Attenuation of chronic antiviral T-cell responses through constitutive COX2-dependent prostanoid synthesis by lymph node fibroblasts.

Lymphoid T-zone fibroblastic reticular cells (FRCs) actively promote T-cell trafficking, homeostasis, and expansion but can also attenuate excessive T-cell responses via inducible nitric oxide (NO) and constitutive prostanoid release. It remains unclear how these FRC-derived mediators dampen T-cell responses and whether this occurs in vivo. Here, we confirm that murine lymph node (LN) FRCs produce prostaglandin E2 (PGE2) in a cyclooxygenase-2 (COX2)-dependent and inflammation-independent fashion. We show that this COX2/PGE2 pathway is active during both strong and weak T-cell responses, in contrast to NO, which only comes into play during strong T-cell responses. During chronic infections in vivo, PGE2-receptor signaling in virus-specific cluster of differentiation (CD)8 cytotoxic T cells was shown by others to suppress T-cell survival and function. Using COX2flox/flox mice crossed to mice expressing Cre recombinase expression under control of the CC chemokine ligand (CCL19) promoter (CCL19cre), we now identify CCL19+ FRC as the critical source of this COX2-dependent suppressive factor, suggesting PGE2-expressing FRCs within lymphoid tissues are an interesting therapeutic target to improve T-cell-mediated pathogen control during chronic infection.

Spatiotemporal distribution characteristics and potential sources of VOCs at an industrial harbor city in southern Taiwan: Three-year VOCs monitoring data analysis.

Kaohsiung City is the largest harbor city in Taiwan. The Linhai Special Industrial Complex (LSIC), which is the largest heavy industrial zone in Taiwan, and other industrial zones and storage station of petrochemicals are adjacent to the Kaohsiung Port. Volatile organic compounds (VOCs), which are discharged from industrial processes in this large industrial area, are likely to cause the poor ambient air quality and atmospheric visibility in Kaohsiung City. This study uses the continuous monitoring data of 54 VOCs during 2018-2020 at eight air quality monitoring stations in the industrialized city to evaluate the spatiotemporal distributions and seasonal variations of VOC concentrations. Principal component analysis and ratios of benzene, toluene, ethylbenzene and xylenes (BTEX) are used to track the potential sources of VOCs for different stations. The highest average concentration of total volatile organic compounds (TVOC) was observed in winter (32.54 ppb), while the lowest TVOC concentration was observed in summer (25.84 ppb), which is related to the prevailing wind directions of monsoons. Kaohsiung is located in the weak monsoon wake area, and air pollutants are easily accumulated in the winter. The southwest wind prevailing in summer results in good diffusion and frequent rainfalls. However, the Qijin station close to the seashore has the highest average TVOC concentration among the eight stations. The seasonal prevailing winds caused the average TVOC concentrations in summer (41.3 ppb) to be higher than that in winter (31.62 ppb) at the Qijin station. It was attributed to the fact that the Qijin Peninsula is vulnerable to VOC emissions from ship sailing in the Taiwan Strait, the processing and export zone, and the shipbuilding yards nearby the Kaohsiung Harbor. Comparing the BTEX ratios of Kaohsiung City with the data of Hong Kong, we found that VOCs were mainly from industrial emissions in Kaohsiung City, which were significantly different from Hong Kong that VOCs were mainly emitted from traffic emissions. Overall, VOCs in Kaohsiung City have been decreased from 2018 to 2020; however, according to the analytical results of ozone formation potential, toluene and m,p-xylenes are the most potential photochemical precursors for ozone formation. The government should enforce and regulate aromatic hydrocarbons from industrial emission sources to reduce the potential formation of ozone.

Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis.

Antibody-secreting plasma cells (PCs) arise rapidly during adaptive immunity to control infections. The early PCs are retained within the reactive lymphoid organ where their localization and homeostasis rely on extrinsic factors, presumably produced by local niche cells. While myeloid cells have been proposed to form those niches, the contribution by colocalizing stromal cells has remained unclear. Here, we characterized a subset of fibroblastic reticular cells (FRCs) that forms a dense meshwork throughout medullary cords of lymph nodes (LNs) where PCs reside. This medullary FRC type is shown to be anatomically, phenotypically, and functionally distinct from T zone FRCs, both in mice and humans. By using static and dynamic imaging approaches, we provide evidence that medullary FRCs are the main cell type in contact with PCs guiding them in their migration. Medullary FRCs also represent a major local source of the PC survival factors IL-6, BAFF, and CXCL12, besides also producing APRIL. In vitro, medullary FRCs alone or in combination with macrophages promote PC survival while other LN cell types do not have this property. Thus, we propose that this FRC subset, together with medullary macrophages, forms PC survival niches within the LN medulla, and thereby helps in promoting the rapid development of humoral immunity, which is critical in limiting early pathogen spread.

