Investigation of Polyurethane Matrix Membranes for Salivary Nitrate ISFETs to Prevent the Drift.

We have investigated human-stress monitoring by making use of salivary nitrate, which can be a candidate for stress markers, with ion-selective field-effect transistors (ISFETs). ISFETs are suitable for on-site single-drop analysis of salivary nitrate within 10 s. However, when ISFETs are used for salivary nitrate, ISFETs have a problem that is called the initial drift. The initial drift makes accurate nitrate monitoring difficult. Thus, the purpose of this study is to prevent the initial drift and to search for a new, simple polymer to possess a better performance of sensor responses than conventional matrix membranes, such as PVC. In this research, we investigated ISFETs using specific matrix membranes, for example KP-13, Pellethane®--, and P7281-PU. The initial drift was evaluated from the fluctuations of the response values generated by the ISFETs when immersed in saliva or aqueous solution. As a result, P7281-PU showed a prevention effect on the initial drift, both in the whole saliva and in various solutions. Furthermore, the cause of drift may be H+ diffusion, and the drift prevention effect of P7281-PU may be affected by urethane bond capturing H+ in the ion-selective membrane. This result suggests that a continuous nitrate monitoring is feasible and may be applied to wearable sensors.

Rehabilitation Approach for Children With Joubert Syndrome and Related Disorders.

Joubert syndrome and related disorders (JSRD) are rare and intractable diseases characterized by delayed psychomotor development, hypotonia and/or ataxia, and abnormal respiratory and eye movements. Cerebellar vermis agenesis and molar tooth signs are distinct on cerebral magnetic resonance imaging (MRI). Children with JSRD present with delayed psychomotor development, including intellectual disability and emotional or behavioral problems. Rehabilitation treatments are provided to promote psychomotor development. However, limited reports and evidence exist on rehabilitation treatments for children with JSRD. Three children with JSRD received rehabilitation treatment. The children received rehabilitation treatment once a week to once every one to two months at our hospital and/or other facilities. All patients received physical, occupational, and speech-language-hearing therapy, depending on their symptoms and conditions. In children with tracheostomies due to abnormal respiration, respiratory physical therapy and speech-language-hearing therapy, including augmentative and alternative communication, were needed. For hypotonia and ataxia, an orthotic intervention was considered in all three cases, and foot or ankle-foot orthoses were used in two cases. Although there is no specific or established rehabilitation method for children with JSRD, appropriate rehabilitation approaches, including physical, occupational, speech-language-hearing therapies and orthotic intervention, should be considered and provided to improve their function and expand their activity and participation. Orthotic intervention for hypotonia seems reasonable for improving gross motor development and function in children with JSRD.

Low-dose oral cyclophosphamide therapy reduces atherosclerosis progression by decreasing inflammatory cells in a murine model of atherosclerosis.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease responsible for most cases of heart disease and stroke in Western countries. The cytotoxic drug cyclophosphamide (CPA) can modulate immune functions, and it has therefore been used to treat patients with autoimmune diseases. Extension of survival of patients with severe atherosclerosis has been reported after CPA treatment, but the underlying mechanism is still poorly understood. METHODS AND RESULTS: We have investigated the effects of CPA in a murine model of atherosclerosis. Continuous oral administration of low-dose CPA (20 mg/kg/day) prevented atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice fed with a high fat diet. After 12 weeks, CPA treatment delayed progression of atherosclerosis in the mice (9.92% vs 3.32%, P < 0.05, n = 7) and reduced the macrophage content of plaques (1.228 vs 0.2975 mm2, P < 0.001). Flow cytometry (FACS) showed that, in peripheral blood and spleen cells, the numbers of B cells and inflammatory T cells (Th1 cells) decreased, and inflammatory monocytes also decreased. However, there were no differences in the bone marrow cells between the two groups. The mRNA levels in the aorta showed significantly decreased inflammatory cytokine (interleukin-6) (P < 0.05), and tended to increase anti-inflammatory cytokine (argininase-1), but no significant differences between the two groups. High dose CPA has cardiotoxicity, but the dose used in this study did not show significant cardiotoxicity. CONCLUSIONS: The results demonstrate that oral treatment with CPA inhibits initiation and progression of atherosclerosis in the apoE-/- mouse model through immunomodulatory effects on lymphoid and inflammatory cells.

Promotion of oxidative stress is associated with mitochondrial dysfunction and muscle atrophy in aging mice.

AIM: We examined the changes in oxidative stress, mitochondrial function and muscle atrophy during aging in mice. METHODS: We used 6-, 12- and 24-month (6 M, 12 M and 24 M)-old C57BL/6J mice. Skeletal muscles were removed from the lower limb and used for quantitative real-time polymerase chain reaction, immunoblotting and histological analyses. RESULTS: The muscle weight and myocyte cross-sectional area were significantly decreased in the 12 M and 24 M mice compared with those of the 6 M mice. The levels of the oxidative stress markers, nicotinamide adenine dinucleotide phosphate oxidase 2, nicotinamide adenine dinucleotide phosphate oxidase 4, mitochondrial 4-hydroxy-2-nonenal and 3-nitrotyrosine, were significantly higher in the 24 M mice compared with those of the 6 M mice. Furthermore, the 24 M mice had lower levels of mitochondrial markers, peroxisome proliferator-activated receptor gamma coactivator 1 (PGC)-α, peroxisome proliferator-activated receptor gamma coactivator-1ß, sirtuin-1, adenosine triphosphate synthase mitochondria F1 complex α subunit 1 and mitochondrial cytochrome c oxidase 1. The ubiquitin-proteasome pathway genes muscle ring finger-1 and atrogin-1 were significantly upregulated in the 12 M and 24 M mice, and protein synthesis markers (phosphorylated-Akt and -p70 ribosomal S6 kinase) were significantly lower in the 24 M mice compared with the 6 M mice (all P < 0.05). CONCLUSIONS: These findings have important implications for the mechanisms that underlie sarcopenia and frailty processes. Geriatr Gerontol Int 2020; 20: 78-84.

Lack of IκBNS promotes cholate-containing high-fat diet-induced inflammation and atherogenesis in low-density lipoprotein (LDL) receptor-deficient mice.

BACKGROUND: IκBNS, a nuclear IκB protein, regulates a subset of Toll-like receptor (TLR) dependent genes. A cholate-containing high-fat diet (HFD(CA(+))) induces TLR4 mediated early inflammatory response. The present study aims to clarify that the lack of IκBNS promotes atherogenesis in low-density lipoprotein receptor-deficient (LDLr-/-) mice fed HFD(CA(+)) compared with those fed a cholate-free HFD (HFD(CA(-))). METHODS AND RESULTS: Mice that lacked IκBNS (IκBNS-/-) were crossed with LDLr-/- mice and formation of atherosclerotic lesions was analyzed after 6-week consumption of HFD(CA(+)) or HFD(CA(-)). IκBNS-/-/LDLr-/- mice fed HFD(CA(+)) (IκBNS-/-/LDLr-/-(CA(+))) showed a 3.5-fold increase of atherosclerotic lesion size in the aorta compared with LDLr-/-(CA(+)) mice (p < 0.01), whereas there was no difference between LDLr-/-(CA(-)) and IκBNS-/-/LDLr-/-(CA(-)) mice. Immunohistochemical analysis of the aortic root revealed that HFD(CA(+)) significantly increased Mac-3 (macrophage)-positive area by 1.5-fold (p < 0.01) and TLR4, interleukin-6 (IL-6) expression by 1.7-fold (p < 0.05) and 1.5-fold (p < 0.05), respectively, in IκBNS-/-/LDLr-/-(CA(+)) compared with LDLr-/---(CA(+)) mice. Furthermore, active STAT3 (pSTAT3)-positive cells were significantly increased by 1.7-fold in the lesions of IκBNS-/-/LDLr-/-(CA(+)) compared with LDLr-/-(CA(+)) mice (p < 0.01). These findings suggest that IκBNS deficiency and HFD(CA(+)) promote atherogenesis in LDLr-/- mice via TLR4/IL-6/STAT3 pathway. Finally, we showed that the monocytes from peripheral blood of IκBNS-/-/LDLr-/-(CA(+)) mice were found to contain the highest proportion of Ly6Chi monocytes among the four groups, suggesting that lack of IκBNS enhanced inflammation in response to HFD(CA(+)) feeding. CONCLUSIONS: The present study is the first to demonstrate that the activation of innate immune system using HFD(CA(+)) induced significant inflammation and atherogenesis in IκBNS-/-/LDLr-/- compared with LDLr-/- mice.

Inhibition of interleukin-1 suppresses angiotensin II-induced aortic inflammation and aneurysm formation.

BACKGROUND: Angiotensin II (Ang II) activates components of the inflammatory cascade, which promotes hypertension and development of abdominal aortic aneurysm (AAA). This study aimed to elucidate the effects of an IL-1 receptor antagonist (IL-1Ra) and an anti-IL-1ß antibody (01BSUR) on Ang II-induced AAA. METHODS AND RESULTS: Male wild-type (WT) and IL-1Ra-deficient (IL-1Ra-/-) mice were infused with Ang II (1000 ng/kg/min) using subcutaneous osmotic pumps for 28 days. Fourteen days post-infusion, both systolic blood pressure (SBP) (Ang II-treated IL-1Ra-/-:149 ±â€¯2 vs. Ang II-treated WT:126 ±â€¯3 mm Hg, p < 0.001) and abdominal aortic width (0.94 ±â€¯0.09 vs. 0.49 ±â€¯0.03 mm, p < 0.001) were significantly higher in IL-1Ra-/- mice than in WT mice. Because 28-day infusion with Ang II in IL-1Ra-/- mice significantly increased the occurrence of fatal aortic rupture (89% vs. 6%, p < 0.0001), both types of mice were infused with Ang II for only 14 days, and histological analyses were performed at 28 days. Interestingly, AAA increased more significantly in IL-1Ra-/- mice than in WT mice (p < 0.001), although SBP did not differ at 28 days in IL-1Ra-/- and WT mice (117 ±â€¯4 vs. 115 ±â€¯3 mm Hg, p = 0.71 (after cessation of Ang II infusion)). Histological analyses showed numerous inflammatory cells around the abdominal aorta in IL-1Ra-/- mice, but not in WT mice. Finally, compared with IgG2a treatment, treatment with 01BSUR decreased Ang II-induced AAA in IL-1Ra-/- mice. CONCLUSIONS: The present study demonstrates that inhibition of IL-1ß significantly suppresses AAA formation after Ang II infusion, suggesting that suppression of IL-1ß may provide an additional strategy to protect against AAA in hypertensive patients.

Possible Role of NADPH Oxidase 4 in Angiotensin II-Induced Muscle Wasting in Mice.

Background: Muscle wasting is a debilitating phenotype associated with chronic heart failure (CHF). We have previously demonstrated that angiotensin II (AII) directly induces muscle wasting in mice through the activation of NADPH oxidase (Nox). In this study, we tested the hypothesis that deficiency of NADPH oxidase 4 (Nox4), a major source of oxidative stress, ameliorates AII-induced muscle wasting through the regulation of redox balance. Methods and Results: Nox4 knockout (KO) and wild-type (WT) mice were used. At baseline, there were no differences in physical characteristics between the WT and KO mice. Saline (vehicle, V) or AII was infused via osmotic minipumps for 4 weeks, after which, the WT + AII mice showed significant increases in Nox activity and NOX4 protein compared with the WT + V mice, as well as decreases in body weight, gastrocnemius muscle weight, and myocyte cross-sectional area. These changes were significantly attenuated in the KO + AII mice (27 ± 1 vs. 31 ± 1 g, 385 ± 3 vs. 438 ± 13 mg, and 1,330 ± 30 vs. 2281 ± 150 µm2, respectively, all P < 0.05). The expression levels of phospho-Akt decreased, whereas those of muscle RING Finger-1 (MuRF-1) and MAFbx/atrogin-1 significantly increased in the WT + AII mice compared with the WT + V mice. Furthermore, nuclear factor erythroid-derived 2-like 2 (Nrf2) and the expression levels of Nrf2-regulated genes significantly decreased in the WT + AII mice compared with the WT + V mice. These changes were significantly attenuated in the KO + AII mice (P < 0.05). Conclusion: Nox4 deficiency attenuated AII-induced muscle wasting, partially through the regulation of Nrf2. The Nox4-Nrf2 axis may play an important role in the development of AII-induced muscle wasting.

An Interleukin-6 Receptor Antibody Suppresses Atherosclerosis in Atherogenic Mice.

IκBNS is a nuclear IκB protein which negatively regulates nuclear factor-κB activity. We demonstrated that IκBNS deficiency accelerates atherosclerosis in LDL receptor-deficient (LDLr-/-) mice via increased interleukin (IL)-6 production by macrophages. Previous studies showed that the increase in IL-6 might contribute to the development of atherosclerotic lesions. However, whether an anti-mouse IL-6 receptor antibody (MR16-1) can protect atherosclerotic lesions in atherogenic mice remains to be elucidated. We investigated atherosclerotic lesions in LDLr-/- and IκBNS-/-/LDLr-/- mice after 16 weeks consumption of a high-fat diet. All mice received intraperitoneal injections of MR16-1 or phosphate-buffered saline (PBS) (control) once a week during a high-fat diet consumption. Treatment of MR16-1 yielded no adverse systemic effects, and we detected no significant differences in serum cholesterol levels in either group. The atherosclerotic lesions were significantly increased in IκBNS-/-/LDLr-/- compared with LDLr-/- mice (p < 0.01) under treatment of PBS. However, MR16-1 treatment abolished the significant difference of atherosclerotic lesions between IκBNS-/-/LDLr-/- and LDLr-/- mice. Interestingly, MR16-1 also significantly decreased atherosclerotic lesions in LDLr-/- mice compared with PBS treatment (p < 0.05). Immunostaining revealed percent phospho-STAT3-positive cell were significantly decreased in the atherosclerotic lesions of MR16-1 treated both IκBNS-/-/LDLr-/- and LDLr-/- mice compared with PBS-treated mice, indicating MR16-1 could suppress atherosclerotic lesions via the inhibition of IL-6-STAT3 signaling pathway. This study highlights the potential therapeutic benefit of anti-IL-6 therapy in preventing atherogenesis induced by dyslipidemia and/or inflammation.

Contemporary sex differences among patients with acute coronary syndrome treated by emergency percutaneous coronary intervention.

Acute coronary syndrome (ACS) is an important cause of mortality and morbidity in the general population. Recent advances in percutaneous coronary intervention (PCI) and optimal medical treatment have helped to improve the prognosis of patients with ACS. The previous reports indicated that women with ACS have a higher risk of adverse outcomes. However, sex differences in clinical outcomes with contemporary coronary revascularization and medical therapy for ACS have not been elucidated. We analyzed data from 676 consecutive patients with ACS (female, n = 166; male, n = 510) who were treated by emergency PCI between 2011 and 2014 at Juntendo Shizuoka Hospital. The patients were grouped according to sex. We defined major adverse cardiovascular events as a composite of all-cause death and ACS recurrence at 1 year and compared rates of major adverse cardiac events (MACE) between the groups. Women were older (75.4 ± 11.0 vs. 66.2 ± 12.2 years) and had a higher rate of multi-vessel disease, chronic kidney disease, and Killip IV at presentation. The cumulative rate of MACE at 1 year was significantly higher among women than men (17.5 vs. 10.2 %, p = 0.02, log-rank test). However, the association between women and a higher risk of MACE was attenuated after adjusting for age (HR 1.25, 95 % CI 0.77-2.00, p = 0.36) and other variables (HR 0.93, 95 % CI 0.36-2.44, p = 0.88). Adjustment for age and other risk factors attenuated sex differences in mid-term clinical outcomes among patients with ACS after emergency PCI.

Enzymatically triggered self-assembly of poly(ethylene glycol)-attached oligopeptides into well-organized nanofibers.

A unique and programmable peptide self-assembling system has been fabricated by using poly(ethylene glycol)-attached amphiphilic oligopeptide, which shows rapid self-assembly into well-organized beta-sheet nanofibers in response to an enzymatic reaction.

Immunomodulatory Effects of Ambroxol on Airway Hyperresponsiveness and Inflammation.

Ambroxol is used in COPD and asthma to increase mucociliary clearance and regulate surfactant levels, perhaps through anti-oxidant and anti-inflammatory activities. To determine the role and effect of ambroxol in an experimental model of asthma, BALB/c mice were sensitized to ovalbumin (OVA) followed by 3 days of challenge. Airway hyperresponsiveness (AHR), lung cell composition and histology, and cytokine and protein carbonyl levels in bronchoalveolar lavage (BAL) fluid were determined. Ambroxol was administered either before the first OVA challenge or was begun after the last allergen challenge. Cytokine production levels from lung mononuclear cells (Lung MNCs) or alveolar macrophages (AM) were also determined. Administration of ambroxol prior to challenge suppressed AHR, airway eosinophilia, goblet cell metaplasia, and reduced inflammation in subepithelial regions. When given after challenge, AHR was suppressed but without effects on eosinophil numbers. Levels of IL-5 and IL-13 in BAL fluid were decreased when the drug was given prior to challenge; when given after challenge, increased levels of IL-10 and IL-12 were detected. Decreased levels of protein carbonyls were detected in BAL fluid following ambroxol treatment after challenge. In vitro, ambroxol increased levels of IL-10, IFN-γ, and IL-12 from Lung MNCs and AM, whereas IL-4, IL-5, and IL-13 production was not altered. Taken together, ambroxol was effective in preventing AHR and airway inflammation through upregulation of Th1 cytokines and protection from oxidative stress in the airways.

Brain metastases in malignant pleural mesothelioma.

The brain is a rare site of metastasis in malignant pleural mesothelioma (MPM), and its clinical features and prognosis remain unclear. The aim of this study was to investigate the incidence, prognosis, and risk factors for brain metastases (BM) in MPM patients. Between July 1993 and October 2014, 150 patients with histologically proven MPM were included in this retrospective study. The cumulative incidence of BM was estimated with the Kaplan-Meier method, and differences between groups were analyzed by the log-rank test. Multivariate logistic regression analysis was applied to assess risk factors for BM. The median follow-up time was 11 months (range 0-154.0 months). A total of eight patients (5.3 %) developed BM during the course of their illness. Multivariate analysis identified age <65 years (odds ratio [OR] = 5.83, p = 0.038) and International Mesothelioma Interest Group stage IV (OR = 1.69, p = 0.040) as independent factors related to increased risk of developing BM. The 1-and 2-year cumulative rates of BM were 4.0 % (95 % confidence intervals [CI] 1.4-8.5 %) and 5.3 % (95 % CI 2.3-10.2 %), respectively. Our study showed that the overall survival (OS) of patients with BM was worse than that of patients without BM (median OS 6.5 vs. 11.0 months, p = 0.037). The prognosis for BM in MPM patients is poor. Clinicians should perform careful screening for BM, especially in patients with risk factors.

Butyrate blocks interferon-gamma-inducible protein-10 release in human intestinal subepithelial myofibroblasts.

BACKGROUND: Interferon (IFN)-gamma-inducible protein (IP)-10 is a chemoattractant for CXCR 3-expressing T lymphocytes and monocytes. IP-10 has been reported to mediate chronic inflammation such as that in inflammatory bowel disease (IBD). However, the local secretion of IP-10 in the intestine remains unclear. In this study, we investigated IP-10 secretion in human colonic subepithelial myofibroblasts (SEMFs). METHODS: IP-10 secretion was determined by enzyme-linked immunosorbent assay (ELISA), and IP-10 mRNA expression was evaluated by Northern blotting. RESULTS: Interleukin (IL)-10 mRNA was not detected in unstimulated SEMFs. Interferon (IFN)-gamma strongly induced IP-10 mRNA expression. Tumor necrosis factor (TNF)-alpha also stimulated IP-10 mRNA expression, but this was much weaker than that induced by IFN-gamma. The effects of IFN-gamma and TNF-alpha were detected in a dose- and time-dependent manner. These responses were also observed at the protein levels. The IFN-gamma-induced IP-10 secretion was not affected by acetate or propionate, but was significantly reduced by butyrate. Trichostatin A, a specific inhibitor of histone deacetylase, also blocked the IFN-gamma- and TNF-alpha-induced IP-10 mRNA expression, but the effects of trichostatin A were weaker than those of butyrate. The inhibitory effect of butyrate on IFN-gamma-induced IP-10 release was not associated with STAT (signaling transducer and activator of transcription)-1alpha activation. CONCLUSIONS: We demonstrated that human colonic SEMFs are the local site for the secretion IP-10. The regulation of IP-10 release by IFN-gamma and butyrate may play an important role in controlling chronic mucosal inflammation in pathological entities such as IBD.

Prognostic significance of the lymphocyte-to-monocyte ratio in patients with malignant pleural mesothelioma.

OBJECTIVES: Chronic inflammation plays a key role in the pathogenesis of malignant pleural mesothelioma (MPM) as a result of asbestos exposure. Several inflammation-based prognostic scores including the lymphocyte-to-monocyte ratio (LMR), Glasgow Prognostic Score (GPS), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) reportedly predict survival in many malignancies, while the role of LMR in MPM remains unclear. The aim of this study was to evaluate the clinical value of LMR and to compare the prognostic value of these inflammation-based scores in predicting overall survival (OS) in MPM. MATERIALS AND METHODS: One hundred and fifty patients with histologically proven MPM were included in this retrospective study. Kaplan-Meier curves and multivariate Cox-regression analyses were calculated for OS. The area under the receiver operating characteristics curve (AUC) was calculated to compare the discriminatory ability of each scoring system. RESULTS: An elevated LMR was significantly associated with prolonged OS. Patients with LMR <2.74 had significantly poor survival compared with LMR ≥2.74 (median, 5.0 versus 14.0 months; p=0.000). The LMR consistently had a higher AUC value at 6 months (0.722), 12 months (0.712), and 24 months (0.670), compared with other scores. Multivariate analysis showed that the LMR was independently associated with OS. CONCLUSIONS: The LMR is an independent prognostic marker for OS in patients with MPM and is superior to other inflammation-based prognostic scores with respect to prognostic ability.

Suppression of interleukin-1beta- and tumor necrosis factor-alpha-induced inflammatory responses by leukocytapheresis therapy in patients with ulcerative colitis.

BACKGROUND: To elucidate the molecular mechanisms involved in the therapeutic effects of leukocytapheresis (LCAP), we investigated the alterations in the cytokine responses of peripheral blood mononuclear cells (PBMCs) before and after LCAP therapy in ulcerative colitis (UC) patients. METHODS: Twelve patients with UC who did not respond to steroid therapy were enrolled. Nine patients responded to LCAP therapy, but 3 patients did not show clinical improvement. PBMCs were isolated from peripheral venous blood obtained within 5 min before and after the first and second session of LCAP treatment. Cells were stimulated with interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha for 24 h, and the levels of secreted IL-8 and IL-6 were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: LCAP induced a significant decrease in peripheral lymphocyte, monocyte, and platelet counts. IL-1beta- and TNF-alpha-induced IL-8 and IL-6 secretion was significantly decreased after the first and second LCAP treatments. These responses were associated with inhibitory effects on nuclear factor (NF)-kappaB DNA-binding activity. CONCLUSIONS: LCAP downregulates the IL-1beta- and TNF-alpha-induced inflammatory responses in PBMCs isolated from UC patients. The induction of hyporesponsiveness to proinflammatory cytokines may be an important factor mediating the clinical effects of LCAP in UC patients.

Critical role of the Fc receptor gamma-chain on APCs in the development of allergen-induced airway hyperresponsiveness and inflammation.

The FcR common gamma-chain (FcRgamma) is an essential component of the receptors FcepsilonRI, FcgammaRI, and FcgammaRIII, which are expressed on many inflammatory cell types. The role of these receptors in the initiation or maintenance of allergic inflammation has not been well defined. FcRgamma-deficient (FcRgamma(-/-)) and control (wild-type (WT)) mice were sensitized and subsequently challenged with OVA. Following sensitization and challenge to OVA, FcRgamma-deficient (FcRgamma(-/-)) mice developed comparable levels of IgE and IgG1 as WT mice. However, numbers of eosinophils, levels of IL-5, IL-13, and eotaxin in bronchoalveolar lavage fluid, and mononuclear cell (MNC) proliferative responses to OVA were significantly reduced, as was airway hyperresponsiveness (AHR) to inhaled methacholine. Reconstitution of FcRgamma(-/-) mice with whole spleen MNC from WT mice before sensitization restored development of AHR and the numbers of eosinophils in bronchoalveolar lavage fluid; reconstitution after sensitization but before OVA challenge only partially restored these responses. These responses were also restored when FcRgamma(-/-) mice received T cell-depleted MNC, T and B cell-depleted MNC, or bone marrow-derived dendritic cells before sensitization from FcR(+/+) or FcgammaRIII-deficient but not FcRgamma(-/-) mice. The expression levels of FcgammaRIV on bone marrow-derived dendritic cells from FcR(+/+) mice were found to be low. These results demonstrate that expression of FcRgamma, most likely FcgammaRI, on APCs is important during the sensitization phase for the development of allergic airway inflammation and AHR.

Prevention of ethanol-induced liver injury in rats by an agonist of peroxisome proliferator-activated receptor-gamma, pioglitazone.

Agonists of peroxisome proliferator-activated receptor (PPAR)-gamma have been shown to reduce tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance. On the other hand, sensitization of Kupffer cells to lipopolysaccharide (LPS) and their production of TNF-alpha are critical for progression of alcoholic liver injury. This study was intended to determine whether pioglitazone, a PPAR-gamma agonist, could prevent alcohol-induced liver injury. Rats were given ethanol (5 g/kg b.wt.) and pioglitazone (500 microg/kg) once every 24 h intragastrically. Ethanol for 8 weeks caused pronounced steatosis, necrosis, and inflammation in the liver. These pathological parameters were diminished greatly by pioglitazone. Kupffer cells were sensitized to LPS after ethanol for 4 weeks as evidenced by aggravation of liver pathology induced by LPS (5 mg/kg) and enhancement of LPS (100 ng/ml)-induced intracellular Ca2+ concentration elevation in Kupffer cells. The parameters were diminished by treatment with pioglitazone. LPS-induced TNF-alpha production by Kupffer cells from the 4-week ethanol group was 3 to 4 times higher than control. This increase was blunted by 70% with pioglitazone. Gut permeability was 10-fold higher in the 4-week ethanol group, and pioglitazone treatment did not change the value. Inclusion of TNF-alpha in culture media of Kupffer cells enhanced CD14 expression, LPS-induced intracellular Ca2+ concentration response, and production of TNF-alpha. These results indicate that pioglitazone prevents alcoholic liver injury through abrogation of Kupffer cell sensitization to LPS.