediated mechanism. The in vivo pharmacokinetics of pGlnMA-CCP is practically comparable to those of a CCP covered with poly(polyethylene glycol methacrylate) (pPEGMA), which inhibits protein adsorption and prolongs blood retention, implying that the biocompatible properties of pGlnMA are similar to those of pPEGMA. Furthermore, pGlnMA-CCP accumulates in cancer tissues at a higher level than that of pPEGMA systems. The results demonstrate that the properties of cancer targetability, tumor permeability, efficient tumor accumulation, and biocompatibility can be obtained by grafting pGlnMA onto nanoparticles, suggesting a high potential of pGlnMA as a ligand for cancer-targeting nanomedicines.

A combination of polyglycolic acid fabric and fibrin glue prevents air leakage from a lung defect.

OBJECTIVES: Air leakage after lung resection is a common morbidity that may lengthen hospital stay. Applying sealant to a lesion is an effective prophylaxis in clinical practice. This study aimed to examine the effect of a combination of a bioabsorbable polyglycolic acid (PGA) fabric and fibrin glue (FG) on air sealing by measuring the in vitro mechanical strength and degradation of the fabric, and in vivo histological changes after implantation. METHODS: A defect was created in the canine left upper lung lobe, and then filled with a fibrinogen solution and covered with a PGA sheet spray-coated with fibrinogen and thrombin. After 1 and 4 weeks, air leakage from the lesion was examined in vivo under airway pressure. Tissue samples were harvested for histological assessment. RESULTS: The mechanical strength of the PGA fabric remained at 80-90% of the baseline level for 1 week in phosphate-buffered saline, and then rapidly decreased to zero thereafter. Air leakage from the lung defect was prevented by the combination of PGA fabric and FG at 1 and 4 weeks. Histological examinations showed that PGA bundles persisted with a non-specific inflammatory response for 2 weeks and then gradually broke into sparse yarns surrounded by collagen fibres and capillaries by 8 weeks. The lung defect was filled with FG at 1 week and by granulation tissue thereafter. CONCLUSIONS: These results provide evidence for the efficacy of a combination of PGA fabric and FG for the prevention of air leakage in the critical period after lung surgery.

Bioorthogonal micellar nanoreactors for prodrug cancer therapy using an inverse-electron-demand Diels-Alder reaction.

Block copolymer micelles functionalized with tetrazine groups can act as nanoreactors to activate a trans-cyclooctene-functionalized prodrug for releasing anticancer drugs via a bioorthogonal inverse-electron-demand Diels-Alder (IEDDA) reaction. In addition, the IEDDA reaction can be accelerated in the micellar nanoreactor system compared to the free tetrazine system. Moreover, In vivo prodrug activation in a mouse tumor model led to the inhibition of tumor growth without significant systemic toxicity. These results demonstrated their potential for applications as bioorthogonal micellar nanoreactors for cancer chemotherapy.

Impact of Zwitterionic Polymers on the Tumor Permeability of Molecular Bottlebrush-Based Nanoparticles.

Biocompatible polymers possessing antifouling properties for biomolecules are necessary to be combined with nanoparticles for cancer chemotherapy to improve their retention in blood and subsequent tumor accumulation. However, these properties simultaneously lead to poor affinity to cells, and low tumor tissue permeability subsequently, which is one of the major barriers in achieving efficient anticancer efficacy. To address this, we try to elucidate the tumor permeability of nanoparticles using molecular bottlebrushes (MBs) as model polymeric nanoparticles composed of various biocompatible polymers. An MB comprising nonionic poly[(ethylene glycol) methyl ether methacrylate] (PEGMA) shows no tumor permeability at all, whereas zwitterionic MBs composed of poly(phosphobetaine methacrylate), poly(sulfobetaine methacrylate), or poly(carboxybetaine methacrylate) penetrate deeply into tumor tissues. The carboxybetaine-based MBs showed an efficient cellular uptake into cancer cells while the other MBs did not, which enable them to penetrate into tumor tissues via the transcytosis pathway. Additionally, their permeability is based on intercellular or intracellular pathways, which might be related to the zwitterionic betaine properties that recognize protein transporters on cancer cells. Surprisingly, incorporating only 10 mol % of the zwitterionic betaine polymers into PEGMA-based MBs significantly enhances their tissue permeability. This platform technology enables us to redesign the PEG-based nanoparticles developed for cancer chemotherapy in clinical applications.

Dramatically Increased Binding Constant of Water-Soluble Cyclodextrin Hyperbranched Polymers: Explored with Diffusion Ordered NMR Spectroscopy (DOSY).

We report that the polymerization of cyclodextrin (CD) with epichlorohydrin (ECH) dramatically increases the binding constant of CD to vanillin, from 55 to 8.4 × 103 M-1, by approximately 100 times, as determined by diffusion ordered spectroscopy (DOSY)-1H NMR. The binding constant increased with an increase of the ECH content of the polymer, although ECH polymers without CDs showed no affinity at all, suggesting that the hydrophobicity of the ECH network outside of CDs helps to enhance the binding. This increased binding constant allows CD-ECH polymers to increase the drug loading ratio, which may be one of the most critical issues for drug delivery systems.

Ultra-thin surgical swab: its development and clinical application.

INTRODUCTION: Ultra-thin (diameter: 3 mm) surgical swabs have not been in practical use as it is difficult to manufacture these using the pre-existing methods; therefore, a new technology has been adopted. This study aimed to evaluate the safety and efficiency of ultra-thin surgical swabs in bench-top and preclinical settings. MATERIAL AND METHODS: We performed liquid particle counter (LPC) test, cotton strength test, shaft bending comparison and surgical vision test for checking the durability of swabs as bench-top investigation, and laparoscopic surgery in a porcine model as preclinical investigation. All tests were compared with conventional 5-mm swabs. RESULTS: The ultra-thin swabs had fewer eluted particles in the LPC test, endured a 5 kg pulling force in the cotton strength test, their shaft did not break at 100 mm bending in the shaft bend comparison test, and interfered less in the surgical vision test. They were used for manipulating organs with no damage in preclinical investigation. CONCLUSIONS: Three millimeters ultra-thin surgical swabs manufactured with the new manufacturing technology are effective and safe.

Inflammogenic effect of polyacrylic acid in rat lung following intratracheal instillation.

BACKGROUND: Some organic chemicals are known to cause allergic disorders such as bronchial asthma and hypersensitivity pneumonitis, and it has been considered that they do not cause irreversible pulmonary fibrosis. It has recently been reported, however, that cross-linked acrylic acid-based polymer, an organic chemical, might cause serious interstitial lung diseases, including pulmonary fibrosis. We investigated whether or not intratracheal instillation exposure to cross-linked polyacrylic acid (CL-PAA) can cause lung disorder in rats. METHODS: Male F344 rats were intratracheally instilled with dispersed CL-PAA at low (0.2 mg/rat) and high (1.0 mg/rat) doses, and were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months after exposure to examine inflammatory and fibrotic responses and related gene expressions in the lungs. Rat lungs exposed to crystalline silica, asbestos (chrysotile), and NiO and CeO2 nanoparticles were used as comparators. RESULTS: Persistent increases in total cell count, neutrophil count and neutrophil percentage, and in the concentration of the cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2 and C-X-C motif chemokine 5 (CXCL5), which correlated with lung tissue gene expression, were observed in bronchoalveolar lavage fluid (BALF) from 3 days until at least 1 month following CL-PAA intratracheal instillation. Persistent increases in heme oxygenase-1 (HO-1) in the lung tissue were also observed from 3 days to 6 months after exposure. Histopathological findings of the lungs demonstrated that extensive inflammation at 3 days was greater than that in exposure to silica, NiO nanoparticles and CeO2 nanoparticles, and equal to or greater than that in asbestos (chrysotile) exposure, and the inflammation continued until 1 month. Fibrotic changes also progressed after 1 month postexposure. CONCLUSION: Our results suggested that CL-PAA potentially causes strong neutrophil inflammation in the rat and human lung.