Assessment of Polyethylene Glycol-Coated Gold Nanoparticle Toxicity and Inflammation In Vivo Using NF-κB Reporter Mice.

Polyethylene glycol (PEG) coating of gold nanoparticles (AuNPs) improves AuNP distribution via blood circulation. The use of PEG-coated AuNPs was shown to result in acute injuries to the liver, kidney, and spleen, but long-term toxicity has not been well studied. In this study, we investigated reporter induction for up to 90 days in NF-κB transgenic reporter mice following intravenous injection of PEG-coated AuNPs. The results of different doses (1 and 4 µg AuNPs per gram of body weight), particle sizes (13 nm and 30 nm), and PEG surfaces (methoxyl- or carboxymethyl-PEG 5 kDa) were compared. The data showed up to 7-fold NF-κB reporter induction in mouse liver from 3 h to 7 d post PEG-AuNP injection compared to saline-injected control mice, and gradual reduction to a level similar to control by 90 days. Agglomerates of PEG-AuNPs were detected in liver Kupffer cells, but neither gross pathological abnormality in liver sections nor increased activity of liver enzymes were found at 90 days. Injection of PEG-AuNPs led to an increase in collagen in liver sections and elevated total serum cholesterol, although still within the normal range, suggesting that inflammation resulted in mild fibrosis and affected hepatic function. Administrating PEG-AuNPs inevitably results in nanoparticles entrapped in the liver; thus, further investigation is required to fully assess the long-term impacts by PEG-AuNPs on liver health.

Chronic exposure to high fat diet triggers myelin disruption and interleukin-33 upregulation in hypothalamus.

BACKGROUND: Hypothalamic inflammation including astrogliosis and microglia activation occurs after intake of high fat diet (HFD) in rodent models or in obese individuals. However, the effect of chronic HFD feeding on oligodendrocytes (OLGs), a myelin-producing glial population in the central nervous system (CNS), remains unclear. In this study, we used 8-week old male C57BL/6 mice fed by HFD for 3-6 months to induce chronic obesity. RESULTS: The transmission electron microscopy imaging analysis showed that the integrity of hypothalamic myelin was disrupted after HFD feeding for 4 and 6 months. Moreover, the accumulation of Iba1+-microglia with an amoeboid hypertrophic form was continually observed in arcuate nucleus of HFD-fed mice during the entire feeding time period. Interleukin-33 (IL-33), a tissue alarmin upon injury to the CNS, was detected with an increased level in hypothalamus after HFD feeding for 3 and 4 months. Furthermore, the in vitro study indicated that exposure of mature OLGs to IL-33 impaired OLG cell structure along with a decline in the expression of myelin basic protein. CONCLUSIONS: Altogether, our findings demonstrate that chronic HFD feeding triggers hypothalamic myelin disruption in accompany with IL-33 upregulation and prolonged microglial activation in hypothalamus. Given that the addition of exogenous IL-33 was harmful for the maturation of OLGs, an increase in IL-33 by chronic HFD feeding might contribute to the induction of hypothalamic myelin disruption.

A trade-off dual-factor model to investigate discontinuous intention of health app users: From the perspective of information disclosure.

Numerous mobile apps have been developed for making our lives more convenient and improving our quality of life. Health apps are among them. These types of apps are designed to help users for recording their health-related behaviors and to give advice about improving users' physical conditions. However, users frequently do not continue to use these health apps. As a result, the companies of health apps have paid the development cost but cannot get back the benefit from the apps they launch. To find out the reason, this study conducts an empirical investigation and develops a trade-off dual-factor model to dissect the reason why users discontinue use of health apps. The research model is based on the perspectives of information disclosure and expectation-confirmation theory. Users may worry about the disclosure of individual health privacy; however, on the other hand, they enjoy the functions of health apps, proffering various kinds of health-related assistance. The decision of whether or not to continue using this kind of app turns into a trade-off issue. To delve into the determinants, we conduct an online survey and collect 242 qualified responses as our research samples. Structural equation modeling is employed to analyze the samples in this study. The result reveals that our research model explains 31% of the variance. The findings and implications can serve as references for researchers and practitioners.

Trapping of naive lymphocytes triggers rapid growth and remodeling of the fibroblast network in reactive murine lymph nodes.

Adaptive immunity is initiated in T-cell zones of secondary lymphoid organs. These zones are organized in a rigid 3D network of fibroblastic reticular cells (FRCs) that are a rich cytokine source. In response to lymph-borne antigens, draining lymph nodes (LNs) expand several folds in size, but the fate and role of the FRC network during immune response is not fully understood. Here we show that T-cell responses are accompanied by the rapid activation and growth of FRCs, leading to an expanded but similarly organized network of T-zone FRCs that maintains its vital function for lymphocyte trafficking and survival. In addition, new FRC-rich environments were observed in the expanded medullary cords. FRCs are activated within hours after the onset of inflammation in the periphery. Surprisingly, FRC expansion depends mainly on trapping of naïve lymphocytes that is induced by both migratory and resident dendritic cells. Inflammatory signals are not required as homeostatic T-cell proliferation was sufficient to trigger FRC expansion. Activated lymphocytes are also dispensable for this process, but can enhance the later growth phase. Thus, this study documents the surprising plasticity as well as the complex regulation of FRC networks allowing the rapid LN hyperplasia that is critical for mounting efficient adaptive immunity.

Expression and function of interleukin-7 in secondary and tertiary lymphoid organs.

Interleukin-7 (IL-7) is known since many years as stromal-cell derived cytokine that plays a key role for the adaptive immune system. It promotes lymphocyte development in the bone marrow and thymus as well as naive and memory T cell homeostasis in the periphery. More recently, IL-7 reporter mice and other approaches have led to the further characterization of the various stromal cell sources of IL-7 in secondary lymphoid organs (SLO) and other tissues. We will review these advances along with a discussion of the regulation of IL-7 and its receptor, and compare the biological effects IL-7 has on adaptive as well as innate immune cells in SLO. Finally, we will review the role of IL-7 in development of SLO and tertiary lymphoid tissues that frequently are associated with sites of chronic inflammation.

Ovarian and endometrial endometrioid adenocarcinomas have distinct profiles of microsatellite instability, PTEN expression, and ARID1A expression.

AIMS: To understand the role of and differences in molecular alterations between endometrial and ovarian endometrioid adenocarcinomas. METHODS AND RESULTS: We investigated the microsatellite status of 26 ovarian endometrioid adenocarcinomas (OVEMs), 42 endometrial endometrioid adenocarcinomas (EMCAs), and 19 concurrent (endometrial and ovarian) endometrioid adenocarcinomas. We evaluated the expression of the mismatch repair proteins, PTEN and ARID1A, and mutations of PTEN, KRAS, CTNNB1, and PIK3CA. High levels of microsatellite instability (MSI-H) were present in one of 26 OVEMs, 12 of 42 EMCAs, and four of 19 concurrent endometrioid adenocarcinomas. Only four of 19 concurrent endometrioid adenocarcinomas showed identical molecular alterations in their endometrial and ovarian components. Loss of ARID1A or loss of PTEN expression, and MSI-H, were more common in EMCAs than OVEMs (P = 0.044, P = 0.004, and P = 0.012, respectively). MSI-H in endometrial endometrioid adenocarcinomas was also related to loss of ARID1A expression (P < 0.001). In the cohort of MSI-H endometrioid adenocarcinomas involving the endometrium (n = 16), MSH6-deficient cases showed higher frequencies of CTNNB1 and PIK3CA mutations (P = 0.008 and P = 0.036, respectively), but lower frequencies of KRAS mutation (P = 0.011), than PMS2-deficient cases. CONCLUSIONS: The different frequencies of molecular genetic alterations between endometrial endometrioid adenocarcinomas and ovarian endometrioid adenocarcinomas imply that distinct processes may be involved in their tumorigenesis or tumour progression.

In vitro anti-propionibacterium activity by curcumin containing vesicle system.

Propionibacterium acnes acts a critical role in the development of inflammatory acne when it overgrows in pilosebaceous units. The spread of multiple drug resistance bacteria indicates a growing need for new antimicrobial agents. The objective of this study is to develop lipid vehicles to deliver curcumin and inhibit P. acnes in the skin. The inhibitory activities of the curcumin containing vehicles against P. acnes were studied by the bioluminescence assay. Curcumin accumulation patterns in neonate pig skin were studied using Franz diffusion cells and confocal laser scanning microscopy. The physicochemical properties of the curcumin containing vehicles including interfacial tension, size distribution and viscosity were analyzed. Significant curcumin accumulation (362±8 µg/g skin) was observed with the lipid vehicles developed herein. Curcumin (0.43 µg/mL) in the vehicles significantly inhibited the growth of P. acnes. Confocal laser scanning microscopy confirmed the formation of curcumin reservoir in the skin by the curcumin-loaded vehicles. Curcumin-loaded vehicles could efficiently accumulate in the skin and inhibit P. acnes in vitro. Our results highlight the potential of using vehicles containing lauric acid and curcumin as an alternative treatment for acne vulgaris.

Antimicrobial activity of curcumin-loaded myristic acid microemulsions against Staphylococcus epidermidis.

The bactericidal properties of myristic acid and curcumin were revealed in a number of studies. However, whether curcumin-loaded myristic acid microemulsions can be used to inhibit Staphylococcus epidermidis, which causes nosocomial infections, has not been reported. Our aim was to develop curcumin-loaded myristic acid microemulsions to inhibit S. epidermidis on the skin. The interfacial tension, size distribution, and viscosity data of the microemulsions were characterized to elucidate the physicochemical properties of the curcumin microemulsions. Curcumin distribution in neonate pig skin was visualized using confocal laser scanning microscopy. Dermal curcumin accumulation (326 µg/g skin) and transdermal curcumin penetration (87 µg/cm(2)/d) were obtained with the microemulsions developed herein. Curcumin at the concentration of 0.86 µg/mL in the myristic acid microemulsion could inhibit 50% of the bacterial growth, which was 12 times more effective than curcumin dissolved in dimethyl sulfoxide (DMSO). The cocktail combination of myristic acid and curcumin in the microemulsion carrier synergistically inhibited the growth of S. epidermidis. The results we obtained highlight the potential of using curcumin-loaded microemulsions as an alternative treatment for S. epidermidis-associated diseases and acne vulgaris.

Ultrafine PEG-coated poly(lactic-co-glycolic acid) nanoparticles formulated by hydrophobic surfactant-assisted one-pot synthesis for biomedical applications.

A novel method was developed for the one-pot synthesis of ultrafine poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs), using an emulsion solvent evaporation formulation method. Using either cetyltrimethylammonium bromide (CTAB) or poly(ethylene glycol)-distearyl phosphoethanolamine (PEGPE) as an oily emulsifier during the emulsion process, produced PLGA particle sizes of less than 50 nm, constituting a breakthrough in emulsion formulation methods. The yield of ultrafine PLGA NPs increased with PEGPE/PLGA ratio, reaching a plateau at around 85%, when the PEGPE/PLGA ratio reached 3:1. The PEGPE-PLGA NPs exhibited high drug loading content, reduced burst release, good serum stability, and enhanced cell uptake rate compared with traditional PLGA NPs. Sub-50 nm diameter PEG-coated ultrafine PLGA NPs show great potential for in vivo drug delivery systems.

A rapid screening method to select microdialysis carriers for hydrophobic compounds.

Microdialysis is a minimally invasive sampling technique which is widely applied in many fields including clinical studies. This technique usually has limitation on sampling hydrophobic compounds as aqueous solutions are commonly used as the perfusates. The relative recovery of hydrophobic compounds is often low and irreproducible because of the non-specific binding to microdialysis membranes or catheter tubing. Carriers such as cyclodextrins have been used to improve the recovery and consistency, however the identification of an optimal carrier can only be achieved after time-consuming and costly microdialysis experiments. We therefore developed a rapid, convenient, and low-cost method to identify the optimal carriers for sampling hydrophobic compounds with the use of centrifugal ultrafiltration. Doxorubicin was used as the model compound and its relative recoveries obtained from centrifugal ultrafiltration and from microdialysis were compared. The results show that the relative recoveries are highly correlated (correlation coefficient ≥ 0.9) between centrifugal ultrafiltration and microdialysis when different types or different concentrations of cyclodextrins were used as the carriers. In addition to doxorubicin, this method was further confirmed on three other drugs with different hydrophobicity. This method may facilitate and broaden the use of microdialysis perfusion on sampling or delivering hydrophobic substances in various applications.

The Nuclear Function of IL-33 in Desensitization to DNA Damaging Agent and Change of Glioma Nuclear Structure.

Glioma, the most common subtype of primary brain tumor, is an aggressive and highly invasive neurologically tumor among human cancers. Interleukin-33 (IL-33) is considered as a dual functional cytokine, an alarmin upon tissue damage and a nuclear chromatin-associated protein. Despite that, IL-33 is known to foster the formation of the inflammatory tumor microenvironment and facilitate glioma progression, evidence showing nuclear IL-33 function is still poor. In this study using lentivirus-mediated IL-33 gene knockdown (IL33KD) and IL-33 overexpression (IL33oe) in rat C6 glioma cells and human glioma cell lines (U251MG and U87MG), we found that IL33oe-glioma cells had resistance to the insults of the alkylating agent, temozolomide (TMZ), possibly because of the increased expression of DNA repair genes (i.e., BRCA1, BRCA2, Rad51, FANCB, and FANCD) in IL33oe-glioma cells. Alternatively, examination of glioma nuclear shape from transmission electron microscopy (TEM) imaging analysis and immunofluorescence for histone protein H2A staining showed that IL33KD attenuated the abnormal cancerous nuclear characteristic, such as indentation, long clefts, and multiple nucleoids. Yet, IL33oe promoted the changes in glioma nuclear shapes, such as the formation of multiple lobes. We further found that histone proteins, H2A and H3, were reduced in IL33KD glioma cells. The non-histone DNA-binding nucleoproteins, the high mobility group A1 (HMGA1) and HMGA2, were also downregulated by IL33KD. In contrast, IL33oe increased H2A and H3 proteins and HMGA1 and HMGA2 in glioma cells. Altogether, the upregulation of nuclear IL-33 expression was along with an increase in the expression of DNA repair genes, contributing to the desensitization of glioma cells to DNA damaging agents. Moreover, nuclear IL-33 proteins in cooperation with chromatin-associated proteins regulate glioma nuclear structure, which might be crucial for glioma progression and malignancy.

Chemotherapeutic Regimens and Chemotherapy-Free Intervals Influence the Survival of Patients with Recurrent Advanced Epithelial Ovarian Carcinoma: A Retrospective Population-Based Study.

We aimed to evaluate factors influencing the outcomes of patients with platinum-sensitive recurrent epithelial ovarian carcinoma (EOC). Patients with advanced-stage EOC, who received debulking surgery and adjuvant chemotherapy for recurrence, were obtained from the National Health Insurance Research database of Taiwan between 2000 and 2013. A total of 1038 patients with recurrent advanced-stage EOC were recruited. The platinum + paclitaxel (PT) group had the best five-year overall survival (OS) compared with the other three groups (p < 0.001). The hazard ratios (HRs) of five-year OS for the platinum + liposomal doxorubicin (PD), topotecan (TOP), and pegylated liposomal doxorubicin (PLD) groups were 1.21 (p = 0.07), 1.35 (p = 0.016), and 1.80 (p < 0.001), respectively, compared with the PT group. The PT group also had lower hazard ratios of five-year OS for patients with platinum therapy-free interval (TFIp) between 6 and 12 months compared with the other three groups (p < 0.0001). However, the HRs of five-year OS did not differ between the PT and PD groups in patients with TFIp >12 months. Patients with TFIp >12 months had lower HRs of five-year OS compared with those with TFIp of 6-12 months, regardless of whether they were treated with platinum-based (p = 0.001) or non-platinum-based (p = 0.003) regimens. Chemotherapeutic regimens and TFIp influenced the outcomes of patients with recurrent EOC. For patients with TFIp of 6-12 months, the PT regimen is the first choice based on their best overall survival result. For patients with TFIp >12 months, either platinum-based or non-platinum regimens could be used because of their similar excellent overall survival.

Short hairpin RNAs against eotaxin or interleukin-5 decrease airway eosinophilia and hyper-responsiveness in a murine model of asthma.

BACKGROUND: Eosinophilia plays the major role in the pathogenesis of asthma and correlates with the up-regulation of eotaxin, which, together with interleukin (IL)-5, is important for differentiation, chemo-attraction, degranulation, and survival of eosinophils in local tissue. In a previous study, we found that administration of lentivirus-delivered short hairpin RNA (shRNA) to suppress the expression of IL-5 inhibited airway inflammation. The present study aimed to investigate the role of eotaxin shRNA and the synergistic effect of eotaxin and IL-5 shRNAs on airway inflammation in an ovalbumin (OVA)-induced murine model of asthma. METHODS: Lentivirus-delivered shRNAs were used to suppress the expression of eotaxin and/or IL-5 in local tissue in an OVA-induced murine asthma model. RESULTS: Intra-tracheal administration of lentivirus containing eotaxin shRNA expressing cassette (eoSEC3.3) efficiently moderated the characteristics of asthma, including airway hyper-responsiveness, cellular infiltration of lung tissues, and eotaxin and IL-5 levels in bronchio-alveolar lavage fluid. Administration of lentiviruses expressing IL-5 or eotaxin shRNAs (IL5SEC4 + eoSEC3.3) also moderated the symptoms of asthma in a mouse model. CONCLUSIONS: Local delivery of lentiviruses expressing IL-5 and eotaxin shRNAs provides a potential tool in moderating airway inflammation and also has the potential for developing clinical therapy based on the application of shRNAs of chemokines and cytokines involved in T helper 2 cell inflammation and eosinophilia.

Lentiviral-mediated GATA-3 RNAi decreases allergic airway inflammation and hyperresponsiveness.

GATA-3 is the key transcriptional factor for Th2 commitment in T cells and is strongly associated with asthma and allergic disease. We studied the silencing of the GATA-3 gene expression using RNA interference (RNAi) delivered by a lentiviral vector, to evaluate the therapeutic role of GATA-3 short hairpin RNAs (shRNAs) in a murine model of asthma. Mice were sensitized with OVA and instilled intratracheally (IT) with GATA-3 shRNAs lentiviral vector (Lenti-si-GATA-3) once, 48 hours before challenge. After three challenges with the OVA antigen, the mice were assessed for airway hyperresponsiveness (AHR) and inflammation. With infection of Lenti-si-GATA-3 in EL-4 cells, GATA-3 gene expression was abrogated and downstream Th2 cytokines, such as interleukin-4 (IL-4) and IL-5, were also significantly inhibited. IT delivery of Lenti-si-GATA-3 in OVA-immunized mice resulted in a strong inhibition of local GATA-3 gene expression. Treatment with Lenti-si-GATA-3 successfully alleviated OVA-induced airway eosinophilia and Th2 cytokine release. While evaluating AHR by means of enhanced pause (Penh) and pulmonary resistance (R(L)) using body plethysmography, it was found that the administration of Lenti-si-GATA-3 had significantly decreased AHR in OVA-immunized mice. These results suggest that inhibition of GATA-3 gene expression by shRNAs lentiviral vectors strongly attenuates antigen-induced airway inflammation and hyper-responsiveness in mice.

Detection of genetically modified maize MON810 and NK603 by multiplex and real-time polymerase chain reaction methods.

In this study, the event-specific primers for insecticide-resistant maize, MON810, and herbicide-tolerance maize, NK603, have been designed. Simplex PCR and multiplex PCR detection method have been developed. The detection limit of the multiplex PCR is 0.5% for MON810 and NK603 in 50 ng of the template for one reaction. Quantitative methods based on real-time quantitative PCR were developed for MON810 and NK603. Plasmid pMulM2 as reference molecules for the detection of MON810 and NK603 was constructed. Quantification range was from 0.5 to 100% in 100 ng of the DNA template for one reaction. The precision of real-time Q-PCR detection methods, expressed as coefficient of variation for MON810 and NK603 varied from 1.97 to 8.01% and from 3.45 to 10.94%, respectively. The range agreed with European interlaboratories test results (25%). According to the results, the methods for quantitative detection of genetically modified maize were acceptable.

Small interfering RNA targeting nerve growth factor alleviates allergic airway hyperresponsiveness.

Airway hyperresponsiveness is the hallmark of allergic asthma and caused by multiple factors. Nerve growth factor (NGF), a neurotrophin, is originally known for regulation of neural circuit development and function. Recent studies indicated that NGF contributes to airway hyperresponsiveness and pathogenesis of asthma. The objective of this study is to develop a small interfering RNA against NGF to attenuate airway hyperresponsiveness and further elucidate the underlying mechanism. In a murine model of allergic asthma, the ovalbumin-sensitized mice were intratracheally delivered small interfering RNA against NGF or administered an inhibitor targeting NGF receptor, tropomyosin-related kinase A, as a positive treatment control. In this study, knockdown NGF derived from pulmonary epithelium significantly reduced airway resistance in vivo. The levels of NGF, proinflammatory cytokines and infiltrated eosinophils in airway were decreased in small interfering RNA against NGF group but not in tropomyosin-related kinase A inhibitor and mock siRNA group. Furthermore, induction of neuropeptide (substance P) and airway innervation were mediated by NGF/tropomyosin-related kinase A pathway. These findings suggested that NGF targeting treatment holds the potential therapy for antigen-induced airway hyperresponsiveness via attenuation of airway innervation and inflammation in asthma